# CRITERIA DOCUMENT: RECOMMENDATIONS FOR AN OCCUPATIONAL EXPOSURE STANDARD FOR CARBON MONOXIDE
recommends that employee exposure to carbon monoxide (CO) at the workplace be controlled by requiring compliance with the standard set forth in the following eight sections.
Control of employee exposure to CO at his place of employment at the limits stated will (1) prevent acute CO poisoning, (2) protect the employee from deleterious myocardial alterations associated with levels of carboxyhemoglobin (COHb) in excess of 5 percent and (3) provide the employee protection from adverse behavioral manifestations resulting from exposure to low levels of CO.
The recommended standard is measurable by techniques that are valid, reproducible and currently available to industry and governmental agencies and is attainable with existing technology. The recommended standard is designed to protect the safety and health of workers who are performing a normal 8-hour per day, 40-hour per week work assignment. It is not designed for the population-at-large and any extrapolation beyond the general worker population is unwarranted. Because of the well-defined relationship between smoking and the concomitant exposure to CO in inhaled smoke the recommended standard may not provide the same degree of protection to those workers who smoke as it will to nonsmokers. Likewise, under conditions of reduced ambient oxygen concentration, such as would be encountered by workers at very high altitudes (e.g., 5,000 -8,000 feet above sea level), the permissible exposure stated in the recommended standard should be appropriately lowered to compensate for loss in the oxygen-carrying capacity of the blood. In 1-1 addition, workers with physical impairments that interfere with normal oxygen delivery to the tissues (e.g., emphysema, anemia, coronary heart disease) will not be provided the same degree of protection as the healthy worker population. The criteria and the standard recommended in this docu ment will be reviewed and revised as necessary.

# 1-2 (a) Concentration
(1) Occupational exposure to carbon monoxide shall be controlled so that no worker shall be exposed at a concentration greater than 35 ppm determined as a time-weighted average (TWA) exposure for an 8-hour workday, as measured with a portable, direct reading, hopcalite-type carbon monoxide meter calibrated against known concentrations of CO, or with gas detector tube units certified under Title 42 of the Code of Federal Regulations, Part 84.
(2) No level of carbon monoxide to which workers are exposed shall exceed a ceiling concentration of 200 ppm.

# (b) Calibration, Sampling and Analysis
Procedures for calibration of equipment, sampling and analysis of CO samples shall be followed as provided in Appendix I.

# Section 1 -Work Environment 1-3
Because employees with overt cardiovascular disease may not be protected by an occupational exposure to 35 ppm of CO, a medical program should be instituted consisting of preplacement and periodic examinations with special attention to the cardiovascular system and to medical con ditions which could be exacerbated by exposure to CO. Such a medical program could also provide the opportunity for conducting antismoking programs for high-risk employees. Areas where significant exposure to carbon monoxide is likely to occur shall be posted with a sign stating:

# CARBON MONOXIDE (CO) DANGER High concentrations may be fatal
Provide adequate ventilation High concentrations in air may be explosive
Seek immediate medical attention if you experience any of the below symptoms:
1 -Severe Headache 2 -Dizziness 3 -Nausea and vomiting Gas masks are located: (Specific location to be filled in by employer) For purposes of this section the term "significant exposure to carbon monoxide" refers to eight-hour TWA exposures exceeding 25 ppm but excludes such exposure as may be self-administered through smoking.
In the event of an emergency or when a variance has been allowed and the use of respiratory protective equipment authorized by the Secretary of Labor, the employer shall provide and insure that the employee wears, as appropriate, one of the following respiratory protective devices approved by NIOSH or the Bureau of Mines as provided in Part 11 of Title 30, Code of Federal Regulations: (a) Type N Gas Mask (Emergency Situation):
For entry into or escape from an environment containing not over 20,000 ppm, which is not deficient in oxygen, for a total exposure period of not more than 30 minutes. Areas in which large amounts of CO are stored, used or emitted, or areas within the workplace through which large amounts of CO are trans ported, shall be provided with sufficient respiratory protective devices of the types specified in Section 4 and shall be readily accessible to persons who may be located in the area to assure a timely, orderly evacuation of the area by all persons in the event of accidental, massive release of CO.
An automatic visual and audible alarm that is set to be activated when the CO concentration reaches 500 ppm should be employed in such areas. Employees working in such areas shall be informed of the hazards and symptoms of acute CO poisoning (see Section 6) and shall be trained to implement an emergency evacuation plan designed for such an occurrence. Periodic drills, held not less frequently than every six months, shall be conducted to assure that such plans are adequate and effective in case of an emergency situation.
(c) Fire Hazards Adequate fire extinguishing agents shall be readily available in the areas outlined in paragraph (b) of this section since CO will burn when mixed with air and may be explosive when concentrations of between 12.5 percent to 74.2 percent are reached.
Section 5 -Emergency Procedures 1-7 (a) Each employee who receives significant exposure to carbon monoxide  shall be apprised of all hazards, relevant symptoms, appropriate emergency procedures, and proper conditions and precautions for the safe use of CO or safe exposure to CO and shall be instructed as to the location of such information, which shall be kept on file as prescribed in paragraph (b) of this section and shall be readily accessible to all employees at each establishment where CO is involved in industrial processes and operations. (a) Each container in which CO is stored shall be examined for leaks upon its arrival at the establishment or upon filling and shall be reexamined periodically at least every three months.
(b) Prior to transferring CO from a storage container, an inspection shall be conducted to detect any gas leaks in the transport system (e.g., cylinder seal with gas regulator, regulator apparatus, regulator seal with transport conduits, conduit system, etc.). (1) Personal exposure ("breathing zone") samples- shall be collected in accordance with procedures specified in Appendix I in all workplaces where employees are significantly exposed to CO , Samples will be collected and evaluated as both TWA and ceiling concentration values.
(2) Frequency of monitoring should be at least annually. It is recognized that more frequent monitoring may be indicated in certain circum stances depending upon the nature of the process, the rate of production, the effectiveness of control measurements, the time of day and seasonal variation, however, more frequent monitoring requirements cannot be recommended until there are extensive studies of specific operations in industry.
(3) Blood analysis for COHb, as specified in Appendix II, shall be performed on all persons employed in work areas when, in the judgment of the OSHA Industrial Hygienist, biologic standards are needed to evaluate borderline exposure to CO (see Chapter V). and experiments and any other information available to him which will assure insofar as practicable that no employee will suffer diminished health, functional capacity, or life expectancy as a result of his work experience.
The National Institute for Occupational Safety and Health (NIOSH), after a review of data and consultations with others, formalized a system for the development of criteria upon which standards can be established to protect the health of employees from exposure to hazardous chemical and physical agents. It should be emphasized that any criteria documentation for a recommended standard should enable management and labor to develop better engineering controls and more healthful work practices and should not be accepted as a final goal in itself.
1 In evaluating occupational hazards and setting priorities, it was determined that the potential for exposure of employees at the workplace to CO was greater than that for any other chemical or physical agent.
The significance of the CO dose-response relationship in man is attested furthermore by numerous research studies which have been documented in II-l the scientific literature. In a recent conference on the biological effects of CO sponsored by the New York Academy of Sciences, the findings and views of scientists from the United States, Australia, England, France, and 2 Denmark were presented.
Background information for this report was obtained from many sources, including those directly cited and listed in the references. In addition 3 there is a bibliography of nearly 1,000 references and abstracts on CO The criteria contained in this document were developed to assure that the recommended standard based thereon would (1) protect employees against both acute and chronic CO exposure, (2) be measurable by techniques that are valid, reproducible and available to industry and governmental agencies and (3) be attainable with existing technology.

# II-2
In 1969 the Committee on Effects of Atmospheric Contaminants on Human Health and Welfare, appointed by the Environmental Studies Board of the National Academy of Sciences, reported on the evaluation of current knowledge concerning the effects of CO on man.^ While this report deals primarily with the effects on man of exposure to CO from air pollution sources, it is pertinent to note the following statement in the Introduction: "...Today, the two main sources of carbon monoxide appear to be cigarette smoke and the internal combustion engine. And the subject of concern has changed from the acute effects of short-term exposure...to the lasting effects of long-term, low-level exposure, of a duration anywhere from a month to a lifetime, and in the range of CO concentrations that would produce 0.5-10% COHb." Thus, in the case of occupational exposures to CO, a worker's smoking habits must be taken into consideration when evaluating the environment. This factor has not been generally considered until the past few years.
It should be emphasized that the above report raised many questions concerning the effects of low-level exposures to CO, and that Committee recommended many additional research studies in this area.
Although important evidence exists which indicates that subtle aber rations may occur in the central nervous system (CNS) during exposure to levels of CO lower than those of the recommended standard, the significance of these changes and their translation to effects upon employee safety and health is not entirely clear. The diversity of opinions and the conflicting experimental evidence existing in this area does not permit the clear-cut assessment of the scientific merit of such data or its extrapolation to the normal working population at this time. If reliable data become available which clearly demonstrate significant impairment of employee II-3 behavior during exposure to very low levels of CO (producing less than 5 percent COHb), then the criteria for the recommended standard will be reassessed on the basis of the additional evidence.

# II-4 III. BIOLOGIC EFFECTS OF EXPOSURE TO CARBON MONOXIDE
Carbon monoxide (CO) is an odorless, colorless, tasteless gas which is an active reducing agent for chemicals at elevated temperatures, but is principally encountered as a waste product of incomplete combustion of carbonaceous material. A summary of the physical properties is presented in Table I. The best understood biologic effect of CO is its combination with hemoglobin (Hb) to form carboxyhemoglobin (COIIb) , thereby rendering the hemoglobin molecule less able to bind with oxygen. This action of CO results in more persons succumbing each year to acute CO poisoning than to any other single toxic agent, except alcohol.6

# Extent of Exposure
With the single exception of carbon dioxide (CO2X total emissions of CO each year exceed those of all other atmospheric pollutants combined.
In 1968 it was estimated that 102 million tons of CO were released into the atmosphere by the major sources of emission.^ Over one-half of this amount (58 percent) was produced by the gasoline-powered internal combustion engine. Specified industrial processes accounted for approximately 10 percent of the total. A summation of CO emission estimates for 1968 by specific industrial processes is presented in Table II.
From Table II it can be observed that large amounts of CO are emitted from petroleum refineries, iron foundries, kraft pulp mills, sintering mills, lampblack plants and formaldehyde manufacturers. Major sources of CO production within the first four industries have been identified as the cupola in the iron foundry, the catalytic cracking units in the petroleum refineries, the lime kilns and the kraft recovery furnaces in the kraft paper mills, and the sintering of blast furnace feed in sintering plants.

# III-l
Aside from the above major industrial processes which produce large quantities of CO, there are numerous operations (arc welding, automobile repair, traffic control, tunnel construction, etc.) where the occupational exposure for a worker to CO can be considerable. In fact any industrial process or operation where incomplete combustion of carbonaceous material occurs may easily be of consequence as concerns occupational exposure to CO.

# Historical Reports and Theoretical Considerations
Man's intimate association with carbon monoxide as a true environmental hazard began with his discovery of fire. Since that time his technological history has been one of advancement by means of incomplete combustion. The seriousness of exposure to high concentration of CO has been realized since the earliest medical writings. The Greeks and Romans used exposure to CO 7 as a means of execution of criminals and committing suicide.
Priestly discovered the chemical composition of CO in the late 18th within the range, 220 to 290 and later investigations have generally confirmed this range, although at a slightly lower level, under conditions of complete hemoglobin saturation by oxygen and CO.^ ^ Briefly, the affinity constant may be expressed as the number of moles of oxygen which must be present with each mole of CO in order to maintain an equal saturation of hemoglobin. While CO actually combines less rapidly with reduced hemo globin than does oxygen, the tenacity of the binding between CO and hemo globin is some 200 to 300 times that of oxygen. This saturation of hemoglobin by either oxygen or CO occurs in four steps involving intermediates with four equilibrium constants:
k' k' Hb4 + X ^ XHb4 KX = k '2 XHb . + X (X) 0Hb . K9 = ; --- 4 k.2 2 4 ^ k-2 ill k,3 (X)2Hb4 + X  = ? <X)3Hb4 K3-Rj- k '4 k 'i (X)3Hb4 + X ^ (X)4Hb4 K4 -I
n the above equations, X represents either oxygen or CO with a different equilibrium constant for each equation. It has been determined that in both cases is much higher (18 to 50 times higher) than K-^, K2 , or K3 because k'^ is much greater than Under these circumstances the last ligand to bind to hemoglobin (K^ equation) dissociates much more 15 readily than it binds.
The differences between the four constants depend on intra-molecular forces occurring as a result of the interactions of each III-3 ligand with the others, or with other portions of the hemoglobin molecule.
Hence, the effect is an allosteric one resulting in conformational changes in the hemoglobin molecule. These differences in reaction rates affect the dissociation of oxygen or CO from hemoglobin such that, as can be observed in Figure 1, the shapes of the respective dissociation curves are sigmoidal rather than parabolic, as is the case with myoglobin, which possesses only 16 one heme group with a single dissociation constant.
Likewise

# III-4
The difference in the partial pressure of oxygen (Pq^) between freshly oxygenated arterial blood (P = 100 mm Hg) and mixed venous blood2 (P = 40 mm Hg) represents a release to the tissues of approximately Oo 16 5 milliliters 0^/100 milliliters blood.
A shift of the steep portion of the oxyhemoglobin dissociation curve to the left would tend to change the release of oxygen to the tissues appreciably.
While the dissociation curve shifts to the right, allowing for a more efficient dissociation of oxygen to the peripheral tissues under conditions of reduced ambient oxygen tension (hypoxic hypoxia), just the opposite 4,16,19,21 situation occurs during exposure to CO (anemic hypoxia).
The leftward shift during CO exposure occurs because of the much greater affinity of CO for hemoglobin and in spite of the fact that the amount of oxygen in 4 physical solution in the blood remains near normal.
The oxygen content of the blood is not only lowered during exposure to CO, but the shift of the oxyhemoglobin dissociation curve to the left decreases the amount of remaining oxygen that is made available to the tissues. As mentioned earlier in this report it has been confirmed that an 51 52 endogenous source of CO exists as a product of heme catabolism. '

# III-8
When an ct-methylene bridge in the heme portion of hemoglobin is broken during 51 the catabolic process, a molecule of CO is released.
It has been estimated that this production amounts to approximately 0.3 to 1.0 milliliter(ml)/hour with an additional 0.1 milliliter(ml)/hour resulting from a similar catabolic process involving other heme-containing compounds (e.g., myoglobin and cyto-6,53 chrome and catalase enzymes).
This endogenous production of CO, which gives rise to approximately 0.5 to 0.8 percent COHb, would not be expected to be of important physiologic consequence per se since the hypothesized mechanism has evolved with man, but its removal would merit due consideration in a closed system such as a submarine or a space capsule. Also, in the determination of total CO exposure this quantity must be included as "base line" COHb.

# Cardiovascular Effects of CO
The critical importance of cardiovascular involvement during exposure 6,28,49-6*0 to CO is becoming increasingly evident.
While the brain has a higher requirement for oxygen than the heart, in contrast to the cerebral circulation the coronary circulation must supply an even increased amount of oxygen during periods of generalized tissue hypoxia; since under these circumstances the heart is forced to increase both its rate and its output 49 in order to meet the normal oxygen demands of the body.
This increase in myocardial activity demands an increased oxygen supply to the myocardium which must be met by the coronary circulation. Under hypoxic conditions increased oxygen supply to the peripheral tissues can be accommodated by increased blood flow (via vascular dilatation) and/or increased oxygen extraction by the tissues. As mentioned earlier the peculiar dissociation characteristics of O^Hb permits an oxygen reserve which is used at reduced III-9
P . The myocardium under these circumstances appears only to increase 2 the flow of blood rather than to extract an additional amount of oxygen from the coronary circulation. While the peripheral tissues normally extract only 25 percent of the oxygen content of the perfusing arterial blood during resting conditions, the myocardium extracts 75 percent, thus leaving the mixed venous blood only 25 percent saturated. This mechanism has the overall effect of maintaining the myocardial oxygen tension at a higher level than would be present in other muscle tissue and thus insures a continual aerobic metabolism, even under hypoxic duress. In terms of oxygen tension, the mixed venous blood of the peripheral tissues is approximately 40 mm Hg while the mixed venous blood of the coronary circulation is only 20 mm Hg. In the presence of COHb (and the shift to the left of the oxyhemoglobin dissociation curve), however, the arterio-venous difference can only be maintained by an increased flow in the coronary circulation.
In an individual with diminished coronary circulation because of coronary heart disease, however, this situation may result in a decrease in the mixed venous oxygen tension of the myocardium precipitated by an inability to maintain the normal arterio-venous gradient. This hypoxic effect is further enhanced, as mentioned above, by an increase in cardiac rate and output as a general response to peripheral tissue hypoxemia. A person with diminished coronary circulation caused by coronary heart disease, consequently, may be constantly near the point of myocardial tissue hypoxia. This exposure to CO increased the COHb slightly less than 1 percent per minute.  It appears that the canine may be able to tolerate a much higher level of COHb than is the human before significant myocardial changes occur.

# Jaffe
has emphasized the relationship between CO poisoning and an elevated titer of serum lactic dehydrogenase as an indicator of myocardial damage. He speculated that "...even 'normal' amounts of carbon monoxide may operate as the last straw in precipitating coronary attacks." Mien rats 65 were exposed to 500 ppm CO for four hours Lassiter, Coleman, and Lawrence observed a statistically significant aberration in the plasma lactic dehydrogenase isoenzyme distribution which was considered to be highly indica tive of myocardial damage. The COHb level in the animals at termination of exposure was <40 percent.
The relationship between chronic cigarette smoking and increased risk of 66 coronary heart disease (CHD) is undeniable, as is the fact that cigarette smoking causes increased exposure to CO. A CO concentration of 4 percent (40,000 ppm) in cigarette smoke, which will cause an alveolar concentration of 0.04 to 0.05 percent (400 to 500 ppm) will produce a COHb concentration 6,67-69 70 3 to 10 percent.
Goldsmith estimated that the cigarette smoker is exposed to 475 ppm of CO for approximately six minutes per cigarette.
In a review article on CO and human health} Goldsmith and Landaw stated that the COHb level in the one-pack-a-day cigarette smoker is 5.9 percent, which they say is a sufficient concentration to impose a serious health threat to persons with underlying vascular insufficiency.
In another paper these two investigators used a regression analysis of expired air samples from 3,311 longshoremen and found a COHb of 6.8 percent in two-pack-a-day smokers and 1.2 percent COHb in nonsmokers. They believed that the high level in the nonsmokers, above the 0.5 to 0.8 percent normally present as a result of endogenous production, was accounted for by occupa tional exposure.
In a study by Kjeldsen"^ COHb levels of both smokers and nonsmokers were compared from 934 'tHD-free"persons. The mean COHb was 0.4 percent for nonsmokers and 7.3 percent for cigarette smokers who inhaled. In addition, the mean level of COHb for all 416 smokers in the study, regard less of inhalation habits or number of cigarettes smoked, was 4.0 percent.
A similar study is presently being conducted to determine the range 72 of COHb in the American public by Stewart and Peterson. The presently available data, from Milwaukee, has demonstrated that the mean COHb levels for nonsmokers is 1.33 0.85 percent and for smokers is 4.47 2.52 percent. In an epidemiologic survey involving approximately 4,000 middle-aged males, who were kept under medical surveillance for 8 to 10 years, Doyle 74 and co-workers found that one-pack-a-day smokers had about a three-fold greater risk of myocardial infarction than did nonsmokers, or former smokers.
The finding that death rates for ex-smokers were no higher than for 16 nonsmokers prompted Bartlett to state that the effect of cigarette smoking on this particular pattern is completely reversible when an individual ceases to smoke. He concluded that smoking caused a myocardial hypoxemia by some acute, reversible process, which was probably unrelated to the formation of hard, irreversible, atherosclerotic lesions and that CO would fit such an epidemiologic pattern very well. He further stated, however, that other components of cigarette smoke, including nicotine, may be responsible for this pattern and that the question, in his estimation, remained unsolved.
Astrup, Kjeldsen, and Wanstrup,^ reporting on an investigation in progress in 19 70 in which 1,000 randomly chosen individuals were examined for evidence of arteriosclerotic disease, demonstrated a clear relationship between this disease and high COHb levels after smoking. They further stated that it is very likely "...that it is the inhalation of CO in tobacco smoke that is, in part, responsible for the much higher risk of smokers to develop coronary heart disease and other obliterating arterial diseases in comparison to that of nonsmokers." pain in the patients exposed to 50 ppm for four hours. The same level of significance was also found for the patients exposed to 100 ppm although the differences of results between the two regimes were not significantly different. The other parameter measured, duration of pain, was statisti cally significant (p <0.05) only for the patients exposed to 100 ppm CO.
Again the differences of results between the lower and higher exposures were not significant. Knelson concluded, using this particular protocol of exposure, that patients with angina pectoris who were exposed to CO and then exercised experienced pain earlier and pain lasted longer, than when these same patients were exposed to ambient air.
An interesting set of data has been produced recently by Horvat and 7Q co-workers ' concerning the effect of oxygen breathing on the threshold of angina pain in patients with confirmed coronary heart disease. The investigators first determined the angina threshold while the patients breathed air by increasing the heart rate via right atrial pacing. Patients were then, unknowingly, switched to 100 percent oxygen and the heart paced to the previously determined angina threshold. Angina pain did not occur in nine of eleven patients. Associated with this improvement was increased lactate extraction from an average of -17 15 to +18 10 percent (p <0.025).
In four of six patients lactate production turned to lactate extraction, in six of seven patients S-T abnormalities in the EKG were improved as well as improvement in pulsus alternans in three of five patients. These data present significant evidence that oxygen breathing permits the heart to do more work before coronary insufficiency develops. They also indicate the validity of the approach used by Knelson in determining   Lloyd and co-workers noted that while certain areas (e.g., janitors) had an excess of deaths due to heart disease, other areas had a deficit in this specific cause of mortality.
In attempting to determine why an apparent selection for health should have been more likely among steelworkers dying from heart disease, it was
suggested that such persons may have been more likely to migrate between work areas. Thus, employees exhibiting symptoms of cardiac insufficiency (e.g., shortness of breath) may move to less physically demanding jobs on their own. Similarly, employees with CHD who return to work following an attack are often returned to less physically demanding jobs (e.g., janitors and mechanical maintenance). As a result the investigators indicate that selection for health may have been more important than environmental factors in explaining the excess in mortality from heart disease among janitors and mechanical maintenance personnel. If this suggestion is correct, then the work areas from which those employees dying from heart disease migrated would not be expected to show similar increases in deaths from heart disease. For example, if these employees migrated from the areas aforementioned that produce significant exposure to CO, then those areas would be expected to have a lower SMR for heart disease. Although this rate for those areas was not published in the paper, because of statistical insignificance, the SMR for all deaths in those areas, as mentioned, did not demonstrate trends which were statistically significant.
Based upon this study, then, it would not seem possible either to infer or to deny that occupational exposure to CO at the three work places in question resulted in an excess of deaths due to heart disease.
More information is needed concerning daily exposure of workers, engaged in various levels of activity, to specific sources of CO within their working environment and the correlation of such information to both smoking habits and to nonoccupational exposure.

# III-32
Regardless of CO source, however, the rate of CO excretion from the blood is dependent upon the concentration in the ambient air, and for smokers with elevated COHb levels who are occupationally exposed to CO, their excretion of CO will be proportionally delayed.
Because the recommended standard for occupational exposure to CO is designed to protect employees with CHD, it is necessary to characterize the extent of this disease among the general worker population.
Friedberg has defined CHD to represent clinical heart disease due to lesions of the coronary arteries. However, the term, CHD, is generally used to refer to the process of atherosclerosis of the coronary arteries leading to disturbances in the myocardial blood supply. It is in this latter context that the term applies in the criteria document.
It is an established fact that each year more persons in the U.S. die 103 from CHD than from any other disease.
Coronary atherosclerotic heart 104 disease is the most common form of cardiac disease in adults in the U.S.
During the Korean War autopsies performed on young soldiers, with an average age of twenty-two years, revealed that 77.3 percent had gross pathologic 104 , 105 " evidence of CHD.
A study of autopsies in a stabilized population of 30,000 revealed that CHD was the cause of death in 40 percent of the males.

# Friedberg states:
"The diagnosis of coronary (atherosclerotic) heart disease refers to clinical manifestations and not to the mere presence of atherosclerotic lesions. Extensive pathologic lesions may be present but cannot be diagnosed unless they produce overt clinical manifestations or are revealed by coronary angiography."
In most cases the first clinical manifestation of CHD is expressed''"e ither as the angina pectoris syndrome or as frank myocardial infarction.

# III-33
According to the Framingham, Massachusetts, study conducted by the USPHS, CHD was first manifested in one-sixth of the cases of CHD as sudden death. produced in the myocardium of patients with coronary artery disease during acute exposure to concentrations of CO sufficient to produce a COHb content of less than 9 percent provides metabolic evidence of myocardial hypoxia occurring under this regime. His finding that in patients with coronary artery disease the coronary blood flow did not increase at this level of COHb saturation, although it did increase in controls, serves to further underscore the possible consequences for an individual with coronary heart disease (CHD) who is carrying less than 9 percent COHb. Furthermore, it 111-35 must be emphasized that these coronary patients were at rest and were not subjected to exercise. The consequences of this additional stress were 7 8 documented earlier in the study by Knelson. His discovery that the time to onset of pain was diminished in cigarette smokers with angina pectoris during exercise immediately following exposure to 50 ppm of CO for four hours (average COHb of 3.0 percent), provides considerable evidence that workers with CHD, and particularly those with CHD who smoke, should not be exposed to concentrations of CO which will produce a level of COHb in excess of 5 percent.
Similarly, the effects of CO on behavior are not in complete agreement.
As mentioned previously, several mechanisms have been suggested to possibly account for the differing results. These suggestions can be summarized by noting that no one study has completely replicated the experimental design of any previous study that indicated a behavioral impairment due to CO Because the emission of CO is on so large a scale it becomes difficult to single out, identify and rank individual sources in order of importance as concerns occupational exposure. Indeed, as emphasized earlier in this report, the smoking habits of the worker have a tremendous bearing on his actual daily exposure to CO. The CO pollution from traffic to and from the place of employment likewise will affect his total daily exposure.
Several studies concerning occupational exposure to CO are presented below.   The investigators commented on the results of the study by saying:
V-6
to recognize the effect that the level of activity has upon the uptake of CO and to judiciously evaluate the exposure of his employees and limit their activity accordingly. The data in Appendix IV have been included specifically for this purpose. In addition, the employer must give special consideration to limiting the activity of employees exposed to CO at high altitudes in order to compensate for the dual loss in oxygen-carrying capacity of the blood.
V-7

# VI. COMPATIBILITY WITH AIR QUALITY STANDARDS
The Environmental Protection Agency (EPA), under provisions of the Clean Air Act (PL 91-604), promulgated national primary and secondary air quality 123 standards on April 30, 1971.
The primary and secondary standards for "in the comments, serious questions were raised about the soundness of this evidence. Extensive consideration was given to this matter. The conclusions reached were that the evidence regarding impaired time-interval discrimination had not been refuted and that a less restrictive national standard for CO would therefore not provide the margin of safety which may be needed to protect the health of persons especially sensitive to the effects of elevated carboxy hemoglobin levels. The only change made in the national standards for CO was a modification of the 1-hour value. The revised standard affords protection from the same low levels of blood carboxyhemoglobin as a result of short-term exposure. The national standards for carbon monoxide, as set forth below, are intended to protect against the occurrence of carboxyhemoglobin levels above 2 percent. It is the Administrator's judgment that attainment of the national standards for carbon monoxide will provide an adequate safety margin for protection of public health and will protect against known and anticipated adverse effects on public welfare."

# VI-1
The air quality standard is designed to protect the population-at-large and takes into consideration 24-hour per day exposure of the very young, the very old, and the seriously ill. The evidence presented in this (NIOSH) criteria documentation supports the concept of the necessity of providing protection for that portion of the general worker population with coronary heart disease (CHD), who are especially sensitive to elevated levels of COHb.
Although the Administrator of EPA has stated above that the evidence concerning the impairment of time-interval discrimination at low levels of COHb, presumably as low as 2 percent, has not been refuted, neither has such evidence been confirmed.
VI-2

# VII. APPENDIX I SAMPLING AND ANALYSIS OF CARBON MONOXIDE (CO)
Worker exposure to CO shall be measured with a portable, direct reading, hopcalite-type carbon monoxide meter calibrated against known concentrations of CO, or with gas detector tube units certified under Title 42 of the Code of Federal Regulations, Part 84. Samples shall be collected from the worker's breathing zone and a sufficient number shall be collected at random intervals throughout the workday so that a statistically accurate determination of compliance may be made as outlined in the following section.

# Principles for Air Sampling for Carbon Monoxide (CO)
The characteristic manner in which CO proceeds from the pulmonary alveolar spaces, through the blood capillary membrane "barrier," into the plasma, through the red blood cell membrane, ultimately to combine with hemoglobin imposes certain requirements for air sampling if proper deter mination of compliance with the recommended standard is to be made. The rate of CO diffusion from the lung to hemoglobin depends upon the partition coefficient for CO between alveolar air and pulmonary blood. The magnitude of this coefficient is such as to delay transfer of CO to the circulating hemoglobin (Hb). This time delay makes it essential in any estimation of the carboxyhemoglobin level to know how long the exposure was experienced as well as the CO concentration during the exposure. Reference to Figure 2 shows that a continuous exposure of over eight hours' duration is required to attain maximum combination of CO with hemoglobin at the recommended standard of 35 ppm.

# Air Sampling Methods

# VIII-1
The sampling and analytical procedures recommended below will provide the necessary data to determine compliance with the recommended standard.
The methodology and equipment utilized to collect and analyze samples to determine concentrations of CO in the air or concentration of COHb in the exposed worker shall be subjected to a proficiency and/or calibration test program conducted by NIOSH or by another agency of the federal govern ment under agreement with NIOSH for certification for such determinations.

# Determination of Compliance
The following procedure shall be used to determine compliance with the eight-hour, time-weighted average standard based on a small number of instantaneous (grab) samples collected at random intervals during the workday.
Given: the results of r i samples with a mean m and a range (difference between least and greatest) jr. If, for from 3 to 10 samples, m is greater than the total of: An extensive review of the methodology covering the determination of 12 4 carbon monoxide has been prepared by Maehly. In an updating review of Because carboxyhemoglobin constitutes the toxic product formed during carbon monoxide intoxication, and because the carboxyhemoglobin formed is quite stable, the analyst is presented with the opportunity of directly evaluating the toxic agent. In so doing, two facts are established:
(1) proof that an exposure has occurred, and (2) quantitative proof the exposure has produced a particular toxic concentration in the body.
Diffusion, chromatographic and gasometric methods all involve liberation of carbon monoxide from hemoglobin and either gasometric transfer operations or secondary titrations which are technically difficult for the microliter gas volumes involved. This limitation is even more critical when the effects of temperature and pressure on gas volumes are considered. Careful evaluation of the methods for direct measurement of carboxyhemoglobin has been reviewed in detail. Of these methods, three are considered to be feasible for con sideration as the recommended method.

# (a)
The colorimetric method of Amenta uses small blood samples and measures the absorbance of an ammonia-hemolyzed sample at three wave-length

# Analytical Methodology
IX-1 settings on the spectrophotometer: 560, 575, and 498 nm. In calculating the results, the absorbance of the mixture at 498 nm (an isosbestic point) is the denominator in the equation for oxyhemoglobin, carboxyhemoglobin, and the unknown. This mathematical manipulation gives a value corrected for the total hemoglobin concentration (i.e., the R factor). The values (IL = 1.097, R = 0.057) are then used for calculating percentage COHb by 2 the ratio R^ -R^/R^^-R^q XIOO = percentage COHb. The relatively small absorbance difference observed with this method reduces its precision and accuracy, especially in the low COHb range (ca. 10 percent).

# (b) The method of Harper
involves hemolyssis of blood by distilled water, addition of a buffer (pH 7.2) and reduction of oxyhemoglobin by sodium hydrosulfite. The reduced hemoglobin is then converted to methemoglobin by the addition of potassium ferricyanide. The carboxyhemoglobin is converted to methemoglobin at a slower rate than reduced hemoglobin; therefore, the carboxyhemoglobin can be measured before appreciable conversion to methemoglobin takes place. The method requires a careful control of timed manipulations to obtain reproducible results.

# Range and Sensitivity
For 1 ml of oxalated blood the range is 0 to 100 percent saturation COHb. Sensitivity is 0.5 percent saturation.

# Interferences
Hemolyzed blood contains pigments arising from the breakdown of hemoglobin and will cause interference in the method. Bile pigments may also interfere.

# Precision and Accuracy
The difference in concentrations obtained by this procedure and compared to results obtained on the same samples analyzed by the Van Slyke method are not significant at the 5 percent level [t-Value = 1.81 (14 deg.  (A) Chemical stability, incompatibility, hazardous decomposition products, and hazardous polymerization.
X-2 (A) Detailed procedures to be followed with emphasis on precautions to be taken in cleaning up and safe disposal of materials leaked or spilled.
This includes proper labeling and disposal of containers containing residues, contaminated absorbants, etc.
(ix) Section VIII. Special Protection Information.
(A) Requirements for personal protective equipment, such as respirators, eye protection and protective clothing, and ventilation, such as local exhaust (at site of product use or application), general, or other special types.
(x) Section IX. Special Precautions.
(A) Any other general precautionary information, such as personal protective equipment for exposure to the thermal decomposition products listed in Section VI, and to particulates formed by abrading a dry coating, such as by a power sanding disc.
(xi) Hie signature of the responsible person filling out the data sheet, his address, and the date on which it is filled out.
(xii) The NFPA 704M numerical hazard ratings as defined in Section (c) (5) following. The entry shall be made immediately to the right of the heading, "Material Safety Data Sheet" at the top of the page and within a diamond symbol preprinted on the forms.
N i in O ir - -1 - - - - - - - - - - - - - - - - - - - - (M ao r < NO o m < r"
< u e O o O O O o o o O o ' J o O O O O o O 0 0 - - - - - - - - - - - - - - - - - - - - o o O O o *? o o o c o o CJ o o O i j O o o H
O o  O o o o o o o o O O O   O o  O - - - - - - - - - - - - - - - - - - - -  o       o o    o o  c  o o C M ro 4- tn o O' <\l i f s co 4 4-f-o rr. O' nj in 00 *4
-i H o o o  O    O    o o o   o     o o o  O O o Q  O o   O O  o  - - - - - - - - - - - - - - - - - - - -  o         o O o o   G    if 4-4-4" 4" 4" 4-4-4-4-'4' 4-4" 4-4-4- 4-4-  i- - -fr -  i' > O O o o o o ei o o o o o o o o o o o o o - - - - - - - - - - - - - - - - - - - - O O o o o o o o o o o o o o o o o o o o O o o o o o o o o o o o a o o o c o o o  ->1 -> r- 1 - -1 - *- t
(V i IN J N >l\J MMl\J U l U l IM> yji -J 00 vC e-1 P J t- -J i -J > 1-J 00 co \D o H - u> O ) 00 - N i o i-1-si i ' V UN J - - - - - - - - - - - e - - e - - - - e N ) - *4 o S' o -J o O ' 'O s U l U J o -J PO x j o U J -J 00 M!-- o s 1 -O ' o 03 O ' f - O ' O v _ n 0 ( -- -S' -S' V- - . -t- -r -r -t- > JN -e - -e -  o   o o o C i o  o o o o c- o o o o o -  - - - - - - - - - - - - - - - - - - C, O o o o o o o o o o o o  o  o  I ' .I o O o o o o o o CJ c o o o o o o o o  o  o r1 tc tw  -1 -i-I-11 -- K -  -r-r-> I-1t-t-'   i- u >u >u >Ul f'J l\J i-- H - )-- 0 0 U ) M  X ) O ' U > -J -p ' 0 0 Ul IV -o O ' Ul -i' Ul rsj - "  o   o o    O  o  o  o     - - -  - - - - - - - - - - - - - - -   o      o o o   o  o o  o   N J h o IV rvj rsj N > O J O J U J u >Ul J- Ul -s i 0 0  - o r o h - 00 U) Ul si -sj -si CD 0 0 sD sO  PO Ul O' o - rsj u l o C OUl  - - - - - -  - # - - - -  - - - - - - u >Ul 05 N J O' rsj >  I " C OM O' vO  Ul cr-Ul O'  Ul Ul 0 0 o IN i -sj - -si -St O' PO - u i - - C ON) O' -si U ) X) tj 0 n o Time i" 4> - p- f'- - -f' - -r> f- * 4> -f' o o o O O o o o o o o o o o o a O o o o - e - - - - - - - - - - - - - - - - - - o o o o o o o o o o o o o o o o o o o o o o o Ci o o o o o o o o O o o o o o Ci o ro ro ro N) (V J (V )
- -  - - t - -  -  - - - - - - - - - 1- O I O D I-1 O ' Ni o t-- O '
- - - - - - - - - - - - - -  - - - - - o o o o c o o o o o o o o o o o o o C 1 H 9 t  ' t i ' 0 a n > N) N) N> N) NJ ro ro Ui Ui OJ U> > U1 > o >- ro h- U) u> 00 CD o UI 00 u> 1-- 0D vD U I OJ ro - - -  - - - - - - - - - - - - - -  
u> o sO UJ OD