Acute Exposure Guideline Levels
CH 2 CH-CHO
2. HUMAN TOXICITY DATA
4.4. Other Relevant Information 1. Species Variability
4.2.2. Intraspecies Variability
Experiments in mice did not indicate that very young or very old animals were more susceptible to lethal effects of CO exposure (Winston and Roberts 1978; Pesce et al. 1987). However, there is considerable variability within hu- man subpopulations: a COHb of about 15% only leads to very slight symptoms, such as headache, in healthy adults (Stewart et al. 1970; WHO 1999a). In con- trast, the same COHb was reported to cause long-lasting defects in the cognitive development and behavioral alterations in children (Klees et al. 1985) or even to contribute to death from myocardial infarction in individuals with coronary ar- tery disease (Grace and Platt 1981; Balraj 1984). In case reports of myocardial infarction, other subjects exposed under the same conditions (and sometimes had higher COHb) did not experience effects above the AEGL-2 (Grace and Platt 1981; Atkins and Baker 1985).
Subpopulations at higher risk for toxic effects of CO include the following groups:
1. Fetuses are at higher risk because of higher CO affinity and slower CO elimination (see Sections 2.3 and 4.4.4). The severity of exposure and maternal clinical signs appear to be associated with fetal mortality (Koren et al. 1991). A review by Greingor et al. (2001) noted that CO crosses the placenta through passive diffusion or is facilitated by a carrier. As the fetus increases in age and weight, placental CO diffusion increases. When the mother is exposed to CO, the amount of oxygen in her blood decreases, and oxygen transported across the placenta decreases and puts the fetus in a hypoxic state. CO crosses the placenta
as it dissociates from maternal hemoglobin and binds to fetal hemoglobin. The only source of fetal oxygen is the mother, and maternal treatment for CO poi- soning reduces fetal COHb levels (Greingor et al. 2001). Clearance of CO in the fetus would be dependent on the mother’s oxygen intake. Children have the same type of hemoglobin as adults but are more susceptible than adults because they breathe a greater amount of air per body weight than adults.
The binding affinities of embryonic hemoglobin suggest that fetuses are more susceptible to CO intoxication when compared with adult hemoglobin.
Embryonic hemoglobins (Gower I, Gower II, and Portland) are present until about 8-12 weeks of gestation. Fetal hemoglobin is expressed from about 5 weeks of gestation until 9 months after birth. Adult hemoglobin starts being produced between 3-6 months after birth (Orville 2008). Under physiologic conditions, the binding constants of fetal and adult hemoglobin to CO are 0.09 µM and 0.13 µM, respectively, meaning that the binding affinity for CO is higher for fetal hemoglobin than for adult hemoglobin (Di Cera et al. 1989). The rate constants for the binding of CO to the three embryonic hemoglobins are 3.0
× 10−6 M/s (Gower I), 2.0 × 10−6 M/s (Gower II), and 3.5 × 10−6 M/s (Portland) compared with 4.0 × 10−6 M/s for adult hemoglobin at pH 6.5 (Hofmann and Brittain 1996). No data were located that reported on whether embryos are more susceptible than fetuses. Data on the susceptibility of embryos to CO are mostly qualitative.
2. Children are at higher risk because they develop acute neurotoxic ef- fects (e.g., headaches and nausea), long-lasting neurotoxic effects (e.g., memory deficits) and impaired ability to escape (e.g., syncopes) at lower COHb concen- trations than adults (see Section 2.2.2.1). Children also have developing organs (brain and lungs), which may be affected differently than the developed organs of adults (ATSDR 2002). Children tend to be more susceptible than adults be- cause they breathe a greater amount of air per body weight than adults.
3. People are at higher risk who have pre-existing diseases, either known or unknown, that already decrease the availability of oxygen to critical tissues;
this group includes those who have coronary artery disease (see Sections 2.2.1 and 2.2.1.1), chronic obstructive lung disease, chronic anemia, and hemoglobi- nopathies, such as sickle cell anemia. For example, in sickle-cell disease, the average lifespan of red blood cells with abnormal hemoglobin is 12 days com- pared with an average of 120 days in healthy individuals with normal hemoglo- bin. “As a result, baseline COHb levels can be as high as 4%. Presumably, ex- ogenous exposure to CO, in conjunction with higher endogenous CO levels, could result in critical levels of COHb. However, it is not known how ambient or near-ambient air levels of CO would affect individuals with these disorders”
(EPA 2000; see also WHO 1999a). Due to physiologic adaptation in these sub- populations, they are not considered more susceptible than patients with coro- nary artery disease.
4. People at high altitude are at higher risk, especially those not living there long enough for physiologic adaptation. “It is important to distinguish be- tween the long-term resident of high altitude and the newly arrived visitor from
low altitude. Specifically, the visitor will be more hypoxemic than the fully adapted resident. One would postulate that the combination of high altitude with carbon monoxide would pose the greatest risk to persons newly arrived at high altitude who have underlying cardiopulmonary disease, particularly because they are usually older individuals. Surprisingly, this hypothesis has never been tested adequately” (WHO 1999a). Due to physiologic adaptation, people living at high altitude are not considered generally more susceptible than patients with coronary artery disease. Because it is generally not advisable for patients with severe coronary artery disease to travel to places at high altitude, it is not con- sidered necessary to especially take that part of the identified susceptible sub- population (that is, patients with coronary artery disease; see below) into ac- count when deriving AEGL values.
An estimated 62 million people in the United States (about 20% of the population) have one or more types of cardiovascular disease (American Heart Association 2002). For the major diseases within the category of total cardiovas- cular disease, about 50 million Americans have high blood pressure, 13 million have coronary heart disease, 4.9 million have heart failure, 4.7 million have cerebrovascular disease (stroke), and 1 million have congenital cardiovascular defects.
The prevalence of cardiovascular diseases increases with age. It is 10% for males and 4% for females at age 25-34, 51% for males and 48% for females at age 55-64, and 71% for males and 79% for females at age 75 or older (American Heart Association 2002).
Coronary heart disease caused more than one of every five deaths in the United States in 2000. Cause of death was listed as coronary heart disease in 681,000 cases and myocardial infarction in 239,000 deaths. Fifty percent of men and 63% of women who died suddenly of coronary heart disease had no previ- ous symptoms of this disease (American Heart Association 2002).
Within the group of people with coronary heart disease, 7.6 million had myocardial infarction (heart attack) and 6.6 million had angina pectoris (chest pain) (American Heart Association 2002). The prevalence of angina pectoris in the British adult population is about 4% (Williams and Stevens 2002).
Angina pectoris is a symptom of coronary heart disease. Common features of an attack are central chest pain, pain radiating to the lower jaw or arms, and shortness of breath. The pain occurs when there is insufficient oxygen delivery to the heart, leading to ischemia. This is usually, although not exclusively, a result of an atheromatous narrowing (stenosis) in one or more of the coronary arteries. Angina can classified broadly as stable or unstable, depending on its severity and pattern of occurrence. Stable angina is typically provoked by exer- cise (e.g., hurrying across a street or climbing a long flight of stairs), stress, or extremes of temperature and is relieved by either rest or sublingual nitrates or both. Unstable angina is understood as anginal pain that occurs with lesser de- grees of exertion, with increasing frequency, or at rest (that is, without exertion).
The pain may be more severe and last longer and requires more intensive inter-
vention (usually hospitalization for initiation of medication under cardiac moni- toring). If left untreated, unstable angina may result in a heart attack and irre- versible damage to the heart. The diagnosis of angina is generally based on clinical history, electrocardiograph stress testing (where patients are exercised on a treadmill to look at the effect on their electrocardiogram), and coronary angiography (to look for narrowings in the coronary arteries) (Williams and Ste- vens 2002).