PRINCIPLES OF TOXICOLOGY

Hypoxia can result from a variety of conditions including anemia; a reduction in the iron carried by
the RBC; ischemia (physical barrier to blood flow) caused by occlusion or vasoconstriction of an artery;
or by an increased oxygen affinity (shift to the left of the oxygen-hemoglobin binding curve), which
reduces the release of oxygen. In situations involving oxygen-deficient atmospheres, the blood oxygen
concentration can drop to a level in which the central nervous system and cardiovascular system risk
impairment.
Hypoxia typically occurs when workers enter confined spaces where the atmospheric oxygen
(normally at 21 percent) is too low to sustain the oxygen saturation of hemoglobin above 80 percent.
Under circumstances of reduced oxygen delivery to the lungs, serious cardiovascular and central
nervous system impairment can develop. The symptoms range in severity from euphoria to loss of
consciousness, seizures, and cardiac arrhythmias. Hemoglobin oxygen saturation less than 80 percent
results in a sense of euphoria, impaired judgment, and memory loss. As the oxygen desaturation of
hemoglobin worsens, the extent of central nervous system effects increase. If oxygen pressure drops
to 30 mm Hg, a level corresponding to approximately 55–60 percent oxygen saturation, consciousness
may be lost. Individuals with ischemic heart disease, such as atherosclerotic coronary vascular disease,
may be more sensitive to hypoxic conditions than in healthy individuals. Individuals with
atherosclerosis may be more prone to hypoxia-induced ischemia, which may lead to arrhythmias
(irregular electrical conduction in the heart) or ischemia-like pains (i.e., chest pain encountered during
angina or a myocardial infarction). Subjects with serious atherosclerosis of the cerebral vasculature
are more likely to develop CNS impairment related to hypoxia than are healthy subjects. Hence,
hypoxia resulting from either low oxygen concentrations or interference with oxygen transport must
be assessed according the subject’s cardiovascular status.
Physiological adaptations can affect oxygen’s affinity for hemoglobin, especially when chronic low
levels of hypoxia are present. 2,3-Diphosphoglycerate (or 2,3-bisphosphoglycerate) concentrations
increase within RBCs under conditions of chronic hypoxia (e.g., high altitudes, various anemias). By
complexing with deoxygenated hemoglobin, 2,3-diphosphoglycerate decreases hemoglobin’s affinity
for oxygen and facilitates oxygen release in peripheral tissues. This is illustrated by a shift to the right
in the oxygen–hemoglobin binding curve. An increase in hydrogen ions (acidity of blood) also causes
the hemoglobin–oxygen binding curve to shift to the right. Hydrogen ions are generated when carbon
dioxide (formed during respiration or oxygen consumption) is converted to bicarbonate. When the
hydrogen ions are then taken up by hemoglobin, oxygen is released. Consequently, ischemic tissue,
where the oxygen tension is low and carbon dioxide is high, is benefited by the increased oxygen
release that occurs in the presence of hydrogen ions. Conversely, if the oxygen–hemoglobin binding
curve is shifted to the left, oxygen binds more avidly to hemoglobin. When this occurs, an even lower
tissue oxygen concentration is required before oxygen can be released.
4.6 CHEMICALS THAT IMPAIR OXYGEN TRANSPORT
Carbon Monoxide
4.6 CHEMICALS THAT IMPAIR OXYGEN TRANSPORT 97
Carbon monoxide binds to hemoglobin, decreasing the available sites for oxygen while increasing the
binding affinity of the oxygen that is already bound. The hemoglobin binding affinity of carbon
monoxide is explained by the Haldane equation, named after the scientist who studied the effects of
carbon monoxide in the late 1800s. The carbon monoxide binding affinity is denoted by M in the
Haldane equation
[HbCO] M[PCO]
=
[HbO2] [PO2]
where HbCO represents the percentage of carboxyhemoglobin (the carbon monoxide-hemoglobin
complex), and HbO2 represents the percentage of hemoglobin bound by oxygen. PCO and P represent
O2