PRINCIPLES OF TOXICOLOGY

function and response to stimuli, (2) the unique membrane-bound T cell receptors responsible for
antigen recognition, and (3) many of the complex events that regulate T-cell maturation. Although the
process of T-cell production begins in the bone marrow, the immature pre–T cell must migrate to the
thymus gland, via the bloodstream, for further development and differentiation. The thymus-dependent
differentiation of T cells into specific subpopulations is governed by the expression of unique cell
surface proteins or receptors known as cluster determinants. Specific types of T cells are defined by
their cluster determinant repertoire, namely, CD4 for T-helper cells, CD8 for T-suppressor cells, and
CD3 as a marker for all T cells. The cluster determinant expression (phenotype of the mature T cell)
ultimately determines the precise function of the mature T cell that leaves the thymus (T helper,
suppressor, memory, and killer cells for example). Thymic maturation of T cells involving the
acquisition and deletion of specific cluster determinants is depicted in Figure 4.2.
The post–bone marrow maturation of B cells in humans is not well understood. Like T cells, B
lymphocytes may also be defined by their own distinct repertoire of cluster determinants (membrane
proteins and protein receptors). Chemicals that affect T and B lymphocyte function are more
appropriately discussed under the topic of immunotoxicity.
4.5 DIRECT TOXICOLOGICAL EFFECTS ON THE RBC: IMPAIRMENT OF OXYGEN
TRANSPORT AND DESTRUCTION OF THE RED BLOOD CELL
Two types of toxicities essentially affect red blood cells: (1) competitive inhibition of oxygen binding
to hemoglobin and (2) chemically induced anemia in which the number of circulating erythrocytes is
reduced in response to red blood cell damage. Inhibition of oxygen transport is the more commonly
observed toxicity directly affecting the RBC.
Carbon monoxide, cyanide, and hydrogen sulfide bind to hemoglobin and can potentially interfere
with its ability to transport oxygen. Carbon monoxide directly inhibits oxygen binding to hemoglobin,
which can result in a spectrum of adverse effects ranging from mild subjective complaints to
life-threatening hypoxia. The mechanism underlying carbon monoxide toxicity is one of the simpler
toxicological phenomena, in terms of its binding to the iron molecule in hemoglobin. However, some
of the consequences of carbon monoxide poisoning, such as cardiovascular and neurological effects,
are much more complex and occasionally are associated with somewhat controversial outcomes (i.e.,
delayed neurological injury, such as memory loss, purportedly expressed as a reduction in neuropsychological
test performance). While cyanide and hydrogen sulfide can also bind to the heme iron in
hemoglobin, their significant toxic effects relate to inhibition of mitochondrial energy production.
Chemically induced methemoglobin and methemoglobinemia associated with hemolytic anemia
occur by two different mechanisms. The first mechanism involves oxidation of hemoglobin (methemoglobin
formation). The second mechanism involves oxidation of hemoglobin coupled to modification
of RBC membrane proteins causing the RBC to be recognized as foreign by the immune system. The
ultimate outcome of either type of toxicity is hypoxia.
Oxygen Transport: Hemoglobin
4.3 THE MYELOID SERIES 95
An understanding of hemoglobin’s protein structure is necessary to fully appreciate how carbon
monoxide, cyanide, and hydrogen sulfide bind to the heme iron of hemoglobin and prevent oxygen
from binding or being released. Hemoglobin (Hb) consists of four separate peptide chains (two alpha
and two beta peptides). Each peptide chain is irregularly folded and surrounds a porphyrin molecule
(protoporphyrin) located in a hydrophobic pocket. An iron molecule is located in the center of the
protoporphyrin ring and forms a coordinate–ligand bond with oxygen. The oxidation state of the iron
atom is an important factor in oxygen binding. Oxygen can only bind to iron when it is in its ferrous
state (+2 oxidation state). Oxidation of the iron atom to its ferric state (+3 oxidation state) produces
methemoglobin, a derivative of hemoglobin that does not form a coordinated ligand bond with oxygen.