C h a p t e r 2
Cellular Responses to Stress, Injury, and Aging
39
Lead competes with the enzymes required for hemo-
globin synthesis and with the membrane-associated
enzymes that prevent hemolysis of red blood cells. The
life span of the red cell is decreased. The gastrointestinal
tract is the main source of symptoms in the adult. This is
characterized by “lead colic,” a severe and poorly local-
ized form of acute abdominal pain. A lead line formed
by precipitated lead sulfite may appear along the gin-
gival margins. The lead line is seldom seen in children.
The kidneys are the major route for excretion of lead.
Lead can cause diffuse kidney damage, eventually lead-
ing to renal failure. Even without overt signs of kidney
damage, lead toxicity leads to hypertension.
In the nervous system, lead toxicity is characterized by
demyelination of cerebral and cerebellar white matter and
death of brain cells. When this occurs in early childhood,
it can affect neurobehavioral development and result
in lower IQ levels and poorer classroom performance.
9
Demyelination of peripheral nerves may occur in adults.
The most serious manifestation of lead poisoning is acute
encephalopathy. It is manifested by persistent vomiting,
ataxia, seizures, papilledema, impaired consciousness,
and coma. Acute encephalopathy may manifest suddenly,
or it may be preceded by other signs of lead toxicity such
as behavioral changes or abdominal complaints.
The threshold level at which lead causes subclinical
and clinical disturbances has been redefined a number
of times over the past 50 years. At one time, a blood
level of 25
μ
g/dL was considered safe. Recent research
suggests that even levels below 10
μ
g/dL are associated
with declines in children’s IQ at 3 to 5 years of age.
10,11
Approximately 99% of children are identified by
screening procedures, which are recommended for high-
risk populations based on the likelihood of lead expo-
sure. A screening value greater than 10
μ
g/dL requires
repeat testing for a diagnosis and to determine the need
for treatment. Treatment involves removal of the lead
source and, in cases of severe toxicity, administration of
a chelating agent. A public health team should evaluate
the source of lead because meticulous removal is needed.
MercuryToxicity.
Mercury has been used for industrial
and medical purposes for hundreds of years. Mercury
is toxic, and the hazards of mercury-associated occu-
pational and accidental exposures are well known. In
recent times, the primary concern of the general pub-
lic about the potential hazards of mercury has focused
on exposure from eating certain fish, amalgams used in
dentistry, and vaccines.
12
Mercury is present in four pri-
mary forms: mercury vapor, inorganic divalent mercury,
methyl mercury, and ethyl mercury.
12
Depending on the
form of mercury exposure, toxicity involving the central
nervous system and kidney can occur.
In the case of dental fillings, the concern involves
mercury vapor being released into the mouth. However,
the amount of mercury vapor released from fillings
is very small. There is no clear evidence supporting
health risk from this type of exposure, and removal
of amalgams may temporarily increase blood levels of
mercury.
12
The main source of methyl mercury exposure
is from consumption of long-lived fish, such as tuna and
swordfish. Fish concentrate mercury from sediment in
the water. Because the developing brain is more suscep-
tible to mercury-induced damage, it is recommended
that young children and pregnant and nursing women
avoid consumption of fish known to contain high mer-
cury content. Thimerosal is an ethyl mercury–contain-
ing preservative that helps prevent microbial growth in
vaccines. Concern about potential adverse effects have
led to the creation of single-dose vials that eliminate the
need for thimerosal.
12
In the United States and Canada,
most vaccines are either free of thimerosal or contain
only trace amounts.
Injury from Biologic Agents
Biologic agents differ from other injurious agents in that
they are able to replicate and can continue to produce
their injurious effects (see Chapter 14). These agents
range from submicroscopic viruses to the larger para-
sites. Biologic agents injure cells by diverse mechanisms.
Viruses enter the cell and incorporate its genetic mate-
rial into their cellular DNA, which then enables synthe-
sis of new viruses. Certain bacteria produce exotoxins
that may interfere with cellular protein synthesis. Other
bacteria, such as the gram-negative bacilli, release endo-
toxins that cause cell injury and increased capillary
permeability.
Injury from Nutritional Imbalances
Nutritional excesses and nutritional deficiencies predis-
pose cells to injury. Obesity and diets high in saturated
fats are thought to predispose persons to atherosclerosis.
The body requires more than 60 organic and inorganic
substances in amounts ranging from micrograms to
grams. These nutrients include minerals, vitamins, cer-
tain fatty acids, and specific amino acids. Dietary defi-
ciencies can occur because of a selective deficiency of a
single nutrient. Iron-deficiency anemia, scurvy, beriberi,
and pellagra are examples of injury caused by a lack of
specific vitamins or minerals. The protein and calorie
deficiencies that occur with starvation cause widespread
tissue damage.
Mechanisms of Cell Injury
The mechanisms by which injurious agents cause cell
injury and death are complex. Some agents, such as heat,
produce direct cell injury; other factors, such as genetic
derangements, produce their effects indirectly through
metabolic disturbances and altered immune responses.
There seem to be at least three major mechanisms
whereby most injurious agents exert their effects: free
radical formation, hypoxia and ATP depletion, and dis-
ruption of intracellular calcium homeostasis (Fig. 2-6).
Free Radical Injury
Cell injury inmany circumstances involves the production
of reactive chemical species known as free radicals.
1,2,13–15
These circumstances include ischemia-reperfusion injury,
