DƯỢC LÍ Goodman & Gilman's The Pharmacological Basis of Therapeutics 12th, 2010

impulsivity, short attention span, and inability to follow
even simple sequences of instructions. Recent studies
have shown neurobehavioral deficits even with lead
exposures below the CDC action level of 10 μg/dL.
There is no evidence for a threshold; associations with
neurobehavioral effects are evident at the lowest measurable
blood lead levels (Lanphear et al., 2005).
Because different areas of the brain mature at different
times, the neurobehavioral changes vary between children,
depending on the timing of the lead exposure.
Children with very high lead levels (>70 μg/dL) are at
risk for encephalopathy. Symptoms of lead-induced
encephalopathy include lethargy, vomiting, irritability,
anorexia, and vertigo, which can progress to ataxia,
delirium, and eventually coma and death. Mortality
rates for lead-induced encephalopathy are ~25%, and
most survivors develop long-term sequelae such as
seizures and severe cognitive deficits.
Adults also develop encephalopathy from lead exposure,
although they are less sensitive than children. Encephalopathy in adults
requires blood lead levels >100 μg/dL. The symptoms are similar to
those observed with children. Workers chronically exposed to lead can
develop neuromuscular deficits, termed lead palsy. Symptoms of lead
palsy, including wrist drop and foot drop, were commonly associated
with painters and other lead-exposed workers during previous eras but
are very rare today. Lead induces degeneration of motor neurons, usually
without affecting sensory neurons. Studies in older adults have
shown associations between lead exposure and decreased performance
on cognitive function tests, suggesting that lead accelerates neurodegeneration
due to aging (ATSDR, 2007b).
The neurodevelopmental effects of lead primarily result from
inhibition of calcium transporters and channels and altered activities
of calcium responsive proteins, including PKC and calmodulin
(Garza et al., 2006; Bellinger and Bellinger, 2006). These actions
limit the normal activation of neurons caused by calcium release and
cause inappropriate production and/or release of neurotransmitters.
Lead affects almost all the neurotransmitter pathways, with the
dopaminergic, cholinergic, and glutamatergic systems receiving the
most attention. Neurotransmitter release and PKC signaling determine
which synapses are maintained and which are lost during
development. At high concentrations, lead causes disruption of membranes,
including the blood-brain barrier, increasing their permeability
to ions. This effect is likely responsible for encephalopathy.
Cardiovascular and Renal Effects. Low-level lead exposure
increases blood pressure. Correlations between
lead exposure and blood pressure extend to concentrations
of lead <20 μg/dL. Although the change in blood
pressure is small, ~1 mm Hg for each doubling of the
blood lead concentration, a significant effect persists
across a wide number of studies, and there is evidence
of causality (Navas-Acien et al., 2007). Elevated blood
pressure is a lasting effect of lead exposure. Adults who
were exposed to lead during infancy and childhood
have elevated blood pressure even in the absence of a
recent exposure; thus, blood pressure correlates better
to lead levels in bone than in blood (ATSDR, 2007b).
Lead exposure also is associated with an increased risk
of death due to cardiovascular and cerebrovascular disease
(Schober et al., 2006).
The kidney is a very sensitive target of lead. Lowlevel
lead exposure (blood levels <10 μg/dL) depresses
glomerular filtration. Higher levels (>30 μg/dL) cause
proteinuria and impaired transport, while very high levels
(>50 μg/dL) cause permanent physical damage,
including proximal tubular nephropathy and glomerulosclerosis.
Impaired glomerular filtration and elevated
blood pressure are closely interrelated and likely have
causative effects on one another (ATSDR, 2007b).
The exact mechanisms for the cardiovascular and renal effects
of lead are not known. The cardiovascular effects of lead are thought
to involve the production of reactive oxygen species by lead, through
an unknown mechanism. Reactive oxygen species react with nitric
oxide, which may contribute to the elevated blood pressure by reducing
NO-induced vasodilation and contribute to cardiovascular toxicity
through the formation of highly reactive peroxynitrite (Vaziri and
Khan, 2007). Lead also forms inclusion bodies with various proteins,
including metallothionein, in the kidney. The formation of these bodies
greatly increases intracellular lead concentrations in the kidney
but appears to be protective. It is not known how lead reduces
glomerular filtration rate, although there is evidence that lead targets
kidney mitochondria and may interfere with the electron transport
chain (ATSDR, 2007b).
Hematological Effects. Chronic lead intoxication is associated
with hypochromic microcytic anemia, which is
observed more frequently in children and is morphologically
similar to iron-deficient anemia. The anemia
is thought to result from both decreased erythrocyte life
span and inhibition of several enzymes involved in
heme synthesis, which is observed at very low lead levels
(Figure 67–5).
Inhibition of -aminolevulinate (-ALA) dehydratase and
ferrochelatase is well documented. Ferrochelatase is responsible
for incorporating the ferrous ion into protoporphyrin IX to
form heme. When ferrochelatase is inhibited by lead, zinc is
incorporated in place of iron, resulting in zinc-protoporphyrin,
which is highly fluorescent and diagnostic of lead poisoning. -ALA
dehydratase is the most sensitive of these enzymes to inhibition by
lead; very low levels of lead increase urinary excretion of -ALA.
Lead also causes both immunosuppression and increased inflammation,
primarily through changes in helper T-cell and macrophage
signaling (Dietert and Piepenbrink, 2006).
Gastrointestinal Effects. Lead affects the smooth muscle
of the gut, producing intestinal symptoms that are an early
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CHAPTER 67
ENVIRONMENTAL TOXICOLOGY: CARCINOGENS AND HEAVY METALS