TOXICOLOGY OF HEAVY METALS
LEAD
Lead
poisoning is one of the oldest occupational and environmental diseases in the
world. Despite its recognized hazards, lead continues to have widespread
commercial application, including production of storage batteries (nearly 90%
of US consumption), ammunition, metal alloys, solder, glass, plastics,
pigments, and ceramics. Corrosion of lead plumbing in older buildings or
supplylines may increase the lead concentration of tap water. Environmental
lead exposure, ubiquitous by virtue of the anthropo-genic distribution of lead
to air, water, and food, has declined con-siderably in the last three decades
as a result of the elimination of lead as an additive in gasoline, as well as
diminished contact with lead-based paint and other lead-containing consumer
products, such as lead solder in canned food. Although these public health
measures, together with improved workplace conditions, have decreased the
incidence of serious overt lead poisoning, there remains considerable concern
over the effects of low-level lead exposure. Extensive evi-dence indicates that
lead may have subtle subclinical adverse effects on neurocognitive function and
on blood pressure at low blood lead concentrations formerly not recognized as
harmful. Lead serves no useful purpose in the human body. In key target organs
such as the developing central nervous system, no level of lead exposure has
been shown to be without deleterious effects.
Inorganic
lead is slowly but consistently absorbed via the respiratory and
gastrointestinal tracts. Inorganic lead is poorly absorbed through the skin.
Absorption of lead dust via the respiratory tract is the most common cause of
industrial poisoning. The intestinal tract is the primary route of entry in
nonindustrial exposure (Table 57–1). Absorption via the gastrointestinal tract
varies with the nature of the lead compound, but in general, adults absorb
about 10–15% of the ingested amount, whereas young children absorb up to 50%.
Low dietary calcium, iron deficiency, and ingestion on an empty stomach all
have been associated with increased lead absorption.
Once absorbed from the
respiratory or gastrointestinal tract, lead enters the bloodstream, where
approximately 99% is bound to erythrocytes and 1% is present in the plasma.
Lead is subse-quently distributed to soft tissues such as the bone marrow,
brain, kidney, liver, muscle, and gonads; then to the subperiosteal surface of
bone; and later to bone matrix. Lead also crosses the placenta and poses a
potential hazard to the fetus. The kinetics of lead clearance from the body
follows a multicompartment model, composed predominantly of the blood and soft
tissues, with a half-life of 1–2 months; and the skeleton, with a half-life of
years to decades. Approximately 70% of the lead that is eliminated appears in
the urine, with lesser amounts excreted through the bile, skin, hair, nails,
sweat, and breast milk. The fraction not undergoing prompt excretion,
approximately half of the absorbed lead, may be incorporated into the skeleton,
the repository of more than 90% of the body lead burden in most adults. In
patients with high bone lead burdens, slow release from the skel-eton may
elevate blood lead concentrations for years after expo-sure ceases, and
pathologic high bone turnover states such as hyperthyroidism or prolonged
immobilization may result in frank lead intoxication. Migration of retained
lead bullet fragments into a joint space or adjacent to bone has been
associated with the development of lead poisoning signs and symptoms years or
decades after an initial gunshot injury.
Lead exerts
multisystemic toxic effects that are mediated by mul-tiple modes of action,
including inhibition of enzymatic function; interference with the action of
essential cations, particularly cal-cium, iron, and zinc; generation of
oxidative stress; changes in gene expression; alterations in cell signaling;
and disruption of the integrity of membranes in cells and organelles.
The developing central
nervous system of the fetus and young child is the most sensitive target organ
for lead’s toxic effect. Epidemiologic studies suggest that blood lead
concentrations even less than 5 mcg/dL may result in subclinical deficits in
neurocog-nitive function in lead-exposed young children, with no demon-strable
threshold for a “no effect” level. The dose response between low
blood lead concentrations and cognitive function in young children is
nonlinear, such that the decrement in intelligence associ-ated with an increase
in blood lead from less than 1 to 10 mcg/dL (6.2 IQ points) exceeds that
associated with a change from 10 to 30 mcg/dL (3.0 IQ points).
Adults are less
sensitive to the central nervous system effects of lead, but long-term exposure
to blood lead concentrations in the range of 10–30 mcg/dL may be associated
with subtle, subclinical effects on neurocognitive function. At blood lead
concentrations higher than 30 mcg/dL, behavioral and neurocognitive signs or
symptoms may gradually emerge, including irritability, fatigue, decreased
libido, anorexia, sleep disturbance, impaired visual-motor coordination, and
slowed reaction time. Headache, arthral-gias, and myalgias are also common
complaints. Tremor occurs but is less common. Lead encephalopathy, usually
occurring at blood lead concentrations higher than 100 mcg/dL, is typically
accompanied by increased intracranial pressure and may cause ataxia, stupor,
coma, convulsions, and death. Recent epidemio-logical studies suggest that lead
may accentuate an age-related decline in cognitive function in older adults. In
experimental ani-mals, developmental lead exposure has been associated with
increased expression of beta-amyloid, oxidative DNA damage, and
Alzheimer’s-type pathology in the aging brain. There is wide inter-individual
variation in the magnitude of lead exposure required to cause overt
lead-related signs and symptoms.
Overt peripheral
neuropathy may appear after chronic high-dose lead exposure, usually following
months to years of blood lead concentrations higher than 100 mcg/dL.
Predominantly motor in character, the neuropathy may present clinically with
painless weakness of the extensors, particularly in the upper extremity,
resulting in classic wrist-drop. Preclinical signs of lead-induced peripheral
nerve dysfunction may be detectable by elec-trodiagnostic testing.
Lead can induce an
anemia that may be either normocytic or microcytic and hypochromic. Lead
interferes with heme synthesis by blocking the incorporation of iron into
protoporphyrin IX and by inhibiting the function of enzymes in the heme
synthesis path-way, including aminolevulinic acid dehydratase and
ferrochelatase. Within 2–8 weeks after an elevation in blood lead concentration
(generally to 30–50 mcg/dL or greater), increases in heme precur-sors, notably
free erythrocyte protoporphyrin or its zinc chelate, zinc protoporphyrin, may
be detectable in whole blood. Lead also contributes to anemia by increasing
erythrocyte membrane fragil-ity and decreasing red cell survival time. Frank
hemolysis may occur with high exposure. Basophilic stippling on the peripheral
blood smear, thought to be a consequence of lead inhibition of the enzyme
3’,5’-pyrimidine nucleotidase, is sometimes a suggestive— albeit insensitive
and nonspecific—diagnostic clue to the presence of lead intoxication.
Chronic high-dose lead
exposure, usually associated with months to years of blood lead concentrations
greater than 80 mcg/dL, mayresult in renal interstitial fibrosis and nephrosclerosis.
Lead neph-ropathy may have a latency period of years. Lead may alter uric acid
excretion by the kidney, resulting in recurrent bouts of gouty arthritis
(“saturnine gout”). Acute high-dose lead exposure some-times produces transient
azotemia, possibly as a consequence of intrarenal vasoconstriction. Studies
conducted in general popula-tion samples have documented an association between
blood lead concentration and measures of renal function, including serum
creatinine and creatinine clearance. The presence of other risk fac-tors for
renal insufficiency, including hypertension and diabetes, may increase
susceptibility to lead-induced renal dysfunction.
High-dose
lead exposure is a recognized risk factor for stillbirth or spontaneous
abortion. Epidemiologic studies of the impact of low-level lead exposure on
reproductive outcome such as low birth weight, preterm delivery, or spontaneous
abortion have yielded mixed results. However, a well-designed nested
case-control study detected an odds ratio for spontaneous abortion of 1.8 (95%
CI 1.1–3.1) for every 5 mcg/dL increase in maternal blood lead across an
approximate range of 5–20 mcg/dL. Recent studies have linked prenatal exposure
to low levels of lead (eg, maternal blood lead concentrations of 5–15 mcg/dL)
to decrements in physical and cognitive development assessed during the
neonatal period and early childhood. In males, blood lead concentrations higher
than 40 mcg/dL have been associated with diminished or aberrant sperm production.
Moderate lead
poisoning may cause loss of appetite, constipation, and, less commonly,
diarrhea. At high dosage, intermittent bouts of severe colicky abdominal pain
(“lead colic”) may occur. The mecha-nism of lead colic is unclear but is
believed to involve spasmodic contraction of the smooth muscles of the
intestinal wall, mediated by alteration in synaptic transmission at the smooth
muscle-neuro-muscular junction. In heavily exposed individuals with poor dental
hygiene, the reaction of circulating lead with sulfur ions released by
microbial action may produce dark deposits of lead sulfide at the gingival
margin (“gingival lead lines”). Although frequently men-tioned as a diagnostic
clue in the past, in recent times this has been a relatively rare sign of lead
exposure.
Epidemiologic,
experimental, and in vitro mechanistic data indi-cate that lead exposure
elevates blood pressure in susceptible indi-viduals. In populations with
environmental or occupational lead exposure, blood lead concentration is linked
with increases in systolic and diastolic blood pressure. Studies of middle-aged
and elderly men and women have identified relatively low levels of lead
exposure sustained by the general population to be an indepen-dent risk factor
for hypertension. In addition, epidemiologic stud-ies suggest that low to
moderate levels of lead exposure are risk factors for increased cardiovascular
mortality. Lead can also elevate blood pressure in experimental animals. The
pressor effect of lead may be mediated by an interaction with calcium mediated
con-traction of vascular smooth muscle, as well as generation of oxida-tive
stress and an associated interference in nitric oxide signaling pathways.
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