Transcript Lead toxicity from

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highly desirable properties:
 low melting point,
 malleability,
 durability,
 low cost,
 octane-boosting
 Lead poisoning (plumbism)
is now considered one of the
most common diseases of environmental origin
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Because of unique differences we will discuss lead poisoning
in adults and then children separately.
The earliest recorded lead mine reportedly existed in Turkey
in 6500 BC
 widely used in the manufacture of brass and cosmetics in
Greek Bronze Age
 lead geologically coexisted with silver
 as long as 2200 years ago, 25,000 tons of lead were
produced annually
 Romans used lead in their plumbing, cooking utensils, and in
the vessels that concentrated grape juice for wine
 In wine it enhanced color, wetness, and bouquet
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Hippocrates wrote descriptions of lead colic. Similar
descriptions have been recorded throughout history by
Benjamin Franklin and others
 Initial interest: 1839: clinical course of workers, primarily
painters, who developed lead colic
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mean blood lead level has declined more than 80% since the
performance of NHANES II (1976–1980), from 12.8 μg/dL to
a current level of about 2 μg/dL
 The normal range is now considered to be less than 40
μg/dL.
 However, many clinicians continue to believe that lead
poisoning in adults is defined only by the presence of clinical
symptoms, not by any particular blood lead level.
 The increasing evidence of subclinical effects at low blood
levels in adults argues for defining lead intoxication as a
blood lead level of greater than 25 μg/dL
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OCCUPATIONAL
LEAD PAINT
AIR
WATER
SOIL
HOBBIES
FOLK AND ALTERNATIVE MEDICINES
FOOD
OTHER
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Occupational lead standards were introduced by the Occupational
Safety and Health Administration (OSHA) in 1978
the permissible exposure limit for lead is 50 μg/m3 for an 8-hour
time-weighted average
Workers with blood lead levels of 60 μg/dL or greater must be
removed from the workplace;
those with blood lead levels of 50 μg/dL or greater on three
occasions at 1-month intervals in the prior 3 months must also be
removed from work.
Those with blood lead levels of 40 μg/dL or greater must undergo
medical evaluation.
Employers are responsible for paying the salaries of employees who
are removed from work for lead-related reasons.
Because of the reproductive effects of lead at lower lead levels,
recommendations have been made that the permissible blood lead
level in workers be reduced to 10 μg/dL
the synthesis of methamphetamine may involve lead
acetate.
 Sporadic reports have described lead intoxication from the
injection of lead-contaminated methamphetamine
 Lead absorption from retained bullets can occur in those
with gunshot wounds
 Lead absorption from pleura and synovial fluid is most
efficient
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TOXICOKINETICS
Lead is variably absorbed after ingestion
Absorption is active, mediated by the same mucosal transport
proteins that mediate calcium transport
 dependent on several factors, including the form of lead, particle
size, gastrointestinal (GI) transit time, nutritional status, and
chronologic age (30% to 50% vs 10%).
 increased lead absorption:
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 Iron deficiency
 calcium deficiency
 High fat intake and
 inadequate calories
half-life of about 30 days in adults
 95% of lead is attached to (or within) the erythrocyte; thus,
it is blood lead and not serum lead levels that are measured
 only 1% to 5% in the circulation
 Readily crosses the placenta; fetal blood lead levels are
typically 30% to 35% higher than maternal blood levels
 Blood  soft tissues, including the liver, kidneys, bone
marrow, and brain  hydroxyapatite lattice (inert and
nontoxic)
 bone mobilization (e.g., zero gravity, complete bed rest,
medications, advancing years, thyrotoxicosis, pregnancy)
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If not chelated only about 30 μg/day is excreted by the
kidneys
 Therefore, declining blood lead levels in those with lead
poisoning not undergoing chelation represent only lead’s
distribution into soft tissues, not its excretion
 In occupational monitoring, urinary lead excretion of less
than 50 μg/g of creatinine is within normal limits.
 Lead’s overall half-life is about 10,000 days (20–30 years)
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MECHANISMS OF TOXICITY
toxic to enzymes, particularly zinc-dependent enzymes
 Kidneys:
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 interferes with the heme-containing hydroxylase enzyme,
which converts 25-vitamin D to 1,25-vitamin D (reversible)
 toxic action on the renal tubules  tubulopathy  selective
proteinuria
 Levels > 40 μg/dL, lead produces dense intranuclear inclusion
bodies in renal tubules
 More advanced  interstitial fibrosis & tubular atrophy, with
relative sparing of the glomeruli
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Hematopoietic:
 high affinity for sulfydryl groups, particularly those of metalloenzymes: heme
synthetic pathway, particularly
○ δ- aminolevulinic acid dehydratase  accumulation of δ-aminolevulinic acid, a
putative neurotoxin
○ coproporphyrinogen oxidase, and
○ Ferrochelatase  elevated levels of erythrocyte protoporphyrin (EP)
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Neurons:
 inhibit calmodulin, pyruvate kinase, and other enzymes essential to neuronal
function
 inhibition of cellular functions requiring zinc and calcium
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Lead interferes with normal calcium metabolism, causing
intracellular calcium buildup; it binds to most calciumactivated proteins with 100,000 times greater affinity
CNS
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irritability,
lethargy,
insomnia,
headache,
difficulty concentrating,
memory loss,
Tremor
abnormal auditory brainstem evoked potential
encephalopathy characterized by depressed consciousness, seizures,
and coma, in association with cerebral edema
Life-threatening neurotoxicity usually develops with blood lead levels
exceeding 150 μg/dL.
PNS
axonopathy that results in motor disturbances
 upper extremities more than the lower extremities, the
extensors more than the flexors, and the dominant more
than the nondominant arm
 The initial segmental demyelination eventually leads to
injury of both the axon and cell body
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Kidneys
lead, like cadmium, produces a renal injury characterized by
excretion of β2-microglobulin and N-acetylglucosidase.
(early markers of subacute lead-induced renal injury)
 chronic exposure to lead can result in hypertension
(disturbances in vasomotor tone)
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hematopoietic system
Basophilic stippling of erythrocytes, the precipitation of
nuclearmaterial is a hallmark of severe lead exposure.
 Lead is also a potent suppressor of heme synthesis,
producing anemia once lead levels exceed 50 μg/dL; the
anemia can be either normochromic or hypochromic
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Reproduction
a higher rate of spontaneous abortion and stillbirth
 Lead is one of the few toxins in which paternal exposure is
also associated with adverse reproductive outcomes
 decreased sperm counts and a higher number of abnormal
sperm
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others
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Other complications of lead intoxication include hypertension,
GI disturbances, mild liver function abnormalities, gingival lead
lines (blue discolorations of the gingiva), muscle and joint aches,
and gouty arthritis
diagnostic evaluation
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blood lead level:
 easy to obtain
 poor measure of total body burden
 atomic absorption spectrometry, anodic strip voltammetry, thermal-
ionization mass spectrometry, and inductively coupled plasma–mass
spectrometry (ICPMS)
 All of these, when performed with appropriate quality control measures,
are extremely accurate
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x-ray fluorescence (XRF): difficult in children
EP measurement remains important in the evaluation of lead
exposure
 Less disturbance in adults
 lag behind lead exposure by several days
Although investigators have suggested that Nacetylglucosidase can be used as a marker of lead-induced
renal injury, the clinical utility of this test has not yet been
proved
 measurement of auditory brainstem evoked potentials and
nerve conduction velocity.
 Lumbar puncture should not be performed in patients with
altered mental status from suspected lead poisoning
because the underlying cerebral edema can lead to
herniation
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Treatment
Cessation of further exposure.
 The most important lead chelator developed is dimercaprol:
British antilewisite (BAL)  in addition mercury, arsenic, and
gold
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50% adverse effect
preparation in a peanut oil  only IM
Can produce hemolysis in G6PD deficiency
Other adverse effects: hypotension, rash, vomiting, and a metallic taste
BAL should be administered to any patient with encephalopathy
or a whole blood lead level greater than 100 μg/dL.
 The dose is 4 to 6 mg/kg per dose (maximum 300 mg per dose)
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Another effective lead chelator is calcium disodium ethylene
diamine tetraacetic acid (CaNa2EDTA, calcium edetate)
 The resulting complex is excreted in urine.
 EDTA can be administered intravenously or intramuscularly;
it is not administered orally, (less effective and possibly
enhance GI absorption)
 EDTA has a very short half-life (about 65 minutes). it is
ideally administered by continuous intravenous infusion. But
intramuscular or intravenous administration two to three
times dailyis acceptable. The dose of EDTA given to adults is
1 to 2 g daily.
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EDTA chelates nutrients, particularly zinc, in addition to
lead. Therefore, in order to avoid zinc deficiency, courses of
EDTA are limited to 5 days, followed by at least a 48-hour
hiatus for nutritional recovery.
 EDTA courses are also limited to minimize its nephrotoxicity
(manifested by proteinuria, hematuria, or glycosuria)
 A limitation of EDTA is its relative ineffectiveness with blood
lead levels less than 30 to 35 μg/dL, which narrows its range
of utility
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Oral chelators
These include:
succimer and D-penicillamine
Chelation therapy is often withheld until blood lead levels exceed
70 μg/dL.
 EDTA chelation can exacerbate CNS toxicity when it is used alone
when lead levels greater than 70 to 100 μg/dL; this CNS toxicity
probably represents EDTA promotion of lead penetration into the
brain.
 Thus dual therapy with EDTA and BAL should be considered for
adults with blood lead levels greater than 100 μg/dL.
 BAL can be discontinued once the blood lead level has fallen
below the range of 70 to 80 μg/dL
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Pregnant lead-poisoned women, unless their plumbism is
severe, should not undergo chelation because of the
possibility that the chelating agent will enhance lead
movement across the placenta and be teratogenic
CHILDHOOD LEAD POISONING
Childhood lead poisoning was first reported in Brisbane,
Australia, in 1899 of young children with the ingestion of
paint in their homes
 studies have reported that lead poisoning in children can lead
to subnormal intelligence, hyperactivity, aggression, and
school failure
 According to the 1991 CDC guidelines, blood lead of 10 μg/dL
or greater was demonstrable toxic.
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The peak onset of lead poisoning in children is the second
year of life
 In children, lead paint and dust are the primary source of
lead poisoning
 Lead paints:
1. relatively sweet
2. attractive to curious young children
3. 50% lead by weight
4. Pica
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A reported case of fatal childhood lead intoxication (blood
lead level, 283 μg/dL) occurred after a child ingested a lead
curtain weight, which was retained in the GI tract for several
weeks
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Risk factors:
 oral habits of the child
 developmental delay e.g. Autism
more prevalent in summer than winter.
 tendency for recurrent exposure despite environmental
hazard reduction
 The half-life of lead in the soft tissues of children may be
longer, probably because children have less bone available
for lead incorporation.
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several studies indicate that the amount of lead excreted
into breast milk is negligible unless maternal blood lead
level is greater than 40 to 50 μg/dL
 Because lead freely crosses the placenta, the fetus invariably
receives some amount of maternal lead, presumably in
association with the degree of skeletal lead in the mother,
reflecting her lifelong exposure
 Maternal bone lead has been correlated with fetal
neurotoxicity
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encephalopathy appears in children at blood lead levels as low
as 50 to 60 μg/dL
 Prominent features:
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irritability,
anorexia,
apathy,
listlessness,
abdominal
pain,
obtundation,
if untreated, cerebral edema,seizures, and death
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Peripheral neuropathy can occur in children with lead
intoxication
children with sickle cell disease may be at higher risk for this
complication
subclinical peripheral neuropathy at lead levels as low as 30
μg/dL
Lead can disturb bone development, leading to the formation of
growth arrest, or “lead lines.”
Lead lines are best identified at the metaphyses of long bones,
particularly the distal radius and proximal fibula.
These lines generally appear 3 to 6 weeks after a period of
significant lead exposure and generally correlate with a peak
blood lead level of greater than 45 to 50 μg/dL.
because of the risk for CNS deterioration or death when EDTA
alone is given to children with severe lead intoxication,
 dual therapy with both BAL and EDTA should be instituted for
children with blood lead levels of 70 μg/dL or greater.
 EDTA is begun about 4 hours after the first dose of BAL.
 BAL is given every 6 to 8 hours until the blood lead level is less
than 70 μg/dL.
 EDTA is given in a daily dose of 35 to 50 mg/kg per day (1000 to
1500 mg/m2)
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A “rebound” blood lead level measurement should be
obtained 2 to 3 days after the EDTA is discontinued for those
in whom an immediate second course of EDTA chelation is
anticipated
 It is not uncommon for children with blood lead levels of 60
μg/dL or greater to require two or more courses of EDTA.
 not every child with lead intoxication has a gratifying
response to EDTA chelation, particularly children with blood
levels less than 45 μg/dL,
 EDTA mobilization test  greater than 0.6
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D-Penicillamine
incompletely understood chelating properties
 Effective even in children with blood lead levels of 20 to 35
μg/dL.
 Blood lead levels as low as 3 μg/dL can be achieved
 is given in a dose of about 15 mg/kg daily
 The tablets must usually be crushed or the capsules opened
and placed in food or drink.
 Iron supplementation should be discontinued  65%
decrease
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Children must be monitored every 2 to 4 weeks for evidence
of adverse effects.
 Penicillamine has an overall adverse effect rate of 5% to 10%,
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 GI upset
 Rash
 WBC deppresion
Monitoring laboratory tests include CBC, urinalysis, blood
lead, and EP determinations.
 Typical courses of D-penicillamine therapy are 2 to 3 months
in length.
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Dimercaptosuccinic acid (DMSA) or Succimer
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has been approved for use in children with blood lead levels
exceeding 45 μg/dL.
its safety and efficacy extend to children with blood lead levels
between 25 and 45 μg/dL
it is prudent to use conventional, dual parenteral therapy (EDTA and
BAL) in children with blood lead levels of 70 μg/dL or greater
The current treatment protocol is administration of 10 mg/kg per
dose.
For the first 5 days of succimer therapy, it is given three times daily.
For the next 14 days, treatment is twice a day. A complete course of
DMSA chelation is therefore 19 days.
An alternative regimen is 10 mg/kg/dose, given twice a day for 28
days.
Succimer, unlike BAL, does not produce hemolysis in those
with G6PD deficiency. Also, succimer can be administered
concomitantly with iron therapy.
 Side effects: rash and minor elevations in hepatic
transaminases
 in contrast to penicillamine, succimer discontinuation is
followed by a robust rebound in blood lead level, appearing
2 to 4 weeks after completion of therapy
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Because lead rebounds can be confused with reexposure to
lead, it is important to monitor EP levels. Lead reexposure is
associated with increases in EP values; lead rebound is not.