Transcript Heavy Metals - AOEC

Heavy Metal Toxicity
Scott Phillips, MD, FACP, FACMT, FAACT
Marci Balge, RN, MSN, COHN-S
Arsenic
Lead
Mercury
This educational module was produced by Scott Phillips MD, FACP, FACMT,
FAACT and Marci Balge, RN, MSN, COHN-S for The University of Texas
Health Science Center at San Antonio (UTHSCSA) Environmental Medicine
Education Program and South Texas Environmental Education and
Research Program (STEER-San Antonio/Laredo/Harlingen,Texas)
Administrative support was provided by the Association of Occupational
and Environmental Clinics through funding to UTHSCSA by the Agency for
Toxic Substances and Disease Registry (ATSDR), U.S. Department of
Health and Human Services.
Use of this program must include acknowledgement of the authors,
UTHSCSA and the funding support.
For information about other educational modules contact the UTHSCSA
STEER office, Mail Code 7796, 7703 Floyd Curl Drive, San Antonio,
Texas 78229-3900,(210)567-7407.
Definitions
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‘Metals’ originally included only gold, silver, copper,
iron, lead, and tin.
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Dense, malleable, lustrous
Conduct heat and electricity, cations
Many other elements since added to the list with
some of these characteristics
‘Metalloids’ are elements with features intermediate
between metals and non-metals. Example: arsenic
Periodic Table
‘Heavy metal’
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A metal having an atomic weight
greater than sodium, a density greater
than 5 g/cm3
Some notion of toxicity
Usually includes lead, cadmium and
mercury
Many others may variably be added to
list
Acute single exposures
urine
Metal levels
blood
exposure
time
Case Presentation
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15-month old boy was treated with ampicillin for
abdominal pain and diarrhea. The problem
continued and the parent gave the child multiple
doses of a Central American “home remedy”
called azarcon. The child developed seizures. PE
BP 103/68, P 94, RR 22, Tmax 98 F. Exam:
listless, with poor motor tone. No neck stiffness,
the heart, lungs and abdomen were
unremarkable. Sz re-occurred. WBC 9.6 no
anemia, Plts Nl, Lytes nl, UA nl Spinal tap was nl,
with elevated opening pressure, cerebral edema
was found on Cat Scan of the Head.
Case (cont)
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The child was intubated, given lorazepam,
fosphenatoin and phenobarbital without
control of the Sz. An x-ray reveled a
radiopaque image in the GI tract.
The child expired, despite aggressive
supportive care.
What is azarcon?
Azarcon
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Azarcon is a folk remedy that contains
85-96% lead tetroxide
Other lead containing remedies include
Greta.
Case (cont.)
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The child was found to have a blood
lead level of 124 ug/dl., and died from
lead encephalopathy.
Lead
Lead Paint
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The use of lead in residential paint was banned in
1977
Lead-containing pigments still are used for outdoor
paint products because of their bright colors and
weather resistant properties
Tetraethyl and tetramethyl lead are still used as
additives in gasoline in several countries
Sources of Exposure
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Soil and dust
Paint chips
Contaminated water
Parents lead-related
occupation
Folk remedies
Congenital exposure
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Pica
Developmental delay
Toxicocokinetics and
Toxicoynamics
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Absorption:
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Lungs: depends on size particle
GI:
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Skin:
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Adults: 20-30%
Children: as much as 50% of dietary lead
 Inadequate intake of iron, calcium, and total calories
are associated with higher lead levels
Inorganic lead is not absorbed
Organic lead is well absorbed
Lead is carried bound to the RBC
Pharmacokinetics and
Pharmacoynamics
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Distributed extensively throughout
tissues: bone, teeth, liver, lung, kidney,
brain, and spleen
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Body lead storage: bones- can constitute a source
of remobilization and continued toxicity after the
exposure has ceased
Lead crosses the BBB and concentrates in the
gray matter
Lead crosses the placenta
Excretion:
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Kidneys. The excretion increases with increasing
body stores (30g-200 g/day)
Feces
Clinical Manifestation
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Acute toxicity
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Acute encephalopathy, renal failure and
severe GI symptoms
Chronic and Long Term
Toxicity- Pathophysiology
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Lead has affinity for SH groups and is toxic to zincdependent enzyme systems
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Heme synthesis: hemoglobin, cytochromes
Steroid metabolism and membrane integrity
Interference in vitamin D synthesis in renal tubular cells
(conversion of 1-hydroxyvitamin D to 1,25-hydroxyvitamin
D)
Mitochondrion
Heme
Heme
Oxidase
(microsomal)
Pb
Cytoch-C
Glycine
Succinyl-Coa
Ferro-C
++
4Fe
Pb
Bilirubin
+
Fe
ALA- aminolevulinic acid
 in plasma and urine
COPRO- coprorphyrinogen
 in urine
Protoporphyrin
 accumulates in the RBC
Protoporphyrin IX* ALA-S
Pb
Copro-0
Copro
Copro*
Pb
ALA*
Pb
ALA-D
Uropor
PBG
General Signs and Symptoms
of Lead Toxicity
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Fatigue
Irritability
Lethargy
Paresthesis
Myalgias
Abdominal pain
Tremor
Headache
Vomiting
Weight loss
Constipation
Loss of libido
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Motor neuropathy
Encephalopathy
Cerebral edema
Seizures
Coma
Severe abdominal
cramping
Epiphyseal lead lines in
children (growth arrest)
Renal failure
Range of Lead-induced Health
Effects in Adults and Children
Blood lead
levels
Adults
Children
10 g/dL
Hypertension may occur
•Crosses placenta
•Impairment IQ, growth
•Partial inhibition of heme
synthesis
20 g/dL
Inhibition of heme synthesis
Increased erythrocyte
protoporphyrin
Beginning impairment of nerve
conduction velocity
30 g/dL
•Systolic hypertension
•Impaired hearing()
Impaired vitamin D metabolism
40 g/dL
•Infertility in males
•Renal effects
•Neuropathy
•Fatigue, headache, abd pain
Hemoglobin synthesis inhibition
50 g/dL
Anemia, GI sx, headache,
tremor
Colicky abd pain, neuropathy
100 g/dL
Lethargy, seizures,
encephalopathy
Encephalopathy, anemia,
nephropathy, seizures
Childhood Lead Poisoning
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Childhood lead poisoning is now defined
as a blood lead level of 10 g/dl
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The average lead level of American
children is 2 g/dl
8.9% of American children have lead
poisoning
Lead intoxication is more prevalent in
minority groups and among those living
in the northeast
Neurotoxicity of Lead in
Childhood
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Mental retardation in severe lead intoxication
 5 points in IQ for every 10 g/dl  in blood lead
level- population based studies
Other adverse developmental outcomes:
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Aggression
Hyperactivity
Antisocial behaviors
Learning disability- impairment in memory, auditory
processing, and visual-motor integration. The IQ is normal.
These effects has been demonstrated with blood lead levels
as low as 6 g/dl
Diagnosis
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Evaluation of clinical symptoms and signs
CBC
Serum iron levels, TIBC, ferritin
Abdominal radiographs (for recent ingestion of leadcontaining material)
Whole blood lead level
X-ray fluorescence (XRF)- to asses body burden
Treatment
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Environmental inspection/hazard
reduction
Nutritional supplementation
Chelation therapy
Nutritional Supplementation
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Iron supplementation
Calcium supplementation – calcium rich
foods
Phosphorus supplementation
Frequent food consumption- regular
meals + snacks
Chelation Therapy
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BLL > 70 g/dl or encephalopathy
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Hospital admission
Administration of a parenteral chelator
BLL > 45 g/dl- oral chelator
BLL 25-45 g/dl- if these levels persist
despite environmental intervention
Arsenic
Introduction
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Arsenic is common in the environment
Sources
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Groundwater
Arsenic containing mineral ores
Industrial processes
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Semiconductor manufacturing (gallium arsenide)
Fossil fuels
Wood treated with arsenic preservatives
Metallurgy
Smelting (copper, zinc, lead) and refining of metals and ores
Glass manufacturing
Introduction
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Commercial products
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Food
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Wood preservatives
Pesticides
Herbicides
Fungicides
Seafood and fish
Others
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Antiparasitic drugs
Folk remedies
Soil Pica
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Soil pica behavior: when children ingest large
amounts of soil at a time (e.g. up to 1 teaspoon or
5,000mg)
Children 1 to 2 years old have strongest soil pica
behavior, which may occur as part of their normal
exploratory behavior
Preschool children also purposely eat soil for
unknown reasons
Some cultures promote eating soil, specifically clay,
as part of a cultural practice
Toxicokinetics
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T1/2 of inorganic arsenic in the blood is
10 hrs and of organic arsenic is around
30 hours
2-4 weeks after the exposure ceases,
most of the remaining arsenic in the
body is found in keratin-rich tissues
(nails, hair, skin)
Toxicokinetics
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Inorganic arsenic is converted to organic arsenic
(biomethylation to monomethyl arsonic- MMA or
DMA) in the liver. This may represent a process of
detoxification
Renally excreted (30-50% of inorganic arsenic is
excreted in about 3 days). Both forms are excreted
depend on the acuteness of the exposure and dose
Pathophysiology
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Trivalent forms:
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Pentavalent forms
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bind to sulfhydryl groups leading to inhibition of enzymatic
systems
inhibit the Krebs cycle and oxidative phosporylation. These
lead to inhibition of ATP production
can replace the stable phosphate ester bond in ATP and
produce an arsenic ester stable bond which is not a high
energy bond
Endothelial damage, loss of capillary integrity,
capillary leakage, volume loss, shock
Manifestations of acute arsenic poisoning
Bodily system
affected
Symptoms or signs
Time of onset
Systemic
Thirst
Hypovolemia, Hypotension
Minutes
Minutes to hours
Gastrointestinal
Garlic or metallic taste
Burning mucosa
Nausea and vomiting
Diarrhea
Abdominal pain
Hematemesis
Hematochezia, melena
Rice-water stools
Immediate
Immediate
Minutes
Minutes to hours
Minutes to hours
Minutes to hours
Hours
Hours
Hematopoietic
system
Hemolysis
Hematuria
Lymphopenia
Pancytopenia
Minutes to hours
Minutes to hours
Several weeks
Several weeks
Pulmonary
(primarily in
inhalational
exposures)
Cough
Dyspnea
Chest Pain
Pulmonary edema
Immediate
Minutes to hours
Minutes to hours
Minutes to hours
Liver
Jaundice
Fatty degeneration
Central necrosis
Days
Days
Days
Kidneys
Proteinuria
Hematuria
Acute renal failure
Hours to days
Hours to days
Hours to days
Palmer Keratosis
Biological Monitoring
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Urinary arsenic measurement
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Spot sample (mcg/L)
Timed urine collection (mcg/24 hours)
Normal values
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Spot urine= ~10 mcg/L (10-150 mcg/L)
24 hours urine collection=<25 mcg/24 hours
Whole blood= <1mcg/L (usually is elevated in acute
intoxication)
Biological Monitoring
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Ingestion of seafood may elevate urinary arsenic
levels
If urinary arsenic levels are high
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Ask the patient whether he ingested seafood in the last 72
hours
Speciation can be performed in several laboratories
Methylated derivatives determination in the urine. These
levels are not influenced by the presence of organic arsenic
from marine origin
Treatment of acute poisoning
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Gastric lavage
Activated charcoal does not bind well
inorganic arsenic
Whole bowel irrigation with
polyethylene glycol
Skin decontamination in dermal
exposure
Treatment of acute poisoning
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Supportive care
Chelation therapy should be instituted
promptly (minutes to hours)
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BAL (British anti-Lewisite)- IM
Succimer (DMSA)- PO
DMPS – PO, IV
D-Penicillamine- less effective
Cadmium
What is Cadmium?
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A metal most often encountered in earth’s crust combined with
chlorine (cadmium chloride), oxygen (cadmium oxide), or sulfur
(cadmium sulfide)
Exists as small particles in air, result of smelting, soldering or other
high temp. industrial processes
By-product of smelting of zinc, lead, copper ores
Used mainly in metal plating, producing
pigments, batteries, plastics and as a
neutron absorbent in nuclear reactors
Cadmium is used in batteries
Cadmium and Smelters/Mine
Sites
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Cadmium is a by-product of smelters
Has been a concern at the Summitville
mine site in Colorado
Photo of Smelter
Exposure Sources - Tobacco
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Tobacco smoke (a one pack a day smoker
absorbs roughly 5 to 10 times the amount
absorbed from the average daily diet)
Tobacco smoke is an
important source of
cadmium exposure
Exposure Sources – By Mouth
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Foods (only a small amount is absorbed)
Itai Itai disease (cadmium contamination + diet low in
calcium & vitamin D)
Cadmium a component of chuifong tokwan, sold illegally
as a miracle herb
Low levels are found in grains, cereals, leafy vegetables, and other basic
foodstuffs
Biologic Fate
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Cadmium has no known beneficial function in
the human body
Is transported in the blood bound to
metallothionein
Greatest concentrations found in kidneys & liver
Urinary excretion is slow
Biologic half-life may be up to 30 yrs.
Why Is Cadmium a Health
Hazard?
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Affects lungs & kidneys
2o effects on skeletal system
Binds to sulfhydryl groups, displacing other metals from
metalloenzymes, disrupting those enzymes
Competes with calcium for binding sites on regulatory
proteins
Lipid peroxidation has been demonstrated
Respiratory Effects
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Acute inhalation may mimic metal fume fever
Fever, chills & decreases in FVC and FEV1
Initial symptoms: flu-like symptoms
 Later: chest pain, cough, dyspnea
 Bronchospasm and hemoptysis may occur
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Chronic inhalation MAY result in impairment of
pulmonary function with reduction in ventilatory capacity
Renal Effects
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May cause tubular and glomerular damage
with resultant proteinuria
May follow chronic inhalation or ingestion
Latency period of ~10 yrs
Nephropathy is progressive & irreversible
Renal Effects
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Chronic exposure – progressive renal tubular
dysfunction
Toxic effects are dose related
Critical renal concentration
Decreased GFR
Chronic renal failure
Kidney stones more common
Skeletal Effects
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Bone lesions occur late in severe chronic
poisoning
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Pseudofractures
Other effects of osteomalacia and
osteoporosis
Appear to be secondary to increased urinary
calcium and phosphorus losses
Signs and Symptoms Acute
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Food poisoning (ingestion)
Bronchitis (inhalation)
Interstitial pneumonitis (inhalation)
Pulmonary edema (inhalation)
A condition that mimics metal fume fever
Children who eat dirt
(pica behavior) are at risk
Signs & Symptoms Chronic
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Chronic exposure may result in renal
dysfunction and bone disease
Mild anemia, anosmia & yellow
discoloration of the teeth may occur
Chronic exposure may effect
the sense of smell
Evaluation
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Inhalation
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Chest radiograph
Chronic exposure
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Renal tests
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Serum electrolytes, BUN, serum and urinary
creatinine, serum creatinine, cadmium in blood &
urine, urinary protein
Other tests – CBC & LFTs
Direct Biologic Indicators
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24 hour urine cadmium – reflects
exposure over time an total body
burden
Blood cadmium
Cadmium in hair – not reliable
No quantitative relationship between
hair cadmium levels and body burden
Indirect Biologic
Indicators
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Urinary ß2-microglobulin – evaluate urine
levels > 300 g/g creatinine
Urinary RBP
Urinary metallothionein (MT)
Treatment & Management
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Acute Exposure
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No proven treatment
 Supportive treatment includes fluid
replacement, oxygen, mechanical
ventilation. With ingestion, gastric
decontamination by emesis or
gastric lavage soon after exposure.
Activated charcoal not proven
effective
Chronic – Prevent further exposure
Mercury
Mercury
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Occurs in three forms (elemental,
inorganic salts, and organic compounds)
Contamination results from mining,
smelting, and industrial discharges.
Mercury in water can be converted by
bacteria to organic mercury (more toxic)
in fish.
Can also be found in thermometers,
dental amalgams, fluorescent light bulbs,
disc batteries, electrical switches, folk
remedies, chemistry sets and vaccines.
Mercury - Exposure
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Elemental
 liquid at room temperature that volatizes readily
 rapid distribution in body by vapor, poor in GI tract
Inorganic
 poorly absorbed in GI tract, but can be caustic
 dermal exposure has resulted in toxicity
Organic
 lipid soluble and well absorbed via GI, lungs and
skin
 can cross placenta and into breast milk
Elemental Mercury
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At high concentrations, vapor inhalation
produces acute necrotizing bronchitis,
pneumonitis, and death.
Long term exposure affects CNS.
 Early: insomnia, forgetfulness, anorexia,
mild tremor
 Late: progressive tremor and erethism (red
palms, emotional lability, and memory
impairment)
 Salivation, excessive sweating, renal toxicity
(proteinuria, or nephrotic syndrome)
Dental amalgams do not pose a health risk.
Inorganic Mercury
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Gastrointestinal ulceration or perforation
and hemorrhage are rapidly produced,
followed by circulatory collapse.
Breakdown of mucosal barriers leads to
increased absorption and distribution to
kidneys (proximal tubular necrosis and
anuria).
Acrodynia (Pink disease) usually from
dermal exposure
 maculopapular rash, swollen and
painful extremities, peripheral
neuropathy, hypertension, and renal
tubular dysfunction.
Organic Mercury
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Toxicity occurs with long term exposure and
effects the CNS.
 Signs progress from paresthesias to ataxia,
followed by generalized weakness, visual and
hearing impairment, tremor and muscle
spasticity, and then coma and death.
Teratogen with large chronic exposure
 Asymptomatic mothers with severely affected
infants
 Infants appeared normal at birth, but
psychomotor retardation, blindness, deafness,
and seizures developed over time.
Diagnosis and Treatment
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Dx made by history and physical and
lab analysis. Inorganic mercury can be
measured in 24 hour urine collection;
organic mercury is measured in whole
blood.
The most important and effective
treatment is to identify the source and
end the exposure
Chelating agents (DMSA) may enhance
inorganic mercury elimination.
Dimercaprol may increase mercury
concentration in the brain.
Mercury - Prevention
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Many mercury compounds are no longer sold in
the United States.
Elemental mercury spills:
 Roll onto a sheet of paper and place in
airtight container
 Use of a vacuum cleaner should be avoided
because it causes mercury to vaporize
(unless it is a Hg Vac)
 Consultation with environmental cleaning
company is advised with large spills.
State advisories on public limit or avoid
consumption of certain fish from specific bodies
of water.
Questions?