Heavy Metal Toxicity

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Heavy Metal Toxicity

• Scott Phillips, MD, FACP, FACMT, FAACT
• Marci Balge, RN, MSN, COHN-S

Arsenic
Mercury
Lead
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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
forToxic 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,[phone].
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Definitions

• Metals originally included only gold, silver,
  copper, iron, lead, and tin.
• 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

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Periodic Table
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Heavy metal

• 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

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• Acute single exposures

urine
blood
Metal levels
time
exposure
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Case Presentation

• 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.

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Case (cont)

• 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?

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Azarcon

• Azarcon is a folk remedy that contains 85-96
  lead tetroxide
• Other lead containing remedies include Greta.

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Case (cont.)

• The child was found to have a blood lead level of
  124 ug/dl., and died from lead encephalopathy.

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Lead
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Lead Paint

• 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

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Sources of Exposure

• Soil and dust
• Paint chips
• Contaminated water
• Parents lead-related occupation
• Folk remedies
• Congenital exposure

• Pica
• Developmental delay

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Toxicocokinetics and Toxicoynamics

• Absorption
• Lungs depends on size particle
• GI
• 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
• Skin
• Inorganic lead is not absorbed
• Organic lead is well absorbed
• Lead is carried bound to the RBC

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Pharmacokinetics and Pharmacoynamics

• 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
• Kidneys. The excretion increases with increasing
  body stores (30?g-200 ?g/day)
• Feces

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Clinical Manifestation

• Acute toxicity
• Acute encephalopathy, renal failure and severe GI
  symptoms

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Chronic and Long Term Toxicity- Pathophysiology

• Lead has affinity for SH groups and is toxic to
  zinc-dependent enzyme systems
• 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)

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ALA- aminolevulinic acid ? in plasma and urine
COPRO- coprorphyrinogen ? in urine
Protoporphyrin ? accumulates in the RBC
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General Signs and Symptoms of Lead Toxicity

• Fatigue
• Irritability
• Lethargy
• Paresthesis
• Myalgias
• Abdominal pain
• Tremor
• Headache
• Vomiting
• Weight loss
• Constipation
• Loss of libido

• Motor neuropathy
• Encephalopathy
• Cerebral edema
• Seizures
• Coma
• Severe abdominal cramping
• Epiphyseal lead lines in children (growth arrest)
• Renal failure

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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
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Childhood Lead Poisoning

• 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

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Neurotoxicity of Lead in Childhood

• 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
• 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

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Diagnosis

• Evaluation of clinical symptoms and signs
• CBC
• Serum iron levels, TIBC, ferritin
• Abdominal radiographs (for recent ingestion of
  lead-containing material)
• Whole blood lead level
• X-ray fluorescence (XRF)- to asses body burden

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Treatment

• Environmental inspection/hazard reduction
• Nutritional supplementation
• Chelation therapy

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Nutritional Supplementation

• Iron supplementation
• Calcium supplementation calcium rich foods
• Phosphorus supplementation
• Frequent food consumption- regular meals snacks

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Chelation Therapy

• BLL gt 70 ?g/dl or encephalopathy
• Hospital admission
• Administration of a parenteral chelator
• BLL gt 45 ?g/dl- oral chelator
• BLL 25-45 ?g/dl- if these levels persist despite
  environmental intervention

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Arsenic
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Introduction

• Arsenic is common in the environment
• Sources
• Groundwater
• Arsenic containing mineral ores
• Industrial processes
• Semiconductor manufacturing (gallium arsenide)
• Fossil fuels
• Wood treated with arsenic preservatives
• Metallurgy
• Smelting (copper, zinc, lead) and refining of
  metals and ores
• Glass manufacturing

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Introduction

• Commercial products
• Wood preservatives
• Pesticides
• Herbicides
• Fungicides
• Food
• Seafood and fish
• Others
• Antiparasitic drugs
• Folk remedies

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Soil Pica

• 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

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Toxicokinetics

• 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)

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Toxicokinetics

• 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

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Pathophysiology

• Trivalent forms
• bind to sulfhydryl groups leading to inhibition
  of enzymatic systems
• inhibit the Krebs cycle and oxidative
  phosporylation. These lead to inhibition of ATP
  production
• Pentavalent forms
• 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

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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
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Palmer Keratosis
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Biological Monitoring

• Urinary arsenic measurement
• Spot sample (mcg/L)
• Timed urine collection (mcg/24 hours)
• Normal values
• Spot urine 10 mcg/L (10-150 mcg/L)
• 24 hours urine collectionlt25 mcg/24 hours
• Whole blood lt1mcg/L (usually is elevated in
  acute intoxication)

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Biological Monitoring

• Ingestion of seafood may elevate urinary arsenic
  levels
• If urinary arsenic levels are high
• 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

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Treatment of acute poisoning

• Gastric lavage
• Activated charcoal does not bind well inorganic
  arsenic
• Whole bowel irrigation with polyethylene glycol
• Skin decontamination in dermal exposure

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Treatment of acute poisoning

• Supportive care
• Chelation therapy should be instituted promptly
  (minutes to hours)
• BAL (British anti-Lewisite)- IM
• Succimer (DMSA)- PO
• DMPS PO, IV
• D-Penicillamine- less effective

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Cadmium
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What is Cadmium?

• A metal most often encountered in earths 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
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Cadmium and Smelters/Mine Sites

• Cadmium is a by-product of smelters
• Has been a concern at the Summitville mine site
  in Colorado

Photo of Smelter
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Exposure Sources - Tobacco

• 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
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Exposure Sources By Mouth

• 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
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Biologic Fate

• 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.

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Why Is Cadmium a Health Hazard?

• 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

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Respiratory Effects

• 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
• Chronic inhalation MAY result in impairment of
  pulmonary function with reduction in ventilatory
  capacity

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Renal Effects

• May cause tubular and glomerular damage with
  resultant proteinuria
• May follow chronic inhalation or ingestion
• Latency period of 10 yrs
• Nephropathy is progressive irreversible

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Renal Effects

• Chronic exposure progressive renal tubular
  dysfunction
• Toxic effects are dose related
• Critical renal concentration
• Decreased GFR
• Chronic renal failure
• Kidney stones more common

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Skeletal Effects

• Bone lesions occur late in severe chronic
  poisoning
• Pseudofractures
• Other effects of osteomalacia and osteoporosis
• Appear to be secondary to increased urinary
  calcium and phosphorus losses

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Signs and Symptoms - Acute

• 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
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Signs Symptoms - Chronic

• 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
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Evaluation

• Inhalation
• Chest radiograph
• Chronic exposure
• Renal tests
• Serum electrolytes, BUN, serum and urinary
  creatinine, serum creatinine, cadmium in blood
  urine, urinary protein
• Other tests CBC LFTs

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Direct Biologic Indicators

• 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
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Indirect Biologic Indicators

• Urinary ß2-microglobulin evaluate urine levels
  gt 300 ?g/g creatinine
• Urinary RBP
• Urinary metallothionein (MT)

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Treatment Management

• Acute Exposure
• 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

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Mercury
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Mercury

• 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.

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Mercury - Exposure

• 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

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Elemental Mercury

• 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.

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Inorganic Mercury

• 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.

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Organic Mercury

• 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.

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Diagnosis and Treatment

• 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.

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Mercury - Prevention

• 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.

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Questions?