Heavy Metal Toxicity

Scott Phillips, MD, FACP, FACMT, FAACTMarci Balge, RN, MSN, COHN-S

Mercury

Arsenic

Lead

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,(210)567-7407.

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

Periodic Table

‘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

Acute single exposures

bloodurine

time

Metal levels

exposure

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.

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?

Azarcon

Azarcon is a folk remedy that contains 85-96% lead tetroxide

Other lead containing remedies include Greta.

Case (cont.)

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

Lead

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

Sources of Exposure Soil and dust Paint chips Contaminated

water Parents lead-

related occupation Folk remedies Congenital

exposure

Pica Developmental

delay

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

Pharmacokinetics and Pharmacoynamics

Distributed extensively throughout tissues: bone, teeth, liver, lung, kidney, brain, and spleen

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 (30g-200 g/day)

Feces

Clinical Manifestation

Acute toxicity Acute encephalopathy, renal failure

and severe GI symptoms

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)

Mitochondrion

Copro* Uropor PBG

ALA*Copro-0Copro

Protoporphyrin IX*

Heme Cytoch-C

Bilirubin+Fe

ALA-D

Pb

Pb

Pb

Ferro-C4Fe++

ALA-S

Heme Oxidase(microsomal)

Pb

GlycineSuccinyl-Coa

Pb

ALA- aminolevulinic acid in plasma and urine COPRO- coprorphyrinogen in urine Protoporphyrin accumulates in the RBC

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

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 synthesisIncreased 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

Range of Lead-induced Health Effects in Adults and Children

Childhood Lead Poisoning

Childhood lead poisoning is now defined as a blood lead level of 10 g/dl

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 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

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

Treatment

Environmental inspection/hazard reduction

Nutritional supplementation Chelation therapy

Nutritional Supplementation

Iron supplementation Calcium supplementation – calcium

rich foods Phosphorus supplementation Frequent food consumption-

regular meals + snacks

Chelation Therapy

BLL > 70 g/dl or encephalopathy 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 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

Introduction Commercial products

Wood preservatives Pesticides Herbicides Fungicides

Food Seafood and fish

Others Antiparasitic drugs Folk remedies

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

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)

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

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

Bodily system affected

Symptoms or signs

Time of onset

Systemic ThirstHypovolemia, Hypotension

MinutesMinutes to hours

Gastrointestinal Garlic or metallic tasteBurning mucosaNausea and vomitingDiarrheaAbdominal painHematemesisHematochezia, melenaRice-water stools

ImmediateImmediateMinutesMinutes to hoursMinutes to hoursMinutes to hoursHoursHours

Hematopoietic system

HemolysisHematuriaLymphopeniaPancytopenia

Minutes to hoursMinutes to hoursSeveral weeksSeveral weeks

Pulmonary (primarily in inhalational exposures)

CoughDyspneaChest PainPulmonary edema

ImmediateMinutes to hoursMinutes to hoursMinutes to hours

Liver JaundiceFatty degenerationCentral necrosis

DaysDaysDays

Kidneys ProteinuriaHematuriaAcute renal failure

Hours to daysHours to daysHours to days

Manifestations of acute arsenic poisoning

Palmer Keratosis

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 collection=<25 mcg/24 hours Whole blood= <1mcg/L (usually is elevated in acute

intoxication)

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

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

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

CadmiumCadmium

What is Cadmium? 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 Cadmium is a by-product of smelters Has been a concern at the

Summitville mine site in Colorado

Photo of Smelter

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

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

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.

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

Respiratory Effects Acute inhalation may mimic metal fume fever

Fever, chills & decreases in FVC and FEV1Initial 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

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

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

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

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

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

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

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

Indirect Biologic Indicators

Urinary ß2-microglobulin – evaluate urine levels > 300 g/g creatinine

Urinary RBP Urinary metallothionein (MT)

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

Mercury

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.

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

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.

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.

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.

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.

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.

Questions?