HEAVY METAL POISONING LEAD

Introduction The use of lead in residential paint was banned in 1977

Metals pose a significant threat to health through low-level Lead-containing pigments still are used for outdoor paint products
environmental as well as occupational exposures. One indication of because of their bright colors and weather resistant properties.
their importance relative to other potential hazards is their ranking
Tetraethyl and tetramethyl lead are still used as additives in gasoline
by the U.S. Agency for Toxic Substances and Disease Registry, which
in several countries
maintains an updated list of all hazards present in toxic waste sites
according to their prevalence and the severity of their toxicity. The Sources of Exposure
first, second, third, and seventh hazards on the list are heavy metals:
lead, mercury, arsenic, and cadmium Oil and dust
Paint chips
Contaminated water
Parents lead-related occupation
Definitions
Folk remedies
Metals originally included only gold, silver, copper, iron, lead, Congenital exposure
and tin. Pica
o Dense, malleable, lustrous Developmental delay
o Conduct heat and electricity, cations
Toxicocokinetics and Toxicodynamics

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
Absorption:
Lungs: depends on size particle
GI: Adults: 20-30% Children: as much as 50% of dietary lead
o Inadequate intake of iron, calcium, and total calories
are associated with higher lead levels

Skin:
o Inorganic lead is not absorbed
o Organic lead is well absorbed

Lead is carried bound to the RBC

Pharmacokinetics and Pharmacodynamics

Distributed extensively throughout tissues: bone, teeth, liver,

lung, kidney, brain, and spleen.
HEAVY METAL o Body lead storage: bones- can constitute a source of
remobilization and continued toxicity after the
A metal having an atomic weight greater than sodium, a density exposure has ceased
greater than 5 g/cm3
Some notion of toxicity Lead crosses the BBB and concentrates in the gray matter Lead
Usually includes lead, cadmium and mercury crosses the placenta.
Many others may variably be added to list
Excretion:
Acute Single Exposure
o Kidneys. The excretion increases with increasing body
stores (30 g-200 g/day)
o Feces

Clinical Manifestation

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

DAYRIT JAMES S 1 PHAR404 Clinical Toxicology (Lecture)

Chronic and Long Term Toxicity- Pathophysiology Childhood Lead Poisoning

Lead has affinity for SH groups and is toxic to zinc-dependent Childhood lead poisoning is now defined as a blood lead level of
enzyme systems 10ug/dl
o Heme synthesis: hemoglobin, cytochromes
o Steroid metabolism and membrane integrity
o Interference in vitamin D synthesis in renal tubular cells
(conversion of 1-hydroxyvitamin D to 1,25-hydroxyvitamin
D)

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:
o Aggression
o Hyperactivity
o Antisocial behaviors
o Learning disability- impairment in memory, auditory
General Signs and Symptoms of Lead Toxicity processing, and visual-motor integration. The IQ is
normal. These effects has been demonstrated with
Irritability Motor neuropathy blood lead levels as low as 6 g/dl
Lethargy Encephalopathy
Paresthesis Cerebral edema Diagnosis
Myalgias Seizures
Evaluation of clinical symptoms and signs
Abdominal pain Coma
CBC
Tremor Severe abdominal cramping
Serum iron levels, TIBC, ferritin
Headache Epiphyseal lead lines in children
Abdominal radiographs (for recent ingestion of lead-containing
Vomiting (growth arrest)
material)
Weight loss Renal Failure
Whole blood lead level
Constipation Loss of libido
X-ray fluorescence (XRF)- to asses body burden

Range of Lead-induced Health Effects in Adults and Children 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

DAYRIT JAMES S 2 PHAR404 Clinical Toxicology (Lecture)

Chelation Therapy Toxicokinetics

Chelation Therapy BLL > 70 g/dl or encephalopathy T 1/2 of inorganic arsenic in the blood is 10 hrs and of organic
o Hospital admission arsenic is around 30 hours
o Administration of a parenteral chelator
2-4 weeks after the exposure ceases, most of the remaining
BLL > 45 g/dl oral chelator
arsenic in the body is found in keratin-rich tissues (nails, hair, and
BLL 25-45 g/dl if these levels persist despite environmental
skin)
intervention
Inorganic arsenic is converted to organic arsenic (biomethylation
to monomethyl arsonic- MMA or DMA) in the liver. This may
Management
represent a process of detoxification
The treatment for lead poisoning begins with removing the source of
Renally excreted (30-50% of inorganic arsenic is excreted in
lead e.g. renewing lead pipes. Lead should then be removed from the
about 3 days). Both forms are excreted depend on the acuteness
body using chelation therapy such as calcium edetate (EDTA), d-
of the exposure and dose
penicillamine or dimercaprol. Chelation therapy should be
accompanied by active hydration, and should be continued until the
lead excreted in the urine drops below a level of 500 mcg day. Pathophysiology

Trivalent forms:
o Bind to sulfhydryl groups leading to inhibition of enzymatic
ARSENIC systems
o Inhibit the Krebs cycle and oxidative phosporylation. These
Introduction
lead to inhibition of ATP production
Arsenic is common in the environment
Sources Pentavalent forms
Groundwater o Can replace the stable phosphate ester bond in ATP and
Arsenic containing mineral ores produce an arsenic ester stable bond which is not a high
Industrial processes energy bond
o Semiconductor manufacturing (gallium arsenide)
o Fossil fuels Endothelial damage, loss of capillary integrity, capillary leakage,
o Wood treated with arsenic preservatives volume loss, shock
o Metallurgy
Manifestations of acute arsenic poisoning
o Smelting (copper, zinc, lead) and refining of metals and
ores
o Glass manufacturing

Commercial products
o Wood preservatives
o Pesticides
o Herbicides
o Fungicides

Food
o Seafood and fish

Others
o Antiparasitic drugs
o 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

DAYRIT JAMES S 3 PHAR404 Clinical Toxicology (Lecture)

Biological Monitoring Cadmium and Smelters/Mine Sites

Urinary arsenic measurement Cadmium is a by-product of smelters

o Spot sample (mcg/L) Has been a concern at the Summitville mine site in Colorado
o Timed urine collection (mcg/24 hours)
Exposure Sources Tobacco
Normal values
o Spot urine= ~10 mcg/L (10-150 mcg/L) Tobacco smoke (a one pack a day smoker absorbs roughly 5 to
o 24 hours urine collection=<25 mcg/24 hours 10 times the amount absorbed from the average daily diet)
o Whole blood= <1mcg/L (usually is elevated in acute Tobacco smoke is an important source of cadmium exposure.
intoxication)
Exposure Sources By Mouth
Ingestion of seafood may elevate urinary arsenic levels
If urinary arsenic levels are high Foods (only a small amount is absorbed)
o Ask the patient whether he ingested seafood in the last 72 Itai Itai disease (cadmium contamination + diet low in calcium &
hours vitamin D)
o Speciation can be performed in several laboratories Cadmium a component of chuifong tokwan, sold illegally as a
o Methylated derivatives determination in the urine. These miracle herb
levels are not influenced by the presence of organic arsenic Low levels are found in grains, cereals, leafy vegetables, and
from marine origin other basic foodstuffs

Treatment of acute poisoning Biologic Fate

Gastric lavage Cadmium has no known beneficial function in the human body
Activated charcoal does not bind well inorganic arsenic Is transported in the blood bound to metallothionein
Whole bowel irrigation with polyethylene glycol Greatest concentrations found in kidneys & liver
Skin decontamination in dermal exposure Urinary excretion is slow
Supportive care Chelation therapy should be instituted promptly Biologic half-life may be up to 30 yrs.
(minutes to hours)
o BAL (British anti-Lewisite) IM Why Is Cadmium a Health Hazard?
o Succimer (DMSA) PO
o DMPS PO, IV Affects lungs & kidneys
o D-Penicillamine less effective 2o effects on skeletal system
Competes with calcium for binding sites on regulatory proteins
Lipid peroxidation has been demonstrated
Management
Binds to sulfhydryl groups, displacing other metals from
The main treatment for arsenic intoxication is using the chelating metalloenzymes, disrupting those enzymes
agent dimercaprol. Penicillamine is also used but is less effective at
promoting excretion. Respiratory Effects
Dimercapto-1-sulphonate (DMPS, Unithiol) has been successfully Acute inhalation may mimic metal fume fever
tried in some cases. o Fever, chills & decreases in FVC and FEV1
o Initial symptoms: flu-like symptoms
Patients may also need supportive treatment if they develop liver or
o Later: chest pain, cough, dyspnea
renal failure, or to correct electrolyte and fluid imbalance.
o Bronchospasm and hemoptysis may occur

Chronic inhalation MAY result in impairment of pulmonary

CADMIUM function with reduction in ventilatory capacity
What is Cadmium?
Renal Effects
A metal most often encountered in earths crust combined with
chlorine (cadmium chloride), oxygen (cadmium oxide), or sulfur May cause tubular & glomerular damage w resultant proteinuria
(cadmium sulfide) May follow chronic inhalation or ingestion
Latency period of ~10 yrs
Exists as small particles in air, result of smelting, soldering or other Nephropathy is progressive & irreversible
high temperature industrial processes Chronic exposure progressive renal tubular dysfunction
By-product of smelting of zinc, lead, copper ores Toxic effects are dose related
Critical renal concentration
Used mainly in metal plating, producing pigments, batteries, plastics Decreased GFR
and as a neutron absorbent in nuclear reactors Cadmium is used in Chronic renal failure
batteries Kidney stones more common

DAYRIT JAMES S 4 PHAR404 Clinical Toxicology (Lecture)

Skeletal Effects Supportive treatment includes fluid
replacement, oxygen, and mechanical
Bone lesions occur late in severe chronic poisoning ventilation. With ingestion, gastric
o Pseudofractures decontamination by emesis or gastric
o Other effects of osteomalacia and osteoporosis lavage soon after exposure. Activated
o Appear to be secondary to increased urinary calcium and charcoal not proven effective
phosphorus losses
Chronic Prevent further exposure
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 affect the sense of smell
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
Evaluation o Liquid at room temperature that volatizes readily
o Rapid distribution in body by vapor, poor in GI tract
Inhalation
o Chest radiograph Inorganic
o Poorly absorbed in GI tract, but can be caustic
Chronic exposure o Dermal exposure has resulted in toxicity
o Renal tests
o Serum electrolytes, BUN, serum and urinary Organic
creatinine, serum creatinine, cadmium in blood & o Lipid soluble and well absorbed via GI, lungs and skin
urine, urinary protein o Can cross placenta and into breast milk

Other tests CBC & LFTs

Elemental Mercury

Direct Biologic Indicators At high concentrations, vapor inhalation produces acute necrotizing
bronchitis, pneumonitis, and death.
24 hour urine cadmium reflects exposure over time an total
body burden Long term exposure affects CNS.
Blood cadmium Early: insomnia, forgetfulness, anorexia, mild tremor
Cadmium in hair not reliable Late: progressive tremor and erethism (red palms, emotional
o No quantitative relationship between hair cadmium levels lability, and memory impairment)
and body burden Salivation, excessive sweating, renal toxicity (proteinuria, or
nephrotic syndrome)
Dental amalgams do not pose a health risk
Indirect Biologic Indicators

Urinary 2 -microglobulin evaluate urine levels > 300 g/g Inorganic Mercury
creatinine
Urinary RBP Gastrointestinal ulceration or perforation and hemorrhage are rapidly
Urinary metallothionein (MT) produced, followed by circulatory collapse.

Breakdown of mucosal barriers leads to increased absorption and

Treatment & Management distribution to kidneys (proximal tubular necrosis and anuria).

Acute Exposure Acrodynia (Pink disease) usually from dermal exposure

o No proven treatment o maculopapular rash, swollen and painful extremities, peripheral
neuropathy, hypertension, and renal tubular dysfunction.

DAYRIT JAMES S 5 PHAR404 Clinical Toxicology (Lecture)

Organic Mercury

Toxicity occurs with long term exposure and effects the CNS.
o 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

o Asymptomatic mothers with severely affected infants
o 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:

o Roll onto a sheet of paper and place in airtight container
o Use of a vacuum cleaner should be avoided because it
causes mercury to vaporize (unless it is a Hg Vac)
o 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.

Management

Inhalation of mercury should be treated with IV hydrocortisone to

minimise pulmonary complications. Acute intakes of inorganic
mercury should be treated with chelating agents such as dimercaprol
or d- penicillamin . Organic mercury poisoning should not be treated
with dimercaprol as this may result in higher mercury levels in the
brain.

DAYRIT JAMES S 6 PHAR404 Clinical Toxicology (Lecture)