Heavy Metal Toxicity Scott Phillips, MD, FACP, FACMT, FAACT Marci Balge, RN, MSN, COHN-S Mercury...
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Transcript of Heavy Metal Toxicity Scott Phillips, MD, FACP, FACMT, FAACT Marci Balge, RN, MSN, COHN-S Mercury...
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?