heavy metal toxicitychanif.lecture.ub.ac.id/files/2019/09/heavy_metals_rev_tx.pdf · ‘heavy...
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Heavy Metal Toxicity
Scott Phillips, MD, FACP, FACMT, FAACT Marci 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 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
‘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
blood
urine
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-0 Copro
Protoporphyrin IX*
Heme Cytoch-C
Bilirubin + Fe
ALA-D
Pb
Pb
Pb
Ferro-C
4Fe++
ALA-S
Heme Oxidase (microsomal)
Pb
Glycine Succinyl-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 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
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 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
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
Cadmium
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 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
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?