heavy metal toxicity dr tajdar husain khan mercury arsenic lead
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Heavy Metal Toxicity
Dr Tajdar Husain Khan
Mercury
Arsenic
Lead
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
‘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
Lead
Soft blue-gray metal Found in the
natural environment Was added to paint
and gasoline in past Still used in
consumer products
What is Lead?What is Lead?
the natural ore galena
How Does Lead Get Into the Environment?How Does Lead Get Into the Environment?
Deterioration of lead-based paint
Leaded gasoline Businesses that
involve lead Lead mines or
smelters
How Are People Exposed to Lead?How Are People Exposed to Lead?
Dust, paint, and/or soil Contaminated food,
water, or alcohol Some imported home
remedies and cosmetics
Endogenous exposure
Lead in Ethnic ProductsLead in Ethnic Products
Mexican: azarcon,greta, liga, Maria Luisa, alarcon, coral, rueda
Asian: chuifong, tokuwan, ghasard, bali goli, kandu,surma, ba-baw-san
Middle Eastern: alkohl, saoott, cebagin
For more examples, see Appendix 1 of: http://www.cdc.gov/nceh/lead/CaseManagement
Azarcon
Azarcon is a folk remedy that contains 85-96% lead tetroxide
Other lead containing remedies include Greta.
Pb Toxicity to Plants, Animals From air, soil, lead shot Dependent on species
Ex: barley sensitive Ex: goldfish insensitive
May inhibit seed germination Paralyzes bird gizzard starvation,
death Impt: ingestion by animals further up
food chain
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Lead Poisoning
Lead has no known biological function. There is no proven safe lower limit for lead. Lead Pb++, competes with Ca++, Fe++
It is cheap, useful,easy to mine, therefore Lead is ubiquitous- in air, food, water, soil,
ceilings etc. Leaded petrol means that all environmental
dusts are high in lead-contaminating ceiling dust, topsoil, window wells etc.
Biologic FateBiologic Fate
Most lead is excreted Children and pregnant
women absorb morelead than others
Exchanged betweenblood, soft tissues,and mineralizingtissues
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Distribution of Lead 95% long bones. Binds into matrix. Released during
osteolysis. 4% brain,liver,
kidneys. 1% blood. Crosses placenta,
foetal BBB is open
Neurologic Effects of LeadNeurologic Effects of Lead
Neurologic effects onchildren documentedat levels below 10 mcg/dL
Low exposure effects:lowered IQ, attention deficits,and impaired hearing
High exposure effects:irritability, convulsions, coma, or death
Similar effects in adults at higherexposure levels
Renal Effects of LeadRenal Effects of Lead
Acute exposure: reversible effects
Chronic exposure: nephropathy (chronic interstitial nephritis)
Childhood exposures → adult renal disease
Hematologic Effects of LeadHematologic Effects of Lead
Interferes with production of hemoglobin
Can induce two kinds of anemia: Acute exposure → hemolytic Chronic exposure → synthetic
Threshold for adults: 50 mcg/dL Threshold for children: 40 mcg/dL
Pb Toxicity within Cells
Not fully known Highly reactive to –SH grps
Mercaptide R—S—Pb—S—R
Can inactivate enz’s, other prot’s Book ex: adenyl cylase (brain
transmission) Book ex: aminotransferase (aa metab)
Similar to Ca, competes At presyn. receptor
Now decr’d Ca avail Bone
Interacts w/ nucleic acids Decr’s protein synth
Decr’d binding tRNA to ribosomes OR may increase protine synth
Nucleus
Ex: Pb best studied Renal tubule DNA, RNA, prot syntheses
stim’d So biochem changes in nuclear structure,
function Karyomegaly Can renal adenocarcinoma w/ high dose
Ex: Methyl-Hg, Cd inhibit nucleic acid synth w/ acute exposure
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Toxicology of Lead 1
Lead disrupts the main structural components of the
blood-brain barrier by primary injury to astrocytes
with a secondary damage to the endothelial
microvasculature. Within the brain, lead-induced
damage occurs preferentially in the prefrontal
cerebral cortex, hippocampus and cerebellum.
Some characteristic clinical features of lead
poisoning may be attributed to this specific
anatomical pattern.
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Toxicology of Lead contd Although the molecular targets for lead are unknown, a vast
amount of evidence accumulated over many years has shown
that lead disrupts processes that are regulated by calcium.
Picomolar concentrations of lead can replace micromolar
concentrations of calcium in a protein kinase C enzyme assay.
Furthermore, lead activates protein kinase C in intact cells and
induces the expression of new genes by a mechanism dependent
on protein kinase C. We propose that the learning deficits caused
by lead are due to events regulated by protein kinase C that most
likely occur at the synapse.
Bressler J, Kim KA, Chakraborti T, Goldstein GMolecular
mechanisms of lead neurotoxicity. Neurochem Res 1999
Apr;24(4):595-600
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Toxicology of Lead 3
The cellular, intracellular and molecular mechanisms of
lead neurotoxicity are numerous, as lead impacts
many biological activities at different levels of
control: at the voltage-gated channels and on the
first, second and third messenger systems. These
effects could be related to lead's ability to interfere
with the regulatory action of calcium in cell functions.
Finkelstein Y, Markowitz ME, Rosen JF Low-
level lead-induced neurotoxicity in children: an
update on central nervous system effects Brain
Res Brain Res Rev 1998 Jul;27(2):168-76
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
Signs and SymptomsSigns and Symptoms
Patient may appear asymptomatic Impaired abilities may include
Decreased learning and memory Lowered IQ Decreased verbal ability Impaired speech and hearing functions Early signs of hyperactivity or ADHD
Symptoms vary by exposure level
Signs and Symptoms: Low ToxicitySigns and Symptoms: Low Toxicity
Myalgia or paresthesia Mild fatigue Irritability Lethargy Occasional abdominal discomfort
Signs and Symptoms: Moderate ToxicitySigns and Symptoms: Moderate Toxicity
Arthralgia General fatigue Difficulty concentrating/Muscular
exhaustibility Tremor Headache Diffuse abdominal pain Vomiting Weight loss Constipation
Signs and Symptoms: Severe ToxicitySigns and Symptoms: Severe Toxicity
Paresis or paralysis Encephalopathy—may abruptly
lead to seizures, changes in consciousness, coma, and death
Lead line (blue-black) on gingival tissue
Colic (intermittent, severe abdominal cramps)
Long bone radiographsLong bone radiographs
Lead Lines
Lead Lines
“Lead Lines” in five year old male with radiological growth retardation and blood lead level of 37.7µg/dl
(Photo courtesy of Dr. Celsa López Campos, Clinical Epidemiologic Research Unit, IMSS, Torreón, México)
Clinical ManagementClinical Management Most important step is removal of
lead exposure Referral to health department Environmental Investigations Other potential sources of lead Education about prevention
Chelation TherapyChelation Therapy
At very high blood lead levels (over 40 mcg/dL for children), chelation may be indicated
Consult with physicians or medical centers with chelation therapy experience
Instructions to PatientsInstructions to Patients
• Reduce source(s) of lead exposure• Maintain a diet high in calcium and
iron• Continue to monitor blood lead levels• If workplace exposure suspected,
contact: Workplace health and safety officer Occupational Safety and Health
Administration (OSHA)
SummarySummary
Primary sources: deteriorated paint, contaminated dust or soil, and some products
Lead is very dangerous to young children and the developing fetus
Certain workers may be exposed Focus on preventing exposure/removing
source
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
What contains Arsenic?• Arsenic was detected in fruits, vegetables,
grain products, fast foods, dairy products, BUT mostly seafoods
– Arthropods (shrimp)– Fish– Bivalves (clams)– Algae
• Arsenic concentration for all seafoods in fast food sandwiches was 2.1 μg/g (dry weight). (Nielson et al. 1991)
• Average intake is about 10–50 µg/day (humans)
– More if seafood is consumed
Arsenic into the Body• Arsenite is more toxic than
arsenateArsenite (0) accumulation in cells is faster than arsenate (-).
It can pass through the cell membrane, but also actively transported into cells
Arsenite = aquaglycoporins 7 and 9 Which also transports water and glycerol
Arsenate = phosphate transporter
• Metabolized by methylationThen excreted in the urine. Methylation occurs in liver, kidney and lungs.
More on MethylationReduce arsenite (via purine nucleoside phosphorylase) to arsenate then methylation (via enzymatic transfer of the methyl group from S-adenosylmethionine (SAM) to arsenite to form monomethylarsonic acid (MMAV) )
Gene that codes for the enzyme responsible for this reaction is just like Cyt 19arsenite+SAM→MMAVMMAV+thiol→MMAIIIMMAIII+SAM→DMAVDMAV+thiol→DMAIIIDMA III = Dimethylarsinous Acid
• Most humans exposed to arsenic excrete 10–30% inorganic arsenic, 10–20% MMA(V+III) and 60–80% DMA(V+III),
Bound to red blood cellsDistributes to liver Binds to sulfhydryl containing
proteins - concentrates in the hair and fingernails (Mees’ Lines)
Distribution
As5+ (Arsenate)
As3+ (Arsenite)
Methylarsenite (in liver)
Dimethylarsenite
(readily eliminated – urine)
Metabolism
3-5 days Excreted: Urine (majority);Skin cells ;SweatT1/2 of inorganic arsenic in the blood is 10 hrs and of organic
arsenic is around 30 hours2-4 weeks after the exposure ceases, most of the remaining
arsenic in the body is found in keratin-rich tissues (nails, hair, skin)
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
ToxicokineticsHALF-LIFE
Inorganic arsenic (arsenic trioxide) 70 to 180 mg can be fatal
Constriction of the throat with difficulty in swallowing
Sever intestinal pain Vomiting, diarrhea Muscle cramps Severe thirst Coma and death
Acute - Toxicity
Chronic exposure (drinking water)• Skin cancer (recognized 100 years ago)• Garlic odor on breath• Excessive perspiration • Muscle tenderness and weakness• Changes in skin pigmentation• Paresthesia in hands and feet • Peripheral vascular disease• Gangrene of feet – Blackfoot disease
Chronic - Toxicity
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
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
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 - Cd
No constructive purpose in the body Extremely toxic even in low concentrations, accumulates in organisms and ecosystems Chemical properties similar to zinc – exchange
in an organism (also can replace Cu, Fe, Ca) Sources: earth crust, fossil fuels, plastic
materials industry, electronic industry, tobacco fume
Absorption after ingestion (1-5%) or by inhalation (better bioavailability)
The first documented case of mass cadmium poisoning in the world - in Toyama Prefecture, Japan in 1950 – Itai-Itai disease (river polluted with waste from factory, water used on rice fields – poisoning from rice)
- In blood transported bound to proteins (formation of complexes), in higher concentrations bound to erythrocytes
- Deposition in liver, kidneys and gonads. Slow excretion (up to 10 years). Does not go to milk and to foetus.
Mechanism of action:- Inhibition of many enzymes, antagonist to
many metals – Zn, Cu, Ca, Fe- Disturbance of cholecalciferol (vit. D)
production, thus influences Ca metabolism- Inhibition of a specific testis hydrolase –
affects activity of gonads- Xenoestrogennic element- Formation of complexes, which are digested
in kidney – release of Cd - damage
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 Tobacco smoke (a one pack a day smoker absorbs roughly
5 to 10 times the amount absorbed from the average daily diet)
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
High Affinity Metal Binding Proteins
In cytosol Intracellular “sinks”
Hold toxic metals away from Sensitive organelles Metabolic sites
Overwhelmed w/ very high metal exposure
Cd Toxicity within Cells Energy prod’n
Chloroplast photophosph’n Mitochondria ATP synth, NADH ox’n,
electron transport Enzyme inhib’n
Book ex: alkaline phosphatase, myosin ATPases
Binds –SH grps Competes w/, displaces Zn
Mitochondria Major intracell
target of many metals Rapid transport
metals across mitoch membr’s
Has high metab activity
Sensitive to disruption
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
Biologic Indicators 24 hour urine cadmium – reflects exposure over time an total body burdenBlood cadmiumCadmium in hair – not reliableUrinary ß2-microglobulin – evaluate urine levels > 300 g/g creatinine Urinary RBPUrinary metallothionein (MT)
No quantitative relationship between hair cadmium levels and body burden
Direct
Indirect
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.
Hg Toxicity within Cells Inhib’n enzymes
Selective affinity to –SH grps R—SH + CH3Hg R—S—Hg—CH3 +
H+ Incr’s permeability Na+, K+
Inhibits active transport mech’s Disrupts fluid/electrolyte balance
Affects chromosomes, mitosis mutagenesis
Protection against Hg Toxicity Metallothionein
Kidney damage when metallothionein saturated
Se Mech unknown, but Se binds cysteine
more tightly than Hg Vitamin E
Mech unknown
Cellular Injuries
Dependent on individual physiological factors Developmental stage Sex Nutritional status Toxicant dose Toxicant combination
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 Controlling mercury compounds in market 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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