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Heavy Metal Toxicity IBE OBIANUJU RAPHEAL GROUP 503


Definitions

  • A heavy metal is one with relatively high density (specific gravity greater than about 5) or of high relative atomic weight

  • ‘Metals’ originally included only gold, silver, copper, iron, lead, and tin.

    • Dense, malleable, lustrous
    • Conduct heat and electricity, captions'
  • Many other elements since has been added to the list with some of these characteristics

  • ‘Metalloids’ are elements with features intermediate between metals and non-metals. Example: arsenic

  • Transition metals, lanthanides, and actinides.





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


Toxicocokinetics and Toxicodynamics

  • 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


Pharmacokinetics and Pharmacodynamics

  • 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 (30g-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)


General Signs and Symptoms of Lead Toxicity

  • Fatigue

  • Irritability

  • Lethargy

  • Paresthesis

  • Myalgias

  • Abdominal pain

  • Tremor

  • Headache

  • Vomiting

  • Weight loss

  • Constipation

  • Loss of libido



The average lead level of American children is 2 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 cases, 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 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











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 and Smelters/Mine Sites

  • Cadmium is a by-product of smelters

  • Has been a concern at the Summitville mine site in Colorado



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)


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


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



Signs & Symptoms - Chronic

  • Chronic exposure may result in renal dysfunction and bone disease

  • Mild anemia, anosmia & yellow discoloration of the teeth may occur



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


Direct Biologic Indicators

  • 24 hour urine cadmium – reflects exposure over time an total body burden

  • Blood cadmium

  • Cadmium in hair – not reliable



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 Exposure

  • Treat renal failure ( renal dialysis)

  • 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.
  • Teratogenic with large chronic exposure

    • Asymptomatic mothers can severely affect 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.

  • Alpha-lipoic acid (ALA) in acute mercury intoxication.

  • D-penicillamine

  • 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.