Heavy Metal Poisonings

• High density naturally occurring elements
• Metals vs Metalloids
• Environmental and human toxicity
• Acute or Chronic exposure

• Human exposure:
• Inhalation
• Ingestion
• Skin contact

• Atomic number = 82
• Atomic weight = 207.21 Da
• Whole blood = < 5 mcg/dL (0.24 mmol/L)

common occupational practice

• Inorganic Lead
• Brightly colored & variable solubility
• Paints
• Lead chromate (yellow)
• Lead oxide (red)

• Organic Lead
• Gasoline additives (tetraymethyl & tetraethyl lead)
• Complexes with several ligands common to biologic molecules, including –OH, -
SH, and NH2
• No known physiologic role

Environmental
• Lead paint (especially pre-1978 homes)
• Leaded gasoline
• Lead plumbing (pipes)
• Dietary supplements
• Moonshine

Occupational
• Metal welders
• Painters
• Automobile factory workers
• Plastics manufacturing
• Plumbers

Gastrointestinal = 10 - 15 %

Inhaled = 30 - 40 %

Cutaneous through intact skin = 0.06%

99% bound to erythrocytes

Tissue distribution results in majority of toxicity - Accumulation throughout life

5% distributed to major lead storage sites $\rightarrow$ Liver, Kidney, Bone marrow, Brain

95% of lead burden is stored in the bones

Increased GI absorption
• 40-50% vs 10-15%

Greater volume of inhaled air per body size
• 2.7-fold higher lung deposition rate

Thinner skin →Increased cutaneous absorption

Rapidly crosses the placental barrier

Bone lead burden
• 70% vs 95% in adults

• Identifies children with higher levels of lead in their blood compared to most children
•1960: >60 mcg/dL
•1978: >30 mcg/dL
•1985: >25 mcg/dL
•2012: >5 mcg/dL
•TODAY (as of May 2021): >3.5 mcg/dL

• Binds and impact numerous enzymatic, receptor, and structural proteins
• Interferes with metabolic pathways in mitochondria and in second-messenger systems regulating cellular energy metabolism
• Affects nucleic acids
• Alteration of DNA methylation

• Blockade of calcium influx at voltage-sensitivecalcium channels
• Neurotransmitter release, receptor activity, and intracellular signaling
• Adversely affect ”synaptic pruning”
• Adverse protein conformational affects
• Associated with Alzheimer's and Parkinson’s
• Cerebral edema
• Memory & learning deficits

Acute
• Encephalopathy
• Seizures
• AMS
• Ataxia
• Optic neuritis

Chronic
• Headache
• Irritability
• Depression
• Fatigue
• Memory deficit
• Sleep disturbance

• Inhibition of enzymes in heme biosynthetic pathway
• Kidney injury → decreased erythropoietin
• Increased membrane fragility → shortened erythrocyte life span

• Occur more frequently with acute poisoning

• Iron deficiency
• Acts synergistically to toxicity, may increase GI lead absorption

• Signs and Symptoms
• Lead induced anemia/hemolytic anemia

• Inhibition of new bone formation
• Growth stunting
• “Lead lines”
• Altered calcium flux and synaptic
transmission

• Signs and symptoms
• Peripheral neuropathy
• ”Lead palsy”
• Wrist and foot drop

• GI toxicity
• Constipation, vomiting,severe abdominal pain
• “Lead colic” at levels >80 mcg/dL

• Cardiotoxicity
• Hypertension–altered calciumconduction
• Direct cardiotoxicity rare

• Nephrotoxicity
• Acuterenal tubular necrosis

• Reproductive toxicity
• Infertility, reduced sperm count
• Premature births
• >40 mcg/dL leadconcentration

• Detailed Exposure History
• Occupational, environmental, travel-related, recreational

• Definitive diagnosis
• Blood lead level (results may take days)

• CBC (anemia)

• X-ray
• Ingested lead containing particles/objects
• Lead lines

• Children
• Assess for PICA
• Consider diagnosis in all patients presenting with acute encephalopathy

• Removal of exposure from lead

Consult Medical Toxicologist/PoisonControl
• Imaging (X-ray)

Depends on:
• Age
• Blood level concentration
• Clinical presentation

GI decontamination
• Imaging shows foreign bodies
• Whole-bowel irrigation (polyethylene glycol)

Chelation
• Forms complexes with lead, increases urinary lead excretion and reduces blood concentrations
• **Start ASAP in symptomatic patients with known exposure, do not wait for lab confirmation**

Acute encephalopathy (seizures)
• Benzodiazepines

• Indicated when neurotoxicity or high blood levels
present
• Crosses the blood brain barrier

• Sulfhydryl group forms nontoxic soluble chelates excreted in urine

• Caution in:
• Hepatic dysfunction, G6PD deficiency

• Oil based (peanut)
• Contraindicated in peanut allergies

• Dosing:
• Children: 75 mg/m2 IM injection q4h x 3-5 days
• Adults: 4 mg/kg IM q4h x 3-5 days

• Binds Lead to displace calcium forming a stable ring compound
• Bone is primary source of chelation
• Used in conjunction with Dimercaprol for Lead > 100 mcg/dL
• Used alone for Lead 45 - 70 mcg/dL
• Monitor renal function

• Dosing:
• 1,000 – 1,500 mg/m2/day continuous IV infusion for 5 days
• Given 4 hours after dimercaprol – prevents redistribution of lead to the CNS
• May limit or reduce dose to minimize nephrotoxicity

• Two-drug regimen resulted in a more rapid decline in blood lead concentration and greater urinary lead excretion
• Dimercaprol – higher lipophilicity, mobilized lead and shifted it extracellularly
• Calcium EDTA – more stable chelate can then be formed

• FDA approved oral metal chelator
• Blood levels > 45 mcg/dL

• Prevents deleterious effect of lead on heme synthesis, blood pressure, and behavior

• Most common adverse events = GI
• Less common = LFT elevation, neutropenia, rash

• Outpatient →Patient still at risk for lead exposure

• Dosing:
• 700 – 1,050 mg/m2/day
• 10 mg/kg (350 mg/m2 in children) PO q8h x 5 days, then 10 mg/kg PO q12h x 2 weeks
• 19 days total therapy

• ***Only recommended when unacceptable adverse reactions to both succimer and CaNa2EDTA occur or are unavailable***
• High side effect profile
• Life-threatening hematologic disorders and dermatologic/ renal adverse effects

• Much less effective than other treatments

• Dosing:
• Optimal dose not defined
• 25-40 mg/kg/day for 4-12 weeks
depending on urine lead concentration

• Atomic number = 33
• Atomic weight = 74.92 Da

• Normal concentrations:
• Whole blood = < 5 mcg/mL (0.067 umol/L)
• Urine (24-hour) = < 50 mcg/L (0.67 umol/L
• < 100 mcg/g creatinine(1.33 umol/g creatinine)

Contaminated soil, water, and food are the primary sources of arsenic for the general population.

Primarily environmental and occupational
• Animal feed
• Computer chips (semiconductors)
• Herbicides/insecticides
• Smelting
• Wood preservatives

Medications
• Herbals/alternative medicines
• Chemotherapeutics

Other
• Moonshine
• Well Water (contaminated)

Tasteless and odorless

Absorbed in the GI tract, respiratory, IV, and mucosal routes
• GI ~ 70% absorbed
• Respiratory – depends on particulate size, compound, and solubility
• Dermal – no toxicity for acute, potential for chronic

Dissolved As2O3 is more toxic than eaten As2O3
• Greater than 90% bioavailability

Cleared from the body in 3 phases

• Inhibits pyruvate dehydrogenase complex
• Decreased citric acid cycle activity →Decreased ATP
• Disruption of oxidative phosphorylation
• Hydrogen peroxide and oxygen radicals
• Decreased gluconeogenesis →worsening hypoglycemia
• Disruption in biotin carboxylation due to decreased acetyl-CoA activity

• Chronic Toxicity
• ”Mees” lines (after 30 days of exposure)
• Hypertension
• Diabetes Mellitus (DM)
• Cardiovascular disease
• Cerebral Vascular disease
• Malignant and Nonmalignant skin changes
• Also lung, bladder, hepatic, malignancies

• Exposure history

• Urine and Blood
• 24-hour urinary concentration equal to or greater than 50 mcg/L, 100
mcg/g creatinine, or 100 mcg total arsenic
• Blood testing is unreliable

• Seafood ingestion
• Arsenobetaine
• Transiently elevates urinary total arsenic excretion up to 1,700 mcg/L

• Hair and Nails (detected within 30 hours of ingestion)
• X-ray

• GI Decontamination
• Controversial, not generally recommended
• Not absorbed by activated charcoal, cholestyramine, bentonite
• N/V, AMS →Airway protection
• Whole bowel irrigation – reasonable with radiopaque material visualized

• Chelation
• Dimercaprol (BAL)
• Succimer

• Dimaval (DMPS) – not approved or marketed in US
• HD? (controversial)

• Atomic number = 80
• Atomic weight = 200.59 Da
• Normal concentrations:
• Whole blood = 10 mcg/L (50 nmol/L)
• Urine = 20 mcg/L (100 mol/L)

• Cathartic
• Gastroenteric irritant effect used to treat constipation

• Diuretic
• Diuretic effect used to treat syphilis by “flushing the virus out”

• Antiseptic
• Antiparasitic
• Preservative in vaccines

• Exposure history

• 24 hour urineconcentration
• Correlates roughlywith exposure severity for inorganic compounds

• Serum concentration for organic compounds due to fecal elimination

Elemental(metallic) mercury is radiopaque on plain radiographs, which can be ordered in cases of
injection or ingestion of elemental mercury

• Molecular weight = 55.86 Da
• Serum normal concentration:
• 80 = 180 mcg/dL
• 14 = 32 umol/L

• Participation in oxygen delivery as part of
hemoglobin
• Stored within the body in the form of ferritin
• Totaliron body stores = 3-4g in adults
• 0.5 to 1g of elemental iron stored as ferritinand hemosiderin
• Primarily in the bone marrow, spleen,liver
• Mobilized from stores in times of iron deficiency

• Iron is found in many over the counter multivitamins
• Iron toxicity is classified as corrosive or cellular.
• Caustic injury to GI mucosa →hematemesis, perforation, and peritonitis
• Iron impairs cellular metabolism in the heart, liver, and central nervous system.
• Free iron enters mitochondria → disrupts oxidative phosphorylation, catalyzes lipid
peroxidation, forms free radicals → Cell death
• When cellular injury occurs, metabolic acidosis is common.
• Life threatening toxicity associated with pediatrics

• 4 – 6 weeks
• Delayed sequalae
• Gastric outlet obstruction secondary to the corrosive effects of iron on the pyloric mucosa
• May present in or skip any of the 5 stages
• Determination of iron toxicity should be based on symptoms & clinical manifestations

History of Ingestion
Corresponding signs
Vitals
Labs

• Standard ferrous sulfate tablets & reduced iron
• Radiopaque and frequently visibly on routine imaging
• May help guide GI decontamination

• Many preparations are not detected
• Chewable, liquid
• Absence does not exclude iron
ingestion

• Do not give ipecac syrup, activated charcoal, cathartics, oral sodium bicarbonate, or phosphosoda.

• Whole bowel irrigation
• Endoscopy/Laparoscopic Gastrotomy

• Chelation
• Patients with:
• Repetitive vomiting
• Lethargy
• Hypotension/shock
• Metabolic acidosis
• Iron concentration > 500 mcg/dL (drawn after 4-6 hours = peak overdose)

• Derived from Streptomyces pilosus
• Binds free iron from inside cells and mitochondria
• but not iron bound to organicmolecules
• 100 mg of deferoxamine can bind 9 mg of elemental iron
• Forms ferrioxamine complex →Renally excreted

• Patient appears well / resolution of systemic toxicity
• Anion gap acidosis resolving
• No further change in urinary color
• Reached 24h

• Clinical recovery of the patient is the most important factor guiding the decision to
terminate deferoxamine therapy
• Measured iron levels are artificially depressed by the presence of deferoxamine and urine color
change can be unreliable
• Deferoxamine chelates freeiron
• Colorationof urine due to excretedferrioxamine complex
• Limited use - not consistently seen inpractice