Metal Toxicity and Chelators

Aluminum (Al)

  • Source/Events
    • Aluminum= Anticholinergic + seizures
    • Foil (chasing dragon)
    • Many medical sources (meds/HD fluids)
      • Dialysis dementia
    • Metalworking/refining
      • “Potroom palsy” (pulm fibrosis similar to pneumoconiosis)
  •  Organ/Toxicity
    • Microcytic hypochromic resistant to iron (before CNS manifestations)
    • Inhibits delta-aminolevulinic acid dehydrogenase leading to accumulation of erythrocyte protoporphyrins
    • Central anticholinergic effect
    • Neuro (acute/chronic) (interacts w ACh pathway in brain, anticholinergic effect)
    • Encephalopathy, myoclonus and seizures – CAN BE DELAYED onset of days to weeks
    • Transported via transferrin
    • Bladder irrigation – hemorrhagic cystitis
  • GI/Decon
    • None
  • Chelation
    • Deferoxamine
      • For both acute+chronic toxicity
      • Improves neurotoxicity, anemia and osteomalacia
      • Need adequate renal function→ DFO mobilizes Al from storage and inc renal elim, therefore in HD it may precipitate encephalopathy – HD for 3-4 hrs, 6-8 hours AFTER chelation

Antimony (Sb)

  • Source/Events
    • Antimonials – treatment of leishmaniasis and schistosomiasis (sodium stibogluconate, Sb5+) NEPHROTOXIN
    • Tartar emetic (antimony potassium tartrate)
    • Stibine (SbH3+) like arsine – think Plumber (HEMOLYSIS)
    • Antimony oxychloride – flame retardant, no toxic link
    • Think about in pts that have leishmaniasis or work with antimonials
    • Should NOT be diagnoses with hair samples- blood
  • Organ/Toxicity
    • Oxidative phosphorylation uncoupler
    • QT prolongation
    • (Stibine) Hemolysis(hallmark)/rhabdo/death – Similar to ARSINE
    • Sod Stibogluc – Nephrotoxin (like ampho, which is also used for leishmaniasis)
    • Derm – Antimony spots, pustules/papules (resemble varicella)
  • GI/Decon
    • AC (maybe MDAC due to entero-recirc)
    • WBI
  • Chelation
    • BAL+bicarb
    • Succimer
    • DMPS (not in US)
    • D-penicillamine can be used
    • Stibine- early exchange transfusion
    • 3+ more toxic than 5+

Arsenic (As)

  • Source/Events
    • Longterm exposure to arsenic environmentally predominantly causes skin lesions (rain-drop, mees lines, hemorrhagic vesicles)
    • Esing Bakery contamination (competing baker)
    • Staffordshire/Manchester beer epidemic
    • As2O3 used as chemo for APML (not to be confused with Cobalt-beer event)
    • Melarsoprol – used for African trypanosomes – actually contains BAL to limit toxicity. Reglgar, Orpiment
    • Can have Mees lines
    • Chronic – “Rain drop” hyperpigmentation
    • Normochromic, normocytic or megaloblasic anemia
    • Karyorrhexis – rupture of RBC cell nucleus w chromatin disintegration into granules
      • can have normocrhomic normocytic megaloblastic anemia
    • Adamsite (DM) rapid onset – Arsenic/Lewisite
    • Organic= Melarsoprol, thiacetoarsemide, arsenobetaine (seafood)
    • Inorganic= Moonshine, opium kelp, homeopathic medicine, chemo, wood preservatives, smelting insecticide, computer chips
    • ARSENIC TRIOXIDE MORE TOXIC than Monomethylarsonous acid (MMA3+)
    • TOXIC erythroderma DIFFERENT from antimony spots
  • Organ/Toxicity
    • HYPOglycemia (uncoupling)+anemia (porphyria)
    • Oxidative phosphorylation uncoupler
      • As3+ =Inh pyruvate dehydrogenase complex PDH (Pyruvate–>acetylCoA)
      • RELEASES CytC leading to apoptosis
      • As5+ substitutes for P in ATP synthesis
      • Decreases glycogen
      • Inhibits: Blocks oxidation of alpha-ketoglutarate
    • QT prolongation
    • Hemolysis/rhabdo/death
    • Peripheral neuropathy (1-3wks) – stocking/glove distribution –> Guilian barre
  • GI/Decon
    • 24 hour urine
    • AC
    • WBI
    • RICE WATER diarrhea
  • Chelation
    • BAL+Bicarb (BAL-metal dissociates in acidic urine)
    • Succimer
    • DMPS (not in US)
    • +/- HD if AKI
    • NAC (inc glutathione)
    • Fluids, lytes, glucose
    • Folate supplementation increases urinary elimination
    • Lewisite (C2H2AsCl3)

Barium (Ba)

  • Source/Events
    • PO contrast w GI perforation → severe hypokalemia progressing to paralysis (shift, not depletion)
  • Chelation/Treatment
    • Supportive care with K and Mag (PO) {cannot give mag sulfate due to formation of barium sulfate intramuscularly)

Bismuth (Bi)

  • Source/Events
    • Erythema of the 9th day – self-resolving rash
    • Analbis – hepatic failure
    • Bismacaine/chromacaine – lyme disease
    • Also check salicylate level
    • Next to lead on periodic table
  • Organ/Toxicity
    • Acute – AKI due to water soluble bi salts
    • Can have concomitant neurotox (decreased dtrs, weakness, myoclonus, WITHOUT AMS)
    • Progressive myoclonic encephalopathy
    • Chronic – Encephalopathy
  • GI/Decon
    • AC/WBI
  • Chelation
    • NAC
    • BAL (can start if no response to inital measures within 48 hours)

Cadmium (Cd)

  • Source/Events
    • IARC group 1
    • Jinzu river in Japan “Itai-Itai/ouch-ouch” – osteomalacia (chronic toxicity)
  • Organ/Toxicity
    • Complexes with metallothionein (Cd-MT) not harmful (natural chelator)
    • Cadmium pneumonitis – hypoxic respiratory failure, death within 3-5 days
    • Binds to SH groups, denatures proteins and inactivates enzymes.
    • Increased sensitivity to mitochondrial stress
    • Nephrotoxicity – most common finding in CHRONIC toxicity
    • Lung cancer
  • GI/Decon
    • GI – CAUSTIC injury
    • NG lavage (inorganic cadmium is powder)
  • Chelation
    • Chelation unproven (d/t Cd-MT?)
    • Maybe succimer for acute GI decon

Cesium (Cs)

  • Source/Events
  • Organ/Toxicity
    • QT prolong/VT/VF – PRINCIPLE toxic effect of non radioactive Cs
    • Radiation (beta-gamma)
  • GI/Decon
    • None
  • Chelation
    • Prussian blue (enterohepatic recirculation) -aka ferric hexacyanoferrate
    • Lidocaine for arrhythmias

Chromium (Cr)

  • Source/Events
    • IARC group 1
    • Metal-on-metal arthroplasty
    • Liberated in STAINLESS STEEL welding
    • CCA (chromium copper arsenate) wood preservative
    • Cr6+ MORE toxic than 3+ (3+ is actualy an essential metal for metabolism of glucose and fats)
  • Organ/Toxicity
    • Corrosive
    • GI hemorrhage
    • Hemolysis
    • Chronic- respiratory
    • Pneumoconiosis
  • GI/Decon
    • Cr6+ – corrosive (?lavage, AC)
    • Only removal of the patient from source, no chelation
  • Chelation
    • DECON+NAC+VITC

Cobalt (Co)

  • Source/Events
    • Co = Cardiac output
    • Beer drinkers cardiomyopathy
    • Cobalt-induced goiter
    • Roncovite (cobat chloride + iron, otc for anemia)
    • Metal-on-metal arthroplasty
    • Cobalt60- gamma emitter
    • ALVAL vasculitis → Aseptic lymphocyte dominated vasculitis associated lesion
  • Organ/Toxicity
    • Hard metal disease – Pulm issues including respiratory irritation, exertional dyspnea, severe dry cough, wheezing, interstitial lung disease (Tungsten carbide)
    • Can cause anion gap
    • Thyroid
    • Blood (but not coag)
    • CNS/PNS
    • Impaired protein syhtesis (inhibits alpha- ketoglutarate dehydrogenase – ATP dysfunction
      • Leads to CARDIOMYOPATHY
    • Other divalent cations inhibiting alpha-ketoglutdehyde
      • Zn, Cd, Cu, Ni
  • GI/Decon
    • No proof +/- AC/WBI
  • Chelation
    • CaEDTA+NAC
    • Succimer+NAC
    • Maybe DTPA-usually reserved for transuranic

Copper (Cu)

  • Source/Events
    • Menkes “kinky hair” syndrome – genetic impaired Cu Gi absorption
    • Wilsons disease – copper tox
    • Cu linked to angiogenesis, tumor growth
    • Paris green, Vienna green or Sweedish green=Copper AND Arsenic- pigment insecticide
  • Organ/Toxicity
    • Red/ox – methemoglobin followed by hemolysis
    • Liver
    • Accumulation in cornea → Green/brown KAYSER-FLEISHER rings
    • GI/Decon
      • Can have BLUE vomit
      • Emesis likely takes care of it
      • AC relative contraindicated
  • Chelation
    • BAL – hepatic elimination
    • D-penicillamine – renal elimination (may cause AKI) used in Wilsons dz
      • 25% cross rxn in pcn allergy, ADR- aplastic
    • Succimer
    • Can use BOTH BAL+D-penicillamine, esp if gastric injury (d-pcn is PO only)
    • Trientine (triethylenetetramine) – 2nd line in Wilson’s Dz.

Iron (Fe)

  • Source/Events
    • Iron necessary for protoporphyrin 9 incorporation into heme
    • Fe fumarate>chloride>sulfate>lactate>gluc
      • 33>28>20>19>12
    • IV much lower
    • Toxic dose 10-20 mg/kg elemental
    • Poor GI absorption, but in OD, oxidative stress INCREASES absorption
    • TIBC factitiously increased
  • Organ/Toxicity
    • I – in MUDPILES
    • Destruction of CRISTAE in mitochondrial membrane
    • Serum iron > 500 indication for DFO unless clinical symptoms with lower levels
    • 5 Stages
      • 1>N/V/D, local effects (6 hrs)
      • 2>Latent resolution (6-24 hrs)
      • 3>Shock 12-24 hours
      • 4> hepatic failure (2-3 days)
      • 5> Gastric outlet obstruction (2-8 wks)
  • Chelation
    • Deferoxamine indicated if
      • >300 and symptomatic
      • >500
    • DFO= neutropenia, agranulocytosis, hypoTN, ARDS = LIMIT to 24 hours.
    • DFO 100mg binds 8.5 mg Fe3+ ion
    • IV ONLY, no IM

Lithium (Li)

  • Source/Events
    • Nephrogenic diabetes insipidus (Hypernatremia, free water deficit)
  • Organ/Toxicity
    • AMS/Cerebral edema
    • SILENT
    • HD if Li > 5 or > 4 w kidney impairment, significant CNS tox, expected time to < 1 is more than 36 hours

Lead (Pb)

  • Source/Events
    • Adult: BLL < 70, asymp – no tx
    • Child: BLL < 20, asymp – no tx (+/- if BLL 20-44)
  • Organ/Toxicity
    • Saturine gout (competitive excretion with uric acid)
    • Inhibits ferrocheletase, increasing protoporphyrin 9 AND inh ALA dehydrogenase, increasing delta-ALA
      (SIADH)
    • Elevation in ICP, encephalopathy
    • Peripheral NS – Foot drop, wrist drop (similar to vincristine, organophosphates)
    • Burton-lines= blueish purple gingival line representing lead sulfide
    • Increase in protoporphyrin-9 levels (heme toxicity)
  • GI/Decon
    • PPIs will decrease ongoing absorption
  • Chelation
    • CaNa2EDTA+BAL
    • Succimer

Manganese (Mn)

  • Source/Events
    • Competes for binding sites on transferrin (absorption increases with iron deficiency)
    • Can substitute for Ca, Mg, Fe
    • Mirrors idiopathic Parkinson’s (but Mn lacks tremor)
    • Occupational hazard
    • German miners “Manganese madness”
    • Late presenting EPS: bradykinesia, postural instability, rigidity, loss of facial expression, impaired speech, impaired gait (cock walk, on balls of feet), tendency to fall BACKWARDS, ABSENCE of dementia
    • Does NOT respond to levodopa
    • Can cause metal fume fever
  • Organ/Toxicity
    • CNS (via oxidative stress)
    • Pulm fibrosis (occupational) – Increase inflammatory markers NO, PgE, TNFa, NKKB
    • Inh COMPLEX 1 in electron transport chain
  • GI/Decon
    • None- chronic exposure normally
  • Chelation
    • CaNa2EDTA (controversial)
    • Deferoxamine (counter Iron abs)

Mercury (Hg)

  • Source/Events
    • Inorganic: Mercuric chloride (corrosive sublimate), Mercurous chloride (calomel)
    • Organic: MethylHg, DimethyHg
    • Elemental (inhalation, methylated in vivo to organic mercury)
      • Light bulbs – 4mg
    • Inorganic (oral, dermal (below))
    • Organic (oral)
    • Minimata bay – methylmercury
    • Ethylmercury=thimerosal (organic, ~48%Hg by weight)
    • Methylmercury (organic) formerly used as a fungicide (50000 poisoned in Iraq in the 70s) symptoms can develop after SIGNIFICANT LATENTCY–> Phenylmercury acetate, inorganic, (dermal and inhalation route)
    • “Pink disease” Idiosyncratic hypersensitivity to mercury ions – erythematous, edematous, hyperkaratotic induration. Rash morbilliform
    • DUAL findings of NEUROPSYCH and KIDNEY abnormalities = ORGANIC Hg
  • Organ/Toxicity
    • Elemental-CNS (rapid onset) salivation (ptyalism), weakness, ARDS
    • Inorganic-GI/caustic- IMMEDIATE gray-discoloration of mucous membranes
    • Organic-pure neuro(onset delayed) – PERMANENT changes
  • GI/Decon
    • Elemental very poorly absorbed in GI
    • Organic usually chronic – no benefit
    • Inorganic if there a caustic injury, no – but otherwise AC
  • Chelation
    • Succimer
    • BAL/Succimer
    • Succimer (BAL only for INORGANIC)
    • Chelators with thiol groups best
    • Volume resus for INORGANIC due to hemorrhagic gastritis

Nickel (Ni)

  • Source/Events
    • Hypersensitivity – 10% incidence in women
    • Nickel carbonyl (metabolized to CO and Ni)
  • Organ/Toxicity
    • Dermatitis
    • Lung cancer
  • GI/Decon
    • None
  • Chelation
    • Diethyldithiocarbamate (DDC) – non a pharmaceutical produce, but prodrug of disulfiram (metabolized to two DDC)
    • Maybe DTPA

Selenium (Se)

  • Source/Events
    • Industry
    • Antidandruff shampoo
    • Gun bluing solution – selenium, copper, hydrochloric acid, methanol, nitric acid
  • Organ/Toxicity
    • Chronic selanosis (similar to chronic arsenic) = “Blind staggers”
    • Caustic burns
    • Respiratory irritant
    • Gun bluing (severe oxidative stress)
    • Brittle hair, nail changes, neuro/psych
  • GI/Decon
    • None
    • Topical sodium thiosulfate for burns
  • Chelation
    • Selenium hexafluoride gas – calcium gluconate
    • Chelation increases AKI
    • HD/CVVH

Silver (Ag)

  • Source/Events
    • Argyria – permanent blue/gray discoloration of skin
  • Organ/Toxicity
    • Not a carcinogen
    • Dermatologic/burns
  • GI/Decon
    • None
  • Chelation
    • None

Thallium (Tl)

  • Source/Events
    • Rodenticide (banned)
    • Acute – dose dependent delayed manifestations (three phases)
      • GI, non specifi ECG changes (< 6hours)
      • Constipation, ECG change, HTN, effusions, AKI, alopecia; motor/sensory neuropathy (painful soles of feet – weight of bedsheets enough to cause pain) (1d-2wks)
      • Resp depression, mees lines, cognitive effecs (> 2 wks)
    • Alopecia, ascending painful neuropathy
    • Can mirror beriberi
  • Organ/Toxicity
    • GI–>renal/pulm–>neuro
    • Potassium mimic – QT prolongation
      • -Pyruvate, succinate dehydrogrenase also dependent on K so inhibits OX Phos
  • GI/Decon
    • AC/MDAC
    • WBI
  • Chelation
    • Prussian blue
      • PB is an exchange resin similar to SPS- exchanges K for thallium. Coformulated with mannitol to prevent consiptation.
    • No SPS, K
    • EXTRIP rec HD

Zinc (Zn)

  • Source/Events
    • Zinc swayback – heme and neurologic
    • Chronic zinc tox manifests and Copper deficiency (wilsons)
    • Zinc phosphide (Zinc+phosphine) – black, fishy vomitus
    • ZnCl – corrosive
  • GI/Decon
    • WBI
    • Topical decon with mineral oil
  • Chelation
    • CaNa2EDTA
    • BAL, DTPA, DMSA
    • Deferpirone
    • NAC

DTPA (chelator)

  • Used for transURANIC metals but not for uranium itself
    DO NOT use for URANIUM or NEPTUNIUM – mobilizes uranium from tissue stores but does not increase urinary elimination
  • Primarily used for plutonium, curium and americium
  • DO NOT USE orally for ingestion
  • Can be used for a bunch of others.
  • Should be given via NEBULIZATION after exposure from explosion
  • Causes HEMOCHROMATOSIS and mucous membrane ulceration due to ZINC depletion → So use CaDTPA initially then switch to ZnDTPA after the first 24 hours.
  • Wear universal precautions
  • Urine, blood, vomit, stool etc, should be disposed of safely since it is contaminated

Miscellaneous notes

  • Phos***
    • Phosphine- PH3
    • Phosgene- COCl2
    • Phosgene oxime- blister agent
  • Arsine/stibine – AsH3/ SbH3
  • Arsenic>Antimony>bismuth
  • No chelation (CnSS)
    • Chromium, Nickel, Selenium, Silver
  • Prussian blue
    • Cesium, Thallium (HD)
  • Deferoxamine
    • Aluminum, manganese, iron- — AMI (deferoxAMIne)
  • BAL – intramuscular because of peanut oil
    • Arsenic, antimony, Bismuth, Copper, Lead, Mercury (inoragnic only), Zinc (AABCHgILZ)
    • Can be used for Methyl bromide (fumigant/fungicide) + NAC
    • Metabolized to inorganic bromide (similar to dextromethorphan bromide – bromism/chloride – cns stim/seizures)
    • Often given with BICARB and/or NAC
    • Chelate-BAL dissociates in acidic urine, should give with NaHCO3 to alkalinize urine
    • Give 4 hours before CaNaEDTA
    • Contraindicated in hepatic impairment (but probably risk v benefit?)
    • Increases brain levels in organic or elemental
  • Succimer/DMPS
    • Arsenic, antimony, Bismuth, Cobalt, Lead, Mercury, Zinc
    • Does not redistribute mercury into the brain
  • CaNaEDTA
    • Cobalt, lead, zinc
  • D-penicillamine
    • Copper, but complex is renally eliminated so may cause AKI
    • Lead, Hg
  • N-acetylcysteine
    • Cobalt, Zinc
  • Disulfiram
    • Nickel
  • Sodium thiosulfate (metabolized to H2S)
    • Selenium
  • Charcoal
    • Antimony, Arsenic, Mercury, Thallium
  • ATP/Cellular respiration
    • Arsenic, antimony, phosphorus
  • Redox/stress
    • Copper, manganese, selenium
  • Neuro
    • Aluminum, bismuth, cobalt, lead, manganese, mercury
  • Caustic
    • Chromium, selenium, silver
  • Cancer
    • Cesium, thallium
  • Other
    • Cadmium (renal), bismuth (renal)
    • Cobalt (thydoid, heart, blood, cns)
    • Zinc (skin)
  • DMPS – can also be used with pyridoxine for tetramine induced seizures poisoning (chinese market poisoning by competitor)
  • Mineral oil GI decon → phenol
  • Phenol: mineral oil GI decon, low molecular weight polyethylene glycol topical decon
  • Phophorus: keep patient wet and clothes under water due to spontaneous combustion
  • Ca-DTPA/Zn-DTPA – Chelator for transuranic metals (plutonium, americium, curium — NOT for uranium or neptunium) (nuclear/radiation, dirty bombs). Maybe for cadmium, nickel, lanthanum (for renal failure patients…)

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