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Metals and Metalloids Dan Rusyniak

drusynia@iupui.edu

What are Metals?

•  80% of the known elements •  Conduct electricity •  Conduct heat •  Malleable •  Luster (reflect light) •  Exist as positive ions in

compounds

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Toxicity of Metals •  Interfere with essential metals –  Lead (calcium and iron)

•  Inhibit enzymes –  Mercury and sulfhydryl containing enzymes

•  Form metal protein complexes –  Cadmium-Metallothionein

•  Direct toxicity –  Iron (fenton reaction)

•  Dependent on chemical form –  Organic vs. Inorganic arsenic

Essential Metals

•  Iron - Heme •  Zinc – Metalloproteinase •  Copper – numerous enzymes/Mito •  Manganese – MnSOD •  Chromium – Insulin •  Molybdenum – Xanthine oxidase •  Selenium – Glutathione peroxidase

Iron

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Declining Iron Cases

•  In 1997, the FDA mandated child-proof “strip packaging” & warning labels to be placed on all iron-containing products

Pediatric Iron Cases/1000 PCC

1988 1992 1996 2000

0

2

4

Year

Human Iron Content •  4 grams total body stores –  65% in hemoglobin –  15-30% –  4% in myoglobin –  1% in various heme compounds

•  1 mg excreted daily (men) •  2 mg excreted daily (women)

Iron  

Free Iron •  Highly Toxic

1.  Fe2+ + H2O2 → Fe3+ + HO• + OH– 2.  Fe3+ + H2O2 → Fe2+ + HOO• + H+

•  Transported bound to proteins –  Absorption – Ferritin –  Transported – Transferrin –  Hemosiderin, ceruloplasmin (hold in Check) –  Used – Ferritin, Hemoglobin, Cytochromes, Myoglobin

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Elemental Iron Content

Ferrous Gluconate 11.6%

Ferrous Lactate 19%

Ferrous Sulfate 20%

Ferrous Chloride 28%

Ferrous Fumarate 33%

Iron dextran 50mg Fe/mL

FSG 357 Fumarate (1/3rd) Sulfate (1/5th) Gluconate (1/7th)

Range of Toxicity •  Minimum toxic dose: 20-60 mg/kg

•  Fatal poisonings >60 mg/kg

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Pathophysiology •  GI –  Corrosive –  Increase iron absorption

•  Hypotension –  GI loss –  Capillary leak

•  Coagulopathy (increased INR) –  Inhibition of serum proteases –  Inhibition of thrombin

Metabolic Acidosis •  Decreased perfusion •  Pseudo-uncoupler –  Excess Fe2+(ferrous) converted to the ferric (Fe3+) form –  Fe3 in mitochondria and attracts electrons from the electron

transport chain

•  Process takes several hours!

Hepatotoxicity •  Portal vein transport •  Free Iron direct hepatotoxicity

•  This process takes several hours!

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Central  

Middle  

Peripheral  

Central  

Middle  

Peripheral  

Peripheral lobular area most susceptible to iron

PV  BD  

HA  

“The 5 Stages”

•  Stage I – (0-6 h) GI

•  Stage II – (6-18 h)“latent”apparent recovery

•  Stage III – (-24h) shock and metabolic acidosis

•  Stage IV – (2-3 d) hepatic

•  Stage V – (weeks) gastrointestinal strictures

Diagnosis •  Serum iron levels –  <300 mcg/dL are rarely symptomatic

•  X-ray (unreliable) –  Elixir preparations are not visible on X-Ray –  Chewable tablets appear on 5% of KUB’s

•  WBC demargination (WBC >15K unreliable) •  TIBC (useless)

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Deferoxamine •  DFO + Fe3+ à ferrioxamine •  Symptomatic levels >?350 ug/dl •  15 mg/kg/hr infusion –  Can increase to 30 mg/kg/hr

•  Vin Rose Urine (unreliable) •  Stop when asymptomatic and levels <150 ug/dl •  Side effects –  Anaphylactoid (hypotension) –  ARDS (?)

Yersinia Sepsis

Iron  

Melby K, et al; Septicaemiae due to Yersinia enterocolitica after oral overdoses of iron

Lead

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Sources •  Children –  Pica (FE deficiency often concurrent) –  Paint –  Folk remedies (Azarcon) –  Ingestion lead objects

•  Adults –  Occupational –  Folk remedies (“Litargirio”) –  Lead foreign bodies

Clinical Effects •  Children –  Anemia –  CNS –  Colic –  Neuropathy (Sickle Cell disease)

•  Adults –  Hypertensions –  Renal (Fanconi syndrome) –  Sterility

Pathophysiology •  Anemia –  Sulfhydrl containing heme synthesis enzymes inhibited –  Build-up of delta-aminolevulinic acid, coproporphyrin and

zinc protoporphyrin –  Microcytic, hypochromic; Fe deficiency –  Basophilic stippling

•  Neuronal –  Inhibition of NMDA (inhibits dendritic arborization) –  Cerebral edema from capillary leak

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Basophillic Stippling

Diagnosis •  Blood lead level (nml <10 ug/dl) •  Skeletal x-rays –  Increased calcium deposition growth plates –  Lead impairs osteoclastic but not osteoblastic activity

•  Bone x-ray fluorescence

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Chelation •  DMSA –  Children >45 µg/dL –  Adults >70 µg/dL

•  BAL –  Unable to take oral –  ? Children >80 µg/dL

•  EDTA –  ? Children >80 µg/dL –  Must be with BAL

HS SH

OH

O O

HO

Pb2+

Pb2+

HS SH

OH

Pb2+

Dimercaptosuccinic Acid (DMSA)

BAL

Ethylenediaminetetraacetic acid (EDTA)

Tetra- ethyl and methyl lead •  Antiknock agent (banned 1995) •  Dealkylated in liver to trialkyllead –  Metabolized to inorganic lead

•  CNS symptoms –  Hallucinations and delusions –  Excitement, insomnia, delirium –  Seizures, coma and death

•  Treatment – –  DMSA, EDTA (? Benefit)

Mercury

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Sources •  Elemental (inhaled) –  Thermometers, amalgams

•  Inorganic (ingested) –  Industry –  Skin whitening creams

•  Organic: –  Fish –  Industry –  Thimerasol

Elemental - Acute •  Vapor exposure –  Acute Febrile Illness –  Pneumonitis –  Renal Failure

•  Ingestion – low toxicity •  Systemic injection - emboli

Clin  Tox.  2008.  46(9):831-­‐3.  

Chronic Elemental Mercury Toxicity •  Vapor exposure •  Tremor – Danbury shakes •  Delirium •  Cerebellar dysfunction •  Peripheral neuropathy

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Elemental - Chronic •  Erethism (Personality changes) –  Withdrawn and Shy –  Irritability –  Memory loss –  Lethargy

•  Acrodynia (Pink or Feer-Swift disease) –  Autonomic changes - Mimic pheochromocytoma –  Dermatologic changes - desquamating rash palms/soles –  Musculoskeletal - weakness

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Inorganic •  GI –  GI bleeds

•  Renal –  Acute - ATN –  Chronic – glomerular nephritis, nephrotic syndrome

hGp://www.nyc.gov/html/doh/html/pr/pr008-­‐05.shtml  

Laboratory Testing •  24 hour Urine – normal < 20ug/L –  Inorganic and elemental

•  Blood mercury –acute exposure – Organic mercury

•  Hair –less accurate may be better in organic mercury

Treatment •  BAL – May increase CNS concentrations •  DMSA •  DMPS •  Supportive Care

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Organic Mercury •  Delay in onset –  Weeks to months

•  Cerebellar degeneration –  Ataxia/Tremor

•  Posterior Column Degeneration –  Paraesthesias –  Weakness

•  Visual –  Concentric Vision Loss

Hunter  and  Russell,  QJM,1940.  547:24  

Mechanism of action •  Organic mercury very lipid soluble – Readily crosses BBB

•  Converted to Hg2+ in CNS •  Concentrates binds to sulfhydryl groups •  Binds to choline-acetyltransferase – Decreased acetylcholine synthesis

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Thimerosal •  Widely used as a vaccine preservative •  Metabolized to ethyl-mercury •  Numerous epidemiologic and longitudinal studies have

shown no association with development of autism

Arsenic •  Abundant heavy metal (metalloid) •  Inorganic (Tri and penta oxides) –  Contaminant of ground water –  Bangladesh (> 20 million persons)

•  Organic –  Seafood – arsenobetaine –  Herbicides

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Organ System Effects

Gastrointestinal Nausea, Vomiting, Diarrhea

Cardiovascular Arrhythmias, shock

Pulmonary Pulmonary Edema Renal Kidney Failure CNS Encephalopathy

Peripheral Nerves Peripheral Neuropathies (delayed, (Guillain Barré mimic)

Hematologic Anemia, basophilic stippling Dermatologic Mees’ Lines and Hyperkeratosis Cancer Skin, Lung, Liver, Bladder

Photo courtesy of Robert Pascuzzi

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Inorganic As causes Torsades

Blood,  1  March  2001,  Vol.  97,  No.  5,  pp.  1514-­‐1516    

Pathophysiology •  Trivalent inhibits TCA cycle (pyruvate dehydrogenase) •  Pentavalent interferes TCA cycle and glycolysis

•  Organic (low toxicity)

Arsine Gas •  Inorganic Arsenic + Acid = AsH3

•  Rapid Hemolysis –  Jaundice –  Hematuria

•  Renal failure

FFP Arsine Plasma

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Laboratory •  24-hr Urine Gold Standard –  False Positives – Seafood –  Normal <100 ug/24 hrs

•  Hair –  Useful for chronic or remote exposures

•  Mees Lines –  Develop late only in ~25% cases

•  Arsine - Hemolysis (Indirect bili, anemia, hematuria)

Chelation

•  DMSA •  BAL •  DMPS

HS SH

OH

O O

HO

As3+

HS SH

OH

As3+

Dimercaptosuccinic Acid (DMSA)

BAL

Thallium

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Thallium •  Sources: Rat poison (Russia, China), homicidal •  Size and charge mimics potassium

–  Disrupts Na-K ATP transport enzymes •  GI symptoms (N/V/D then constipation) •  Rapid progressive neuropathy (Guillain Barré mimic)

–  Sensory motor (very painful) –  Cranial nerve involvement

•  Alopecia (10-14 d) •  Blackened hair roots •  24 h Urine (>20 ug/L)

Treatment •  Prussian Blue (Radiogardase) –  (Potassium ferric Hexacyanoferrate –  3 g/day PO –  Binds Tl in gut

•  Tl enterohepatic circulation

•  Charcoal

•  Hemodialysis

hGp://polypcyst.files.wordpress.com/2011/06/cadmium1.jpg  

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Cadmium •  Sources: Mining, smelting, electroplating, soldering,

batteries, water contamination, smoking •  Pulmonary > GI absorption •  Mechanism: –  Acute – Chemical pneumonitis –  Chronic - Binds to metallothionein causes Fanconi syndrome –  Chronic – Osteomalacia (Itai-Itai)

•  Diagnosis: 24h urine (> 3 ug Cd/g creatinine) •  Diagnosis: β2-microglobulin levels (> 300 u/g cr)

Chromium

Chromium •  Sources: Electroplating, chrome yellow paint, •  Mechanism: hexavalent corrosive and an oxidizer •  Cr+3 doesn’t cross membranes

•  Cr+6 –permeates cells and converted to Cr+3

–  DNA damage

•  Pulmonary and GI absorbed

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Acute Clinical Effects •  Contact dermatitis – 8% of all cases •  Burns •  Corrosive injury -hemorrhagic gastritis •  Acute renal failure – ATN •  Pulmonary edema •  Cancer (nose, lung, throat)

hGp://www.cdc.gov/niosh/topics/skin/occderm-­‐slides/ocderm8.html  

Treatment •  Dermal: 10% topical solution of vit C –  Converts Cr+6 to Cr+3

•  Ingestion –  Lavage -with 1% ascorbic acid solution –  Oral vit C ~ 3grams/gram ingested –  NAC – in rats increases excretion

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Antimony (Stibine) •  Sources: alloy, rubber manufacturing; flame retardant, •  Similar to arsenic

–  (tri and pentavalent forms) –  Stibine gas (causes hemolysis)

•  Mechanism: Similar to arsenic binds sulfhydryl groups and blocks TCA cycle

•  Clinical: –  GI (N/V/D) –  GI hepatitis –  Cardiovascular (T-wave changes and prolonged QT) –  Renal failure

Antimony Treatment •  Same as arsenic •  Think antimony think arsenic

•  Good case in NEJM –  Kostantopoulos, Burns, Pratt, NEJM , 2012. (PMID: 22808962)

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Barium •  Soluble barium (Ba carbonate, Ba chlorate) •  Sources: depilatories, fireworks, glass-making •  Mechanism: shifts K+ into cells and prevents efflux •  HYPOKALEMIA •  Treatment: potassium replacement; sodium/magnesium

sulfate to ppt insoluble salt

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Boron •  Boric acid – pesticide, fungicide •  Irritant – cellular mechanisms poorly understood •  Clinical: – Blue-green emesis, hypotension, renal failure

(immediate) – Agitation/seizures (1 day); – Lobster rash (2-5 days) with alopecia

•  Treatment: supportive

Lung,  Clin  Tox,  47:5,  2009.  

Copper?

Photo  courtesy  of  Robert  Pascuzzi  

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Copper •  Copper Sulfate Algaecide •  Essential mineral (catalase and peroxidase) •  Bound to albumin (blood) and ceruloplasmin (tissue)

•  Powerful emetic: Blue Green Emesis •  Late hepatic failure - centrilobular necrosis •  Cardiovascular Shock •  Hemolytic anemia

•  Treatment: BAL and d-penicillamine

Vineyard Sprayer’s Lung

•  Portuguese vineyard workers •  Bordeaux soln – (1-2%

copper sulfate) •  Interstitial pulmonary fibrosis

and alveolar cell carcinoma •  Liver disease -fibrosis,

cirrhosis and angiosarcoma

Manganese

Saito  and  Sawayama,    J  Neurol  Neurosurg  Psychiatry  2009;80:695    

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Manganese •  Welding, mining, smelting, •  Methcathinone (Potassium permanganate) •  Essential element (SOD) •  Acute (fumes) - Pneumonitis

Manganism •  Chronic dust (oxide) •  Psychosis/schizophrenia (“manganese madness”) •  Parkinsonism (no tremor) •  Whole blood manganese level (normal <15µg/L) •  Normal flourodopa PET

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Selenium •  “Gun Blue”, copper refining, supplements •  “One swallow” in children (gun-blue) may be fatal;

about 5mg/kg is toxic in most cases •  Onion/garlic odor •  GI corrosion •  Coma & Shock •  NAC (?) •  Ascorbic acid may turn salts into elemental selenium

Nickel Carbonyl •  Formed by nickel and CO •  Symptoms –  Initial – giddiness, headache, vomiting – Delayed (12 – 24 hrs) – dyspnea, cyanosis,

leukocytosis, hyperthermia, pneumonitis, delirium •  Treatment – diethyldithiocarbamate trihydrate

(dithiocarb 3 mg/kg q 4 hours)

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Organotin •  Stalinon (diiododiethytin) •  Treatment for boils •  Severe headache and vomiting (day 4) •  Ataxia, urinary retention, diploplia •  Cerebral edema •  Death

From  “Wonderful  Life  with  the  Elements:  The  Periodic  Table  Personified”  by  Japanese  arHst  Bunpei  Yorifuji,  

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Beryllium •  X-ray, Aerospace, Fluorescent lights •  Pulmonary exposure in workers •  Acute Beryllium disease (Pneumonitis) •  Chronic Beryllium disease (granulomatous disease) –  Like sarcoid can effect any organ –  Immune sensitization

•  Unknown lower limit of exposure (PEL of 2ug/m3) •  Lymphocyte proliferation test (BeLPT)

Bismuth •  Chronic use –  GI disease

•  CJD mimic •  Nephropathy •  Blue-black gingiva

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Cobalt •  1965-1966 •  Beer drinkers in Quebec •  Heart Failure •  Polycythemia •  Hypothyroidism •  Cobalt added to beer to

increase foam head •  Cobalt Hips •  Blood level > 7µg/L

Aluminum •  Dialysis Dementia •  Aluminum Phosphate Binders •  Sucralfate •  Aluminum in Water •  Chelator Deferoxamine

Silver/Argyria •  Skin discoloration

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