8/26/14
1
Metals and Metalloids Dan Rusyniak
What are Metals?
• 80% of the known elements • Conduct electricity • Conduct heat • Malleable • Luster (reflect light) • Exist as positive ions in
compounds
8/26/14
2
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
8/26/14
3
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
8/26/14
4
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
8/26/14
5
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!
8/26/14
6
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)
8/26/14
7
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
8/26/14
8
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
8/26/14
9
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
8/26/14
10
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
8/26/14
11
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
8/26/14
12
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
8/26/14
13
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
8/26/14
14
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
8/26/14
15
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
8/26/14
16
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
8/26/14
17
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
8/26/14
18
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
8/26/14
19
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
8/26/14
20
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
8/26/14
21
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
8/26/14
22
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)
8/26/14
23
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
8/26/14
24
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
8/26/14
25
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
8/26/14
26
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
8/26/14
27
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)
8/26/14
28
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,
8/26/14
29
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
8/26/14
30
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
8/26/14
31