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Chela+on of Other Metals (Inappropriate Simplifica+on) Administer Chela7on Metal purged (Pa7ent improvement) Crucial Considera+ons (I) •  Assump+ons –  Metal toxicity correlates with body or compartment burden –  Reducing that burden aJenuates toxicity •  Requirements –  Established toxicity dose-­‐response rela+onship –  Appropriate, reproducible assessment mechanisms •  Toxicity (clinical, biochemical, radiographical) •  Body or compartment burden Crucial Considera+ons (II) •  Metal forms (elemental, organic, inorganic) •  Biochemistry and biophysics –  Binding capabili+es –  Effects of various physiological media •  Pharmacokine+cs and biodistribu+on –  Compartments –  Metal (phase, turnover?) –  Ligand (“chelator”) –  Metal complexes (“chelate”) Crucial Considera+ons (III) •  Toxicity –  Metal –  Chelator –  Chelate •  Clinical relevance –  “Technical” versus “clinical” chela+on –  Decorpora+on versus redistribu+on •  “Bycatch” Bycatch •  “Bycatch occurs if a fishing method is not perfectly selec+ve…. A fishing method is perfectly selec+ve if it results in the catch and reten+on only of the desired size, sex, quality, and quan+ty of target species without other fishing-­‐related mortality. Very few fishing methods meet this criterion.” Na+onal Oceanic and Atmospheric Administra+on Chela+on “Bycatch” •  Bycatch occurs if a chela'on method is not perfectly selec+ve…. A chela'on method is perfectly selec+ve if it results in the chela'on and elimina'on only of the desired form (specia'on), quality, and quan'ty of target metal without other chela'on-­‐related mobidity or mortality. Very few [if any] chela'on methods meet this criterion. Dose-­‐response Homeostasis Adverse Effect Deficiency Dose Toxicity !"#$%&'("#$)'*+",'&$!'-".'*"./$012(+#*./$3+4+#+",
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Aluminum Library of Congress. hJp://www.loc.gov/pictures/resource/cph.3b44599/ Aluminum (Al) Exposures •  Food, water, and an+perspirant •  Bladder hemorrhage •  TPN –  Adult –  Pediatric •  Renal failure –  Phosphorous “chelators” –  Dialysis •  Drug abuse Al Toxicity •  Central nervous system (“dialysis demen+a”) •  Metabolic bone disease •  Anemia •  Cardiomyopathy Deferoxamine C25H48N6O8 MW: 560.68 Ferroxamine C25H48FeN6O8+3 MW: 616.53 PubChem. NLM. PubChem. NLM. Aluminum Chela+on Considera+ons •  Metals –  Aluminum (Al) –  Iron (Fe) •  Binding proteins –  Transferrin (unbound) –  Transferrin-­‐aluminum –  Transferrin-­‐iron •  Chelator (unbound) –  Deferoxamine (DFO) •  Chelates –  Aluminoxamine (AlO) –  Ferrioxamine (FO) Aluminum Chela+on Considera+ons •  Acute vs. chronic exposure •  DFO adverse effects –  Precipitated aluminum encephalopathy and death •  Redistribu+on of DFO-­‐mobilized aluminum into brain •  Ability of AIO complex to cross blood/brain barrier –  Hypocalcemia –  Hyperparathyroidism –  Systemic hypersensi+vity reac+ons –  Infec+on Aluminum Chela+on Considera+ons •  Timing •  Dose •  Dialysis •  Bycatch Alterna+ve Poten+al Chelators •  Deferiprone –  L1, 1,2-­‐ dimethyl-­‐3-­‐
hydroxypyrid-­‐4-­‐one PubChem. NLM. •  Deferasirox –  4-­‐[3,5-­‐Bis (2-­‐
hydroxyphenyl)-­‐1H-­‐1,2,4-­‐
triazol-­‐1yl]-­‐benzoic acid PubChem. NLM. Alterna+ve Chelator Issues •  Deferiprone –  Stoichiometry, 3:1 –  Agranulocytosis –  Copper, zinc bycatch •  Deferasirox –  Stoichiometry, 2:1 –  Renal impairment (failure) –  Hepa+c impairment (failure) –  Gastrointes+nal hemorrhage –  Copper, zinc bycatch Al Chela+on Summary •  Chelator = deferrioxamine (DFO) •  Labeled indica'on (DFO) –  Acute iron intoxica+on –  Chronic iron overload •  Evidence of “technical” and “clinical” efficacy •  Poten+al for worsening Al toxicity •  Consider chelate (AlO) elimina+on Chromium hJp://upload.wikimedia.org/wikipedia/commons/0/08/
Chromium_crystals_and_1cm3_cube.jpg (Crea+ve Commons) Chromium (Cr) Exposures •  Essen+al nutrient •  Environmental –  Water –  Food –  Supplements –  CCA •  Industrial •  Biomedical –  Prostheses –  Stents Chromium (Cr) Toxicity Trivalent (Cr3+) vs. hexavalent (Cr6+) Cr6+: IARC Group I carcinogen Respiratory irrita+on and compromise “Blackjack” derma++s, “chrome holes” and type IV (delayed-­‐type) hypersensi+vity reac+ons •  Gastrointes+nal irrita+on/ulcera+on •  Anemia/hemolysis •  Oligospermia • 
• 
• 
• 
hJp://www.cdc.gov/niosh/topics/skin/
images/derm039.gif hJp://www.cdc.gov/niosh/topics/
skin/images/derm047.gif Chromium (Cr) •  Trivalent (Cr3+) – 
– 
– 
– 
– 
Kine+cs Limited oral absorp+on of Cr3+ salts (0.4-­‐2.5%) 98% fecal elimina+on post oral exposure Rapid urinary elimina+on Poor dermal absorp+on of Cr3+ salts (absent disrup+on) Cellular diffusion •  Hexavalent (Cr6+) –  Endogenous gastrointes+nal tract reducing agents –  Greater absorp+on than Cr3+ –  Facilitated cellular uptake •  Concentra+on in liver, kidney, spleen, sor +ssues, bone •  Increased urinary excre+on in stress, exercise, glucose loads, and in higher insulin resistance •  Pulmonary kine+cs (soluble vs. insoluble compounds) Chromium (Cr) Evalua+on •  Occupa+onal Safety and Health Administra+on (29 CFR 1910.1026(b)) Cr(VI): –  PEL: 5 µg/m3 (8-­‐hour TWA) –  Ac+on level: 2.5 µg/m3 (8-­‐hour TWA) •  No clear correla+on between [Crserum] / [Crblood] and physiologic effects. –  ATSDR: “increases in blood and urine chromium levels cannot be used to predict the kind of health effects that might develop from that exposure.” •  RBC accumula+on •  No commercially available chromium-­‐free needles •  Complete blood count, serum electrolytes, crea+nine, and liver enzymes tes+ng should be performed Chromium Chela+on Considera+ons Human Experience •  Cr(VI)  Cr(V)  Cr(IV)  Cr(III) •  BAL: unclear effects.1 No effect.2 •  EDTA: uninterpretable increased urinary elimina+on over 48 hours3 •  EDTA: rela+vely ineffec+ve short term lowering4 •  EDTA: no increased urinary elimina+on, 4x HD removal5 •  DMPS: “challenge”  unchanged chromium excre+on6 •  NAC+DMPS: “adjuvant therapy”7 •  NAC: without apparent renal toxicity8 1. Ellis EN, 1982. 2. Walpole, 1985. 3. Anderson RA, 1999. 4. Pazzaglia UE, 2011. 5. Kołacinski Z, 1999. 6. Torres-­‐Alanis O, 2000. 7. Lin C-­‐C, 2009. 8. Hantson P, 2005. Chromium Chela+on Considera+ons Human Experience •  Exchange transfusion –  Double: Crplasma 4,163 μg/L  1,043 μg/L; CrRBC 7,795 μg/L  1,474 μg/L1 –  ~double: Crplasma 5.9 μg/L  1.9 μg/L; CrRBC 0.43 μg/L  0.15 μg/L2 •  Hemodialysis –  Crplasma 1,249 μg/L  974 μg/L; CrRBC 990 μg/L  917 μg/L1 –  Cldialysis 12.4 ± 2.4 mL/min (62 mg/8 hours)3 –  Cldialysis 2.5 ± 0.8 mL/min4 –  3.3 mg/9 hours (vs. 3.74 mg/9 hours endogenous)5 •  Ascorbic acid (AA) therapy1,4,6-­‐8 1. Meert,KL, 1994. 2. Kelly WF, 1982. 3. Ellis EN, 1982. 4. Schiffl H, 1982. 5. Kołacinski Z, 1999. 6. Korallus U, 1984. 7. Walpole, 1985.8. Lin C-­‐C, 2009. 9. Hantson P, 2005. Chromium Chela+on Considera+ons Animal Experience •  D-­‐PCN: no increase in urinary clearance1 • 
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BAL: no increase in dialysis or urinary clearance1,2 EDTA: no increase in urinary clearance1 NAC: >3x increased urinary clearance (∼volume)3 AA: +me-­‐dependent mortality and renal effects4 DFO: effec+ve pre-­‐exposure; ineffec+ve post-­‐exposure5 1. Nowak-­‐Wiaderek W, 1975. 2. Ellis EN, 1982. 3. Banner W, 1986. 4. Bradberry SM, 1999. 5. Molina-­‐
Jijon E, 2012. Cr Chela+on Summary •  Species effects •  Address chromium source •  There is liJle evidence to suggest currently available chelators are efficacious •  NAC –  Anecdotal human use –  Limited suppor+ve animal study –  Familiar risk-­‐benefit profile •  Ascorbic acid –  Anecdotal human use –  Poten+al +me-­‐dependent risk-­‐benefit profile Cobalt hJp://www.ornl.gov/info/press_releases/photos/cobaltblue_sconce1.jpg Cobalt (Co) Exposures • 
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Essen+al nutrient Environment Industry Biomedical therapy and research Prostheses An+dote Cobalt Urinary μg/L CDC. Fourth Na+onal Report on Human Exposure to Environmental Chemicals, Updated Tables, 2011. Cobalt (Co) Toxicity •  “Hard metal” or “diamond polisher’s” pulmonary disease •  “Beer drinkers” cardiomyopathy •  Thyroid disease •  Hepatotoxicity •  Neuropathy •  Derma++s/hypersesi+vity •  Polycythemia Cobalt Kine+cs Variable GI absorp+on (∼ Fe, ∼ age) Dermal absorp+on (∼ integrity) Hepa+c concentra+on RBC uptake Prolonged pulmonary reten+on of insoluble Co Fecal elimina+on (∼ variable GI absorp+on) post oral exposure •  Urinary elimina+on post parenteral exposure • 
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Exposure μg/dL 25 20 CoBlood 15 CoUrine 10 5 0 0 50 100 150 Coair
200 (μg/m3) 250 300 350 400 Redrawn from data in Ichikawa Y, 1985. Cobalt Chela+on Considera+ons •  Source/Exposure •  FDA: “no commercially available standardized tests to assess metal-­‐ion levels” •  “Toxic” defini+ons of urinary and blood cobalt concentra+ons incomplete •  RBC par++oning affected by tube contents •  Organ systems evalua+ons –  Respiratory tract (inters++al disease, asthma) –  Skin –  Blood (polycythemia) –  Thyroid (thyromegaly, hypothyroidism) Regulatory Guidance •  U.K. Medicines and Healthcare Products Regulatory Agency –  “inves+gate pa+ents with painful MoM hip replacements. Specific tests should include evalua+on of cobalt and chromium ion levels in the pa+ent’s blood and cross sec+onal imaging including MRI or ultrasound scan” –  “if either cobalt or chromium ion levels are elevated above seven parts per billion (ppb), then a second test should be performed three months arer the first in order to iden+fy pa+ents who require closer surveillance, which may include cross sec+onal imaging” •  U.S. Food and Drug Administra7on –  “there is no evidence to support the need for checking metal ion levels in the blood or special imaging if pa+ents with MoM hip implants have none of the signs or symptoms described above and the orthopaedic surgeon feels the hip is func+oning properly.” –  “There are currently insufficient data to iden+fy any specific metal ion levels that would cause adverse systemic effects. As a result, it is not possible to cite a metal ion threshold value in the blood that would serve to confirm the e+ology of the symptoms.” –  “If metal ion (e.g. cobalt and chromium) levels are assessed, interpret the values in the context of the overall specific clinical scenario including symptoms, physical findings, and other diagnos+c results when considering further ac+ons. If clinical and imaging evalua+ons lead to the suspicion of an adverse reac+on to metal debris (e.g., sor +ssue mass), consider assessing and monitoring serial metal ion levels.” Cobalt Chela+on Considera+ons Human Experience •  CaNa2EDTA EDTA –  Short-­‐term Co lowering (prosthesis)1 –  Four-­‐fold increase in urinary Co excre+on (inges+on)2 –  Small non-­‐significant increase in urinary Co (infusion)3 1. Pazzaglia UE, 2011. 2. Henre+g F, 1988. 3. Waters RS, 2001. PubChem. NLM. Cobalt Chela+on Considera+ons Animal Studies N-­‐acetylcysteine PubChem. NLM. D-­‐penicillamine PubChem. NLM. Trien+ne PubChem. NLM. Cobalt Chela+on Considera+ons Animal Studies EDTA 100% 90% 80% DTPA Survival 70% 60% DTPA L-­‐Cys DMSA 50% 40% 30% 20% 10% 0% 0 0.6 1 1.4 Cobalt Chloride (mmol/kg IP) 1.8 r-­‐PCN Redrawn from data in Llobet JM, 1986. Cobalt Chela+on Considera+ons Animal Studies Elimina7on 80.9% 1.000 77.2% 62.5% Control GSH L-­‐Cys 0.100 0.010 Urinary elimina+on Brain Lung Spleen Blood Heart Skin/hair Skeleton Kidney Muscle 0.001 Liver 60Co : % administered radioac+vity 10.000 Redrawn from data in Levitskaia TG, 2010.
Cobalt Chela+on Considera+ons Animal Studies 60Co : % administered radioac+vity 10.000 Elimina7on 61.9% 1.000 48.3% 46.9% 0.100 Control D-­‐PCN Trien7ne 0.010 Redrawn from data in Levitskaia TG, 2010.
60Co : % administered radioac+vity Cobalt Chela+on Considera+ons Animal Studies Elimina7on 10.00 68.0% 1.00 60.0% 62.0% Control D-­‐PCN Trien7ne 0.10 0.01 0.00 Carcass Kidney Liver Blood Muscle Lung Spleen Skin Urine 24h Redrawn from data in Levitskaia TG, 2011. Co Chela+on Summary •  Evaluate appropriate organ systems for toxicity •  Address cobalt source •  There is liJle human evidence at all with which to provide a specific chela+on recommenda+on –  For 60Co (per REAC/TS and NCRP) •  DTPA preferred •  DMSA, EDTA, NAC suggested –  For others •  NAC & EDTA considered Uranium US DOE. •  Background •  Industry Uranium (U) Exposure –  Mining/Milling –  Refining –  Nuclear fuel processing •  Military conflict –  Weapons assembly –  Combat –  Firefigh+ng •  Environmental remedia+on •  Terrorism Uranium (U) Exposure •  Inhala+on •  Inges+on –  Food/water contamina+on –  Inten+onal •  Absorp+on –  Intact skin –  Wounded skin Uranium (U) Exposure •  Present naturally in virtually all soil, rock & water •  Average daily uranium intake from food: 0.07-­‐1.1 µg/day •  Safe Drinking Water Act limit: 30 µg/L in drinking water •  Clean Air Act: maximum dose to an individual from uranium in the air is 10 millirem •  Uranium Mill Tailings Radia'on Control Act Uranium Urinary μg/L CDC. Fourth Na+onal Report on Human Exposure to Environmental Chemicals, Updated Tables The U.S. NRC ac+on level: 15 μg/L urinary uranium (occupa+onal exposure) U.S. Nuclear Regulatory Commission (U.S. NRC). U.S. Nuclear Regulatory Commission (NRC) Guide 8.22–Bioassay at uranium mills. Washington (DC): NRC; July 1978. Uranium Kine+cs •  Inges+on –  Poor absorp+on (0.1%-­‐6%) •  Inhala+on –  Pulmonary reten+on (t½ = weeks-­‐years) –  Limited absorp+on (≤ 5%) •  Absorp+on •  Shrapnel (DU) •  Accumula+on –  Skeletal, renal, hepa+c •  Elimina+on –  > 50% urinary elimina+on within 24 hours (parenteral exposure) –  ≥ fecal elimina+on (oral exposure) Uranium (U) •  Radiological considera+ons: 238U  234Th  234Pa  234U  230Th  226Ra  222Rn  –  No IARC classifica+on •  While 238U and 235U are “radioac+ve,” their half-­‐lives of alpha-­‐decay to 234Th and 231Th are on the order of billions and millions of years (respec+vely), making them primarily chemical toxicants. •  Chemical toxici+es of uranium species and forms with variant isotopic ra+os (natural, depleted, and enriched) are iden+cal. Uranium (U) •  Hexavalent uranium U(VI), as the dioxo uranyl ca+on [UO2]2+, is the most stable state in vivo. •  Target: renal tubular epithelium •  Respiratory tract (inhala+on) •  Hepa+c dysfunc+on •  Anemia •  Myocardi+s PubChem. NLM. hJp://www2.niddk.nih.gov/NIDDKLabs/Glomerular_Disease_Primer/NormalKidney.htm Specia+on and Solubility Interstitial &
plasma fluids
[U] = 1 µM
Bile
[U] = 1 µM
Reprinted with permission from Sutton M, Burastero SR. Uranium(VI) Solubility and Speciation in Simulated Elemental Human Biological Fluids. Chem.
Res. Toxicol. 2004; 17(11):1468-1480. Copyright 2004 American Chemical Society.
Diethylenetriaminepentaace+c acid (DTPA) •  Cleared by glomerular filtra+on •  Negligible GI absorp+on •  Ineffec+ve –  Bone –  Total body –  Package inserts: Ca-­‐DTPA and Zn-­‐DTPA “treatments are not expected to be effec+ve for uranium and neptunium.” • 
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Nephrotoxicity Suppressed hematopoiesis Teratogenicity/Embryotoxicity “Bycatch” DTPA “Bycatch” •  Zinc, magnesium, manganese, and metalloproteinase deple+on •  Animal models –  Significantly increased urinary elimina+on of Ca, Cu, Fe, Zn, and Mn –  Concomitant inter-­‐+ssue distribu+on –  Enhanced fecal excre+on of Mn Other Chelators Tiron (Tiferron) •  Favorable removal as U(VI)-­‐
+ron2 only at large molar ra+os •  Limited prac+cal value for treatment of uranium exposures PubChem. NLM. Other Chelators Hydroxypyridonates (HOPOs) •  5-­‐LIO(Me-­‐3,2-­‐HOPO) and 3,4,3-­‐LI(1,2-­‐ HOPO) l = n = 3; m = 4; X = H Raymond et al. Assignee: USA a/r/b US DOE. USP4698431 (06 Oct 1987). PubChem. NLM. Other Chelators Hydroxypyridonates (HOPOs) Percent of injected 232U or 233U 100.0% Control (fed) Control (fas/ng) CaNa3-­‐DTPA 10.0% 5-­‐LIO
(Me-­‐3,2-­‐
HOPO) 3,4,3-­‐LI(1,2-­‐
HOPO) 1.0% 0.1% Skeleton So_ 7ssue Kidneys Whole body Urine Feces + GI contents Drawn from data in Durbin PW, 2008. Other Considera+ons •  Address uranium source •  Sodium bicarbonate (NaHCO3) •  Dialysis Sodium Bicarbonate (NaHCO3) Sodium Bicarbonate (NaHCO3) •  Na+onal Council on Radia+on Protec+on and Measurements (NCRP) preferred •  Label –  “Sodium Bicarbonate is further indicated in the treatment of certain drug intoxica+ons, including barbiturates (where dissocia+on of the barbiturate-­‐protein complex is desired), in poisoning by salicylates or methyl alcohol and in hemoly+c reac+ons requiring alkaliniza+on of the urine to diminish nephrotoxicity of hemoglobin and its breakdown products.” Uranium Chela+on Summary •  Not supported: DTPA •  Current recommenda+on: sodium bicarbonate (NaHCO3) •  Consider dialysis •  Experimental: hydroxypyridonates References