black & white slide set, part three · beneﬁt in acute intoxication by inorganic arsenic or...

BLACK & WHITE SLIDE SET, PART THREE

Use & Misuse of Metal Chelation Therapy February 29, 2012, 7:45am-5:00pm EST

Conference & Live Webinar

Roybal Campus, Global Communications Center, B19, Auditorium A

Centers for Disease Control and Prevention, Atlanta, GA

The American College of Medical Toxicology In conjunction with the Medical Toxicology Foundation

with support from the Agency for Toxic Substances and Disease Registry (ATSDR).

Lecture slides are available as PDFs. Only material submitted by the lecturer is available. Please contact the speaker directly if you would like additional versions or materials. The files contained on this page are the intellectual property of the American College of Medical Toxicology, and the authors and speakers. No unauthorized download, copy or distribution of these files is permitted.

American College of Medical Toxicology 10645 N. Tatum Blvd., Suite 200-111, Phoenix, AZ 85028, T: 1602 533 6340

2/23/12

1

The Role of Chela+on During Pregnancy in the Lead Poisoned Pa+ent Mary Jean Brown, ScD, RN Chief Healthy Homes/Lead Poisoning PrevenDon Branch Centers for Disease Control and PrevenDon, Atlanta, GA

“The findings and conclusions in this presentation have not been formally disseminated by the Centers for Disease Control and Prevention/the Agency for Toxic Substances and Disease Registry and should not be construed to represent any agency determination or policy.”

www.cdc.gov/nceh/lead/publicaDons

In the United States, blood lead levels at which chelaDon therapy would be considered is an extremely rare event.

The geometric mean blood lead level of US women 15-‐49 years old is less than 0.5 µg/dL

Approximately 1% of US women of childbearing age have blood lead levels ≥ 5 µg/dL and lead exposure is important for specific subpopulaDons including new immigrants and women with occupaDonal exposure to lead.

2/23/12

2

Severe maternal lead intoxicaDon, such as encephalopathy, will warrant chelaDon regardless of the stage of pregnancy.

Pregnant women with confirmed BLLs ≥45 µg/dL (repeated on at least two venous blood samples collected within 24 hours) may be considered for chelaDon therapy and should be managed in conjuncDon with experts in high-‐risk pregnancy and lead poisoning.

Immediate removal from the lead source is THE FIRST PRIORITY and, in some cases, may require hospitalizaDon.

When chelaDon is being considered, it should be performed in an inpaDent se_ng only with close monitoring of the paDent and in consultaDon with a physician with experDse in the field of lead chelaDon therapy.

Reserving the use of chelaDng agents for later in pregnancy is consistent with the general concern about the use of unusual drugs during the period of organogenesis

Data regarding the reproducDve risk associated with chelaDon during pregnancy are sparse. Most case reports of infant outcomes report on the use of chelaDng agents a`er the first trimester

2/28/12!

1!

The Weight of the Evidence: The Role of Chelation in the Treatment

of Arsenic and Mercury Poisoning

Michael J. Kosnett, MD, MPH Associate Clinical Professor Division of Clinical Pharmacology & Toxicology University of Colorado School of Medicine, and Department of Environmental and Occupational Health Colorado School of Public Health [email protected]

Father J.A. Nieuwland

Dichloro (2-chlorovinyl) arsine “Lewisite”

Capt. Winford Lee Lewis

World War I, Poison Gas, and the “Dew of Death”

London, WWII

2/28/12!

2!

Cl - C = C -As!Cl!

Cl!Lewisite!

Skin LD50 24 mg/kg (rat)!

C!

C!

SH!

SH!+ As - R!

C!

C!

S!

S!As - R!

H - C - C - C - OH! S S H! H H!

H H H!

2, 3 - Dimercaptopropanol!

Dimercaprol “British Anti-Lewisite”!

BAL!

% Decline in O2 uptake (skin + pyruvate)!after Lewisite (0.03mM), 1 hr!

Untreated !50!% ! 2-Mercaptoethanol (.54 mmol) !55! ! BAL (.27 mmol) ! 6!!

[Stocken & Thompson, Biochem J 40:535-548; 1946]!

Survival (rats) after topical lewisite (≈ 35 mg/kg) (Treatment begun at 30 min post exposure) Untreated ! ! ! ! ! 0/27! ! 2-Mercaptoethanol! ! ! ! 0/6 ! ! BAL (50 - 70 mg/kg inunction) ! ! 21/21 !

2/28/12!

3!

Luetscher et al, J Clin Inv 25:534-540; 1946

BAL increases urinary arsenic excretion in humans

Human Arsenic Intoxications Treated with BAL:!Comparison to Untreated Historical Controls!

2. In children admitted to Charity Hospital for arsenic poisoning [Woody & Komentani. Pediatr 1:372-378; 1948]!

! ! ! ! ! ! !! ! ! % Symptomatic!!N !Deaths !LOS(d) !@Admit! @12h!

Without BAL !111 ! 3 ! 4.2 ! 46.2% ! 29.3%!

With BAL ! 42 ! 0 ! 1.6 ! 47.6% ! 0 %!

1. In syphilis patients with arsenical dermatitis, BAL appeared to reduce the average duration of dermatitis (21.5 days vs 62.5 days) [Carleton et al, Quart J Med 17:49-85; 1948]!

Prior to 6d BAL rx! 14 d after start

of BAL rx!

BAL has high incidence of side effects At high therapeutic doses (4 - 5mg/kg i.m. in peanut oil) as many as 2 / 3 of patients experience side effects which commonly include:

Nausea and Vomiting Restlessness Hypertension Lacrimation and Salivation Fever Pain at injection site

2/28/12!

4!

2,3 dimercaptopropane sulfonic acid, Na salt

DMPS, unithiol

LD50 i.p. (m) 1371 mg/kg

2,3 dimercaptosuccinic acid, Na salt

DMSA, succimer

LD50 I.p. (m) 2500 mg/kg

Aposhian et al. Fund Appl Toxicol 4:S58-S70; 1984

DMPS is more potent than DMSA as an arsenic antidote

Reversal of arsenite inhibition of renal PDH enzyme activity in vivo

time Aposhian et al, ibid; 1984

2/28/12!

5!

Efficacy of chelation is enhanced by prompt administration following metal exposure

Delayed chelation is diminished chelation

Time - Dependent Efficacy of Chelation in Experimental Arsenic Poisoning!

1. In Lewisite poisoned rabbits (Eagle et al, 1946):!

One injection BAL 5 min post exposure: 100% survival!Multiple injections begun 6h post exp. 0% "!

2. In arsenite poisoned mice (0.14 mmol/kg sc)!! (Tadlock & Aposhian, 1980):!

0.25mmol/kg DMSA !

at 60 min 79% survival ! !! at 120 min 55% survival!

Randomized Placebo-Controlled Trial of 2,3-Dimercapto-1-propanesulfonate (DMPS) in Therapy of Chronic Arsenicosis Due to Drinking Arsenic-Contaminated Water [Guha Mazumder et al, Clin Toxicol 39:665-674; 2001]

•  21 adults with chronic arsenic exposure (avg ≈ 20 y) and ! !!hyperpigmentation/hyperkeratosis!

•  Removed from As exposure < 3 mo; avg Urine As = 46 µg/L!•  Single-blind randomization to 4 one-week courses of DMPS 100 mg qid! !(n=10) or placebo (n=10) over a 7 week period (in - hospital)!

Primary outcome variable: Change in “clinical score” of multiple signs and symptoms assessed pre- and post-treatment!

Skin biopsy pre- and post-treatment also assessed by blinded pathologist!

2/28/12!

6!

Group Baseline clinical score

Final

clinical score

P -value

DMPS 8.90 ± 2.84 3.27 ± 1.73 0.0002 Placebo 8.50 ± 1.96 5.40 ± 2.12 0.003 Authors’ conclusion: DMPS “caused significant improvement in the clinical score of patients suffering from chronic arsenic toxicity” Many limitations render findings inconclusive, including: •  More than half of clinical improvement resulted from non-blinded assessment of subjective parameters, including “lung disease” (cough, dyspnea, and rales/ronchi), and “weakness”

•  Subjects received nonrandomized “symptomatic treatment” (e.g. bronchodilators)

•  Groups differed by gender: DMPS (9M, 2F); Placebo (5M, 5F)

•  Nonblinded clinical observer reported improvement in skin findings not confirmed by blinded skin biopsy assessment

Acute Human Poisoning by Mercuric Chloride: Decreased Mortality with BAL Compared to Historical

Controls Longcope WT, Luetscher JA. Ann Intern Med

31:545-553; 1949

2/28/12!

7!

Chelators - Acute Hg intoxication

HgCl2 109 mg/kg p.o. to rats. Single dose chelator given 15 minutes later.!

Chelator dose Mortality* Percent Control 9 / 10 90 % BAL (i.p.) 400 µM (50 mg/kg) 5 / 10 50 % DMSA (p.o.) 1600 µM (291 mg/kg) 4 / 10 40 % DMPS (p.o.) 1600 µM (336 mg/kg) 0 / 10 0 %

*by day 14!

[Nielson & Anderson, Hum Exp Toxicol 10:423-430, 1991]!

Immediate DMPS prevents oliguric renal failure from i.v. HgCl2 in rats

HgCl2 1.4 mg/kg (5 µmol). DMPS 54 mg/kg (250 µmol) i.v.!

Urine Volume (ml)!

No DMPS!Immediate!DMPS!

DMPS after!24 hours!

Day 1 14.5 10.0 14.5 Day 2 0.7 6.0 1.0 Day 3 4.0 15.5 7.0 Histopathology (+) (-) (+)

n = 4 per group [Wannag & Aaseth, Acta Pharmacol Toxicol 46:81-88; 1980]!

DMPS exceeds DMSA in reduction of renal Hg content after i.v. HgCl2

[Planas-Bohne, Toxicology 19:275-278; 1981]

HgCl2 (0.67 mg/kg) i.v. to rats. After 24 h, chelators begun at 100 µmol/kg i.p. 4x/wk x 4 wk

Kidney Hg content (% of administered dose) (n = 6 per group)

Control 11.57 ± 0.04 DMSA 5.73 ± 1.02 DMPS 0.71 ± .71

2/28/12!

8!

Antidotal benefit from DMPS is lost if treatment is delayed

HgCl2 1 mg/kg i.v. to rats. DMPS (150 µmol/kg) (32mg/kg)!p.o. given qd x 5 beginning 6 or 24 hours later:!

Group Mortality* Percent Survival time Control 8 / 18 44 % 19 days DMPS @ 6h 1 / 18 6 % 29 DMPS @ 24h 6 / 18 33 % 22

* by 30 d!

[Planas-Bohne, Clin Chem and Chem Toxicol of Metals; pp 119-122; 1977]!

Reported Adverse Effects: DMPS, DMSA!

• Allergic reactions, exanthems (1-10%)!• Mild gastrointestinal complaints (e.g. nausea)(1-10%)!• Isolated, reversible, slight increase in LFT's,

decrease in wbc!• Increase in urinary Cu, Zn w/o ∆ serum levels!

Mobilization does not always equal excretion

Net redistribution of metal deposits, even when accompanied by increased excretion, may have undesirable consequences.

2/28/12!

9!

Dimercaprol (BAL) redistributes arsenic to the brain

Aposhian et al, ibid 1984

Dimercaprol (BAL) redistributes Hg2+ to the brain

Berlin M, Rylander R. J Pharm Exp Ther 146:236-240; 1964

DMPS increases urine mercury excretion in acute Hg vapor intoxication [Cichini GM et al. Intensivmed Notf Med 26:303-306; 1989]!

• 19 caisson workers drilling a subway tunnel developed acute symptomatic Hg° vapor intoxication after a mean of 27h (range ≈ 8 - 40h) exposure. ! • Subjects randomized to DMPS (100 mg or 200 mg tid) or D-Pen 150 mg tid!

2/28/12!

10!

Following subacute exposure to Hg vapor, DMPS and DMSA reduce Hg concentration in kidneys but not the brain

Rats (n = 8 per group) underwent 14 days inhalation to Hgº (244 µg/m3)!Seven days later, treated for 5 days with 1 mmol/kg/day po

DMSA or DMPS, then sacrificed 24 hours later.!

Group!Hg concentration (µg/100g body wt)! Kidney Brain!

Hgº only! 2.78 ± 0.60! 0.088 ± 0.017!

DMSA! 0.46 ± 0.20! 0.076 ± 0.008!

DMPS! 0.10 ± 0.02! 0.098 ± 0.030!Control (n=4) ! (no Hg, no chelator)!

0.17 ± 0.15! 0.0022 ± 0.0005!

Buchet JP, Lauwerys RR. Toxicology 54:323-333; 1989!

Summary!

1. Chelation with DMSA, DMPS, or BAL has therapeutic benefit in acute intoxication by inorganic arsenic or inorganic mercury salts if administered promptly (within minutes to hours)!

2. DMPS and DMSA have a higher therapeutic index than BAL, and unlike BAL do not redistribute As or Hg to the brain!

3. Although chelation for chronic intoxication by As or Hg may accelerate metal excretion and diminish concentration in some organs, therapeutic efficacy in terms of decreased morbidity and mortality is largely unestablished.!

2/28/12

1

The Role of Chela/on in the Treatment of Other Metal Poisonings

Silas W. Smith, MD

NYU School of Medicine Bellevue Hospital Center

NYU Langone Medical Center New York City Poison Control Center

Declara/ons and Disclaimers

Salaried, academic physician.

Nearly everything I will talk about is off-‐label, if one exists.

Trade, product, and commercial names are for iden/fica/on purposes only and do not cons/tute endorsement.

My views do not necessarily reflect the those of my employers, affilia/ons, conference par/cipants, or conference supporters.

Modified from hUp://periodic.lanl.gov/index.shtml

8A1A

2A

3B 4B 5B 6B 7B 8B 11B 12B

3A 4A 5A 6A 7A

element0names0in0blue0are0liquids0at0room0temperatureelement0names0in0red0are0gases0at0room0temperatureelement0names0in0black0are0solids0at0room0temperature

Periodic(Table(of(the(Elements

Los Alamos National Laboratory Chemistry Division

11

1

3 4

12

19 20 21 22 23 24 25 26 27 28 29 30

37 38 39 40 41 42 43 44 45 46 47 48

55 56

58 59 60

72 73 74 75 76 77 78 79 80

87 88

90

57

89 91 92 93 94 95 96

104 105 106 107 108 109 110 111 112

61 62 63 64 65 66 67

97 98 99

68 69 70 71

100 101 102 103

31

13 14 15 16 17 18

32 33 34 35 36

49 50 51 52 53 54

81 82 83 84 85 86

5 6 7 8 9 10

2H

Li

Na

K

Rb

Cs

Fr

Be

Mg

Ca

Sr

Ba

Ra

Sc Ti V Cr Mn Fe Co Ni Cu Zn

Y Zr Nb Mo Tc Ru Rh Pd Ag Cd

* Hf Ta W Re Os Ir Pt Au Hg

** Rf Db Sg Bh Hs Mt Ds Rg Cn

B C N O F

Al Si P S Cl

Ga Ge As Se Br

In Sn Sb Te I

Tl Pb Bi Po At

He

Ne

Ar

Kr

Xe

Rn

39.10

85.47

132.9

(223)

9.012

24.31

40.08

87.62

137.3

(226)

44.96

88.91

47.88

91.22

178.5

(261) (262) (266) (264) (277) (268) (271) (272) (285)

114 115113 116 117 118Uuq Uuh Uuo

(289)

Uup(289)

Uut(286) (291)

Uus(294) (294)

50.94

92.91

180.9

52.00

95.94

183.9

54.94

(98)

186.2

55.85

101.1

190.2 192.2

102.9

58.93 58.69

106.4

195.1 197.0

107.9

63.55 65.39

112.4

200.5

10.81

26.98

12.01

28.09

14.01

69.72 72.64

114.8 118.7

204.4 207.2

30.97

74.92

121.8

209.0 (209) (210) (222)

16.00 19.00 20.18

4.003

32.07 35.45 39.95

78.96 79.90 83.79

127.6 126.9 131.3

140.1 140.9 144.2 (145) 150.4 152.0 157.2 158.9 162.5 164.9 167.3 168.9 173.0 175.0

232.0

138.9

(227) 231 238 (237) (244) (243) (247) (247) (251) (252) (257) (258) (259) (262)

Ce Pr Nd Pm Sm Eu Gd Tb Dy Ho Er Tm Yb Lu

Th

La

Ac Pa U Np Pu Am Cm Bk Cf Es Fm Md No Lr

hydrogen

barium

francium radium

strontium

sodium

vanadium

berylliumlithium

magnesium

potassium calcium

rubidium

cesium

helium

boron carbon nitrogen oxygen fluorine neon

aluminum silicon phosphorus sulfur chlorine argon

scandium titanium chromium manganese iron cobalt nickel copper zinc gallium germanium arsenic selenium bromine krypton

yttrium zirconium niobium molybdenum technetium ruthenium rhodium palladium silver cadmium indium tin antimony tellurium0 iodine xenon

hafnium

cerium praseodymium neodymium promethium samarium europium0 gadolinium terbium0 dysprosium holmium erbium thulium ytterbium lutetium

tantalum tungsten rhenium osmium iridium platinum gold mercury thallium lead bismuth polonium astatine radon

thorium

lanthanum

actinium protactinium0 uranium neptunium plutonium americium curium berkelium californium einsteinium fermium mendelevium nobelium lawrencium0

rutherfordium dubnium seaborgium bohrium hassium meitnerium darmstadtium roentgenium copernicium

1.008

6.941

22.99

Lanthanide0Series*

Actinide0Series**

1s1

[Ar]4s23d104p3[Ar]4s23d3[Ar]4s13d10

[Ne]3s23p6[Ne]3s23p4

[Ar]4s1[Ar]4s23d10

1s2

[He]2s1 [He]2s2

[Ar]4s23d7

[Ne]3s23p5

[He]2s22p1[He]2s22p2 [He]2s22p3

[Ar]4s23d5

[He]2s22p4 [He]2s22p5 [He]2s22p6

[Ar]4s23d104p5

[Ne]3s1 [Ne]3s23p1 [Ne]3s23p3[Ne]3s23p2

[Rn]7s25f146d2

[Ne]3s2

[Ar]4s2 [Ar]4s23d1 [Ar]4s23d2 [Ar]4s13d5[Ar]4s23d6

[Ar]4s23d8 [Ar]4s23d104p1 [Ar]4s23d104p2 [Ar]4s23d104p4 [Ar]4s23d104p6

[Kr]5s1 [Kr]5s2 [Kr]5s24d1 [Kr]5s24d2 [Kr]5s14d4 [Kr]5s14d5 [Kr]5s24d5 [Kr]5s14d7 [Kr]5s14d8 [Kr]4d10[Kr]5s14d10 [Kr]5s24d10 [Kr]5s24d105p1 [Kr]5s24d105p2 [Kr]5s24d105p3 [Kr]5s24d105p4 [Kr]5s24d105p5

[Kr]5s24d105p6

[Xe]6s1 [Xe]6s2

[Xe]6s24f15d1 [Xe]6s24f3 [Xe]6s24f4 [Xe]6s24f5 [Xe]6s24f6 [Xe]6s24f7 [Xe]6s24f75d1 [Xe]6s24f9 [Xe]6s24f10 [Xe]6s24f11 [Xe]6s24f12 [Xe]6s24f13 [Xe]6s24f14 [Xe]6s24f145d1

[Xe]6s24f145d2 [Xe]6s24f145d3 [Xe]6s24f145d4 [Xe]6s24f145d5 [Xe]6s24f145d6 [Xe]6s24f145d7 [Xe]6s14f145d9[Xe]6s14f145d10

[Xe]6s24f145d10 [Xe]6s24f145d106p1 [Xe]6s24f145d106p2 [Xe]6s24f145d106p3 [Xe]6s24f145d106p4 [Xe]6s24f145d106p5[Xe]6s24f145d106p6

[Rn]7s1 [Rn]7s2

[Rn]7s26d2

Xe]6s25d1

[Rn]7s26d1 [Rn]7s25f26d1 [Rn]7s25f36d1 [Rn]7s25f46d1 [Rn]7s25f6 [Rn]7s25f7 [Rn]7s25f76d1 [Rn]7s25f9 [Rn]7s25f10 [Rn]7s25f11 [Rn]7s25f12 [Rn]7s25f13 [Rn]7s25f14 [Rn]7s25f146d1

[Rn]7s25f146d3 [Rn]7s25f146d4 [Rn]7s25f146d5 [Rn]7s25f146d6 [Rn]7s25f146d7 [Rn]7s15f146d9

Inert Elements

Transi.on Metals

Alkali Metals

Alkali Earth Metals

Halogens

Other Metals

Non metals

Essen%al Diagnos%c/ Therapeu%c

Discussed

2/28/12

2

Modified from hUp://periodic.lanl.gov/index.shtml

8A1A

2A

3B 4B 5B 6B 7B 8B 11B 12B

3A 4A 5A 6A 7A

element0names0in0blue0are0liquids0at0room0temperatureelement0names0in0red0are0gases0at0room0temperatureelement0names0in0black0are0solids0at0room0temperature

Periodic(Table(of(the(Elements

Los Alamos National Laboratory Chemistry Division

11

1

3 4

12

19 20 21 22 23 24 25 26 27 28 29 30

37 38 39 40 41 42 43 44 45 46 47 48

55 56

58 59 60

72 73 74 75 76 77 78 79 80

87 88

90

57

89 91 92 93 94 95 96

104 105 106 107 108 109 110 111 112

61 62 63 64 65 66 67

97 98 99

68 69 70 71

100 101 102 103

31

13 14 15 16 17 18

32 33 34 35 36

49 50 51 52 53 54

81 82 83 84 85 86

5 6 7 8 9 10

2H

Li

Na

K

Rb

Cs

Fr

Be

Mg

Ca

Sr

Ba

Ra

Sc Ti V Cr Mn Fe Co Ni Cu Zn

Y Zr Nb Mo Tc Ru Rh Pd Ag Cd

* Hf Ta W Re Os Ir Pt Au Hg

** Rf Db Sg Bh Hs Mt Ds Rg Cn

B C N O F

Al Si P S Cl

Ga Ge As Se Br

In Sn Sb Te I

Tl Pb Bi Po At

He

Ne

Ar

Kr

Xe

Rn

39.10

85.47

132.9

(223)

9.012

24.31

40.08

87.62

137.3

(226)

44.96

88.91

47.88

91.22

178.5

(261) (262) (266) (264) (277) (268) (271) (272) (285)

114 115113 116 117 118Uuq Uuh Uuo

(289)

Uup(289)

Uut(286) (291)

Uus(294) (294)

50.94

92.91

180.9

52.00

95.94

183.9

54.94

(98)

186.2

55.85

101.1

190.2 192.2

102.9

58.93 58.69

106.4

195.1 197.0

107.9

63.55 65.39

112.4

200.5

10.81

26.98

12.01

28.09

14.01

69.72 72.64

114.8 118.7

204.4 207.2

30.97

74.92

121.8

209.0 (209) (210) (222)

16.00 19.00 20.18

4.003

32.07 35.45 39.95

78.96 79.90 83.79

127.6 126.9 131.3

140.1 140.9 144.2 (145) 150.4 152.0 157.2 158.9 162.5 164.9 167.3 168.9 173.0 175.0

232.0

138.9

(227) 231 238 (237) (244) (243) (247) (247) (251) (252) (257) (258) (259) (262)

Ce Pr Nd Pm Sm Eu Gd Tb Dy Ho Er Tm Yb Lu

Th

La

Ac Pa U Np Pu Am Cm Bk Cf Es Fm Md No Lr

hydrogen

barium

francium radium

strontium

sodium

vanadium

berylliumlithium

magnesium

potassium calcium

rubidium

cesium

helium

boron carbon nitrogen oxygen fluorine neon

aluminum silicon phosphorus sulfur chlorine argon

scandium titanium chromium manganese iron cobalt nickel copper zinc gallium germanium arsenic selenium bromine krypton

yttrium zirconium niobium molybdenum technetium ruthenium rhodium palladium silver cadmium indium tin antimony tellurium0 iodine xenon

hafnium

cerium praseodymium neodymium promethium samarium europium0 gadolinium terbium0 dysprosium holmium erbium thulium ytterbium lutetium

tantalum tungsten rhenium osmium iridium platinum gold mercury thallium lead bismuth polonium astatine radon

thorium

lanthanum

actinium protactinium0 uranium neptunium plutonium americium curium berkelium californium einsteinium fermium mendelevium nobelium lawrencium0

rutherfordium dubnium seaborgium bohrium hassium meitnerium darmstadtium roentgenium copernicium

1.008

6.941

22.99

Lanthanide0Series*

Actinide0Series**

1s1

[Ar]4s23d104p3[Ar]4s23d3[Ar]4s13d10

[Ne]3s23p6[Ne]3s23p4

[Ar]4s1[Ar]4s23d10

1s2

[He]2s1 [He]2s2

[Ar]4s23d7

[Ne]3s23p5

[He]2s22p1[He]2s22p2 [He]2s22p3

[Ar]4s23d5

[He]2s22p4 [He]2s22p5 [He]2s22p6

[Ar]4s23d104p5

[Ne]3s1 [Ne]3s23p1 [Ne]3s23p3[Ne]3s23p2

[Rn]7s25f146d2

[Ne]3s2

[Ar]4s2 [Ar]4s23d1 [Ar]4s23d2 [Ar]4s13d5[Ar]4s23d6

[Ar]4s23d8 [Ar]4s23d104p1 [Ar]4s23d104p2 [Ar]4s23d104p4 [Ar]4s23d104p6

[Kr]5s1 [Kr]5s2 [Kr]5s24d1 [Kr]5s24d2 [Kr]5s14d4 [Kr]5s14d5 [Kr]5s24d5 [Kr]5s14d7 [Kr]5s14d8 [Kr]4d10[Kr]5s14d10 [Kr]5s24d10 [Kr]5s24d105p1 [Kr]5s24d105p2 [Kr]5s24d105p3 [Kr]5s24d105p4 [Kr]5s24d105p5

[Kr]5s24d105p6

[Xe]6s1 [Xe]6s2

[Xe]6s24f15d1 [Xe]6s24f3 [Xe]6s24f4 [Xe]6s24f5 [Xe]6s24f6 [Xe]6s24f7 [Xe]6s24f75d1 [Xe]6s24f9 [Xe]6s24f10 [Xe]6s24f11 [Xe]6s24f12 [Xe]6s24f13 [Xe]6s24f14 [Xe]6s24f145d1

[Xe]6s24f145d2 [Xe]6s24f145d3 [Xe]6s24f145d4 [Xe]6s24f145d5 [Xe]6s24f145d6 [Xe]6s24f145d7 [Xe]6s14f145d9[Xe]6s14f145d10

[Xe]6s24f145d10 [Xe]6s24f145d106p1 [Xe]6s24f145d106p2 [Xe]6s24f145d106p3 [Xe]6s24f145d106p4 [Xe]6s24f145d106p5[Xe]6s24f145d106p6

[Rn]7s1 [Rn]7s2

[Rn]7s26d2

Xe]6s25d1

[Rn]7s26d1 [Rn]7s25f26d1 [Rn]7s25f36d1 [Rn]7s25f46d1 [Rn]7s25f6 [Rn]7s25f7 [Rn]7s25f76d1 [Rn]7s25f9 [Rn]7s25f10 [Rn]7s25f11 [Rn]7s25f12 [Rn]7s25f13 [Rn]7s25f14 [Rn]7s25f146d1

[Rn]7s25f146d3 [Rn]7s25f146d4 [Rn]7s25f146d5 [Rn]7s25f146d6 [Rn]7s25f146d7 [Rn]7s15f146d9

Inert Elements

Transi.on Metals

Alkali Metals

Alkali Earth Metals

Halogens

Other Metals

Non metals

Administer Chela.on

Chela/on of Other Metals (Reduc&o ad absurdum)

Purge Metal

(En.rely beneficial effects)

2/28/12

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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

Dose

Toxicity

Adverse Effe

ct

Deficiency Homeostasis

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Aluminum

Library of Congress. hUp://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

Aluminum (Al) Toxicity

•  Central nervous system (“dialysis demen/a”)

•  Metabolic bone disease

•  Anemia

•  Cardiomyopathy

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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) – Ferroxamine (FO)


•  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

Lillevang ST, 1989. McCauley J, 1989. Novar/s, 2011. Sherrard DJ, 1988.

2/28/12

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•  Timing

•  Dose •  Dialysis •  Bycatch

Andriani M, 1996.

AlO/Al

1. Andriani M, 1996. 2. Barat JD, 1996. 3. Douthat WG, 1994. 4. Kan WC, 2010.

Andriani M, 1996

Alterna/ve Poten/al Chelators

•  Deferiprone – L1, 1,2-‐ dimethyl-‐3-‐hydroxypyrid-‐4-‐one

•  Deferasirox – 4-‐[3,5-‐Bis (2-‐hydroxyphenyl)-‐1H-‐1,2,4-‐triazol-‐1yl]-‐benzoic acid

PubChem. NLM.

PubChem. NLM.

Alterna/ve Chelator Issues •  Deferiprone1,2

–  Stoichiometry, 3:1 – Agranulocytosis –  Copper, zinc bycatch

•  Deferasirox2,3 –  Stoichiometry, 2:1 –  Renal impairment (failure) – Hepa/c impairment (failure) – Gastrointes/nal hemorrhage –  Copper, zinc bycatch

1. ApoPharma USA, Inc., 2011. 2. Kontoghiorghes GJ, 1995. 3. Novar/s, 2011.

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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

hUp://upload.wikimedia.org/wikipedia/commons/0/08/Chromium_crystals_and_1cm3_cube.jpg (Crea/ve Commons)

Chromium

Chromium (Cr) Exposures

•  Essen/al nutrient •  Environment

– Water

– Food – Supplements – CCA

•  Industrial •  Biomedical

– Prostheses – Stents hUp://www.netl.doe.gov/newsroom/netlog/

july2011/images/stent.jpg

hUp://www.ecy.wa.gov/programs/tcp/sites_brochure/dirt_alert/other_info/arsenic_treated_wood.html

hUp://www.arb.ca.gov/training/images/290.7.jpg

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Chromium (Cr) Kine/cs

•  Trivalent (Cr3+) –  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, sos /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) Toxicity

•  Hexavalent (Cr6+) vs. trivalent (Cr3+) •  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 •  Cr6+: IARC Group I carcinogen1,2 hUp://www.cdc.gov/niosh/topics/

skin/images/derm047.gif

hUp://www.cdc.gov/niosh/topics/skin/images/derm039.gif

1. IARC, 1990. 2. IARC, 2011.

Chromium Chela/on Considera/ons Human Experience

•  Cr(VI) Cr(V) Cr(IV) Cr(III)

•  BAL: unclear effects.1 No effect2 •  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 plus 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.

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Chromium Chela/on Considera/ons Human Experience (Adjuvant Therapies)

•  Exchange transfusion –  Double: Crplasma 4,163 1,043 μg/L; CrRBC 7,795 1,474 μg/L1 –  ∼Double: Crplasma 5.9 1.9 μg/L; CrRBC 0.43 0.15 μg/L2

•  Hemodialysis –  Crplasma 1,249 974 μg/L; CrRBC 990 917 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-‐9

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

•  AA: /me-‐dependent mortality and renal effects1

•  ALA: no change in urinary clearance2 •  BAL

•  Decreased urinary and stool clearance2 •  No increase in dialysis or urinary clearance3

•  DFO: effec/ve pre-‐exposure; ineffec&ve post-‐exposure4 •  D-‐PCA: decreased urinary clearance2 •  EDTA: no increase in urinary clearance2 •  NAC: >3x increased urinary clearance (∼volume)5

1. Bradberry SM, 1999. 2. Nowak-‐Wiaderek W, 1975. 3. Ellis EN, 1982. 4. Molina-‐Jijon E, 2012. 5. Banner W, 1986.

Cr Chela/on Summary

•  Species effects •  Address chromium source •  There is liUle 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

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hUp://www.ornl.gov/info/press_releases/photos/cobaltblue_sconce1.jpg

Cobalt

Cobalt (Co) Exposures

•  Essen/al nutrient •  Environment

•  Industry •  Biomedical therapy and research

•  Prostheses •  An/dote

Cobalt (Co) Kine/cs

•  Variable GI absorp/on (∼ iron, ∼ age) •  Dermal absorp/on (∼ integrity) •  Hepa/c concentra/on •  RBC uptake •  Oral exposure fecal elimina/on (∼ variable GI absorp/on)

•  Parenteral exposure urinary elimina/on •  Pulmonary exposure prolonged reten/on (insoluble Co)

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Cobalt (Co) Toxicity

•  “Hard metal” or “diamond polisher’s” pulmonary disease

•  “Beer drinkers” cardiomyopathy

•  Thyroid disease •  Hepatotoxicity •  Neuropathy •  Derma//s/hypersesi/vity

•  Polycythemia

Regulatory Guidance •  U.S. Food and Drug Administra.on

–  “…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., sos /ssue mass), consider assessing and monitoring serial metal ion levels.”

•  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 aser the first in order to iden/fy pa/ents who require closer surveillance, which may include cross sec/onal imaging.”

Cobalt Chela/on Considera/ons Human Experience

•  CaNa2EDTA – 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

PubChem. NLM.

EDTA

1. Pazzaglia UE, 2011. 2. Henre/g F, 1988. 3. Waters RS, 2001.

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Cobalt Chela/on Considera/ons Animal Studies

PubChem. NLM.

D-‐penicillamine (PCA)

Trien/ne

N-‐acetylcysteine (NAC)

PubChem. NLM. PubChem. NLM.


PubChem. NLM.

Diethylenetriaminepentaace/c acid (DTPA)

meso-‐2,3-‐dimercaptosuccinic acid (DMSA, succimer)

PubChem. NLM.


Redrawn from data in Domingo JL, 1984.

0%

10%

20%

30%

40%

50%

60%

70%

Control L-‐Cys NAC L-‐Met

0%

10%

20%

30%

40%

50%

60%

70%

L-‐Cys NAC L-‐Met

Mortality

CoCl2 PO

CoCl2 IP

Mortality

CoCl2 Chelated pre-‐administra%on, PO

CoCl2 Chelated pre-‐administra%on, IP

3:1 3:1

3:1

6:1

An%dote An%dote

2/28/12

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Redrawn from data in Llobet JM, 1986.

0%

10%

20%

30%

40%

50%

60%

70%

80%

90%

100%

0 0.6 1 1.4 1.8

Cobalt Chloride (mmol/kg IP)

Survival

EDTA

DTPA

DMSA

NAC L-‐Cys

r-‐PCA


62.5%

80.9%

77.2%

0.001

0.010

0.100

1.000

10.000

Liver

Muscle

Kidn

ey

Skeleton

Skin/hair

Heart

Bloo

d

Spleen

Lung

Brain

Urinary

elim

ina/

on

Redrawn from data in Levitskaia TG, 2010.

60Co

: % adm

inistered radioac/vity

Control GSH L-‐Cys

Elimina.on


46.9%

48.3%

61.9%

0.010

0.100

1.000

10.000

Skeleton

Kidney

Liver

Blood

Muscle

Lung

Spleen

Stomach

Intes.ne

Urine 24h


Elimina.on

Control D-‐PCA Trien.ne

60Co

: % adm


2/28/12

14


Elimina.on

60Co

: % adm


60.0%

68.0% 62.0%

0.00

0.01

0.10

1.00

10.00

Carcass Kidney Liver Blood Muscle Lung Spleen Skin Urine 24h

Control D-‐PCA Trien.ne


Co Chela/on Summary

•  Evaluate appropriate organ systems for toxicity •  Address cobalt source •  There is liUle human evidence at all with which to provide a specific chela/on recommenda/on – For 60Co (per REAC/TS and NCRP)1,2

•  DTPA preferred •  DMSA, EDTA, NAC suggested

– For others •  NAC & EDTA considered

1. Radia/on Emergency Assistance Center/Training Site (REAC/TS), 2011. 2. Na/onal Council on Radia/on Protec/on and Measurements (NCRP), 2008.

US DOE.

Uranium

2/28/12

15

Uranium (U) Exposure

•  Environment –  Background –  Remedia/on

•  Industry – Mining/Milling –  Refining –  Nuclear fuel processing

•  Military conflict – Weapons assembly –  Combat –  Firefigh/ng

•  Terrorism

1. CDC. Na/onal Center for Environmental Health, 2011. 2. U.S. Nuclear Regulatory Commission (U.S. NRC), 1978.

Uranium (U) 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) Toxicity

•  Radiological considera/ons:

238U 234Th 234Pa 234U 230Th 226Ra 222Rn

–  No IARC classifica/on

•  While 238U, 235U, 234U are “radioac/ve,” their half-‐lives of are on the order of billions, millions, and thousands 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.

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Uranium (U) Toxicity

•  Hexavalent uranium U(VI), as the dioxo uranyl ca/on [UO2]2+, is the most stable state in vivo.1,2

•  Renal tubular epithelium •  Respiratory tract (inhala/on) •  Hepa/c dysfunc/on •  Anemia •  Myocardi/s

PubChem. NLM.

hUp://www2.niddk.nih.gov/NIDDKLabs/Glomerular_Disease_Primer/NormalKidney.htm 1. Durbin PW, 2008. 2. Pavlakis N, 1996.

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.

[U] = 1 µM

[U] = 1 µM

Uranium Specia/on and Solubility

Interstitial & plasma fluids

Bile

DTPA •  Negligible GI absorp/on •  Cleared by glomerular filtra/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.”

•  Nephrotoxicity •  Suppressed hematopoiesis

•  Teratogenicity/embryotoxicity •  “Bycatch”

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DTPA “Bycatch”

•  Zinc, magnesium, manganese, and metalloproteinase deple/on

•  Animal models – U-‐DTPA cardiac arrest (porcine)1 – Significantly increased urinary elimina/on of Ca, Cu, Fe, Zn, and Mn (murine)2,3

– Concomitant inter-‐/ssue distribu/on – Enhanced fecal excre/on of Mn (lapine)4

1. Smith VH, 1966. 2. Can/lena LR, 1982. 3. Tandon SK, 1984. 4. Khandelwal S, 1980.

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.

1. Stradling GN, 1991. 2. Durbin PW, 2008.

Other Chelators Hydroxypyridonates (HOPOs)

•  5-‐LIO(Me-‐3,2-‐HOPO) and 3,4,3-‐LI(1,2-‐ HOPO)

PubChem. NLM.

l = n = 3; m = 4; X = H

Raymond et al. Assignee: USA a/r/b US DOE. USP4698431 (06 Oct 1987).

1. Abergel RJ, 2010. 2. Abergel RJ, 2011. 3. Durbin PW, 2008.

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Other Chelators Hydroxypyridonates (HOPOs)

Percen

t of injected

232 U or 233 U

Drawn from data in Durbin PW, 2008.

0.1%

1.0%

10.0%

100.0%

Skeleton Soa .ssue Kidneys Whole body

Urine Feces + GI contents

Control (fed)

CaNa3-‐DTPA

5-‐LIO(Me-‐3,2-‐HOPO)

Control (fas%ng)

3,4,3-‐LI(1,2-‐HOPO)

Other Considera/ons

•  Address uranium source

•  Dialysis •  Sodium bicarbonate (NaHCO3)

Sodium Bicarbonate (NaHCO3)

•  Na/onal Council on Radia/on Protec/on and Measurements (NCRP) preferred1,2

•  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.”

1. Radia/on Emergency Assistance Center/Training Site (REAC/TS), 2011. 2. Na/onal Council on Radia/on Protec/on and Measurements (NCRP), 2008.

2/28/12

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Uranium Chela/on Summary

•  Not supported: DTPA •  Current recommenda/on: sodium bicarbonate

•  Consider dialysis •  Experimental: hydroxypyridonates

US DOE.

Cadmium

Cadmium (Cd) Exposure

•  Background/Environment •  Industry

– Mining

– Refining – Metalworking

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Cadmium (Cd) Kine/cs

•  Inges&on – Poor absorp&on (5%-‐20%)

•  Inhala&on – Excellent absorp&on (≤5%)

•  Accumula/on – Hepa/c – Renal

•  Elimina/on –  t½ = years

Cadmium (Cd) Toxicity

•  Renal injury •  “Itai-‐itai” osteomalacia •  Respiratory tract (inhala/on) •  Gastrointes/nal injury (acute inges/on)

hUp://www2.niddk.nih.gov/NIDDKLabs/Glomerular_Disease_Primer/NormalKidney.htm

Cadmium Chela/on Considera/ons

•  Metals – Cadmium (Cd)

•  Binding proteins – Albumin – α2-‐macroglobulin – Metallothionein

•  Chelators •  Chelates

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21

Cadmium Chela/on Considera/ons Human Experience

•  DMPS

–  Increased cadmium excre/on in “mobilisa/on” tests, unchanged Cdblood1

•  EDTA •  No beneficial effects on chronic Cd-‐induced renal

dysfunc/on2

•  Unchanged clinical status; unchanged Cdserum3

•  +GSH: increased Cdserum3

•  Increased urinary excre/on4

PubChem. NLM.

r-‐DMPS

1. Ruprecht J, 2009. 2. Wu X, 2004. 3. Gill HW, 2011. 4. Waters RS, 2001.

Cadmium Chela/on Considera/ons Animal Experience

•  Marked temporal dependence1-‐4

•  Acyclic polyamines: significant renal damage.5

•  BAL: increased renal1 and hepa/c6 cadmium burden. Decreased survival.7 Enhanced nephrotoxicity.8

•  Carbodithioates: highly dependent upon agent and experimental condi/ons.3,9-‐13

•  DMPS: increased renal cadmium burden.1,7

•  DMSA: improved survival.7 Modestly decreased reten/on.2,14 Dose-‐dependent survival benefit with increased renal burden.3

•  D-‐PCA: increased renal cadmium burden.7 No survival benefit.3 Ineffec/ve.12

•  DTPA: Dose dependent Increased survival.3 Decreased reten/on.2 Decreased residual cadmium.15

•  EDTA: increased renal cadmium burden.6 Survival at lower Cd doses.16 Renal damage.15

•  NAC: improved oxida/ve stress markers with concomitant chelator.17 1. Rau W, 1989. 2. Saríc MM, 2004. 3. Eybl V, 1984. 4. Catelena LR, 1983. 5. Jones MM, 1996. 6. McGivern J, 1979. 7. Bassinger MA 1988. 8. Lyle WH, 1968. 9. Walker EM, 1986. 10. Kargacin B, 1991a. 11. Kargacin B, 1991b. 12. Anderson O, 1988. 13. Catelena LR, 1982. 14. Blanusa M, 2000. 15. Jones MM, 1990. 16. Catelena LR, 1980. 17. Tandon SK, 2003. 18. Blanusa M, 2005.

Cadmium Chela/on Summary

•  Address cadmium source

•  Minimal treatment window

•  Acute toxicity: no defini/ve chela/on benefit – DMSA, DTPA, EDTA

•  Chronic toxicity: chela/on unsupported •  Experimental: carbodithioates

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References

•  Provided separately

Thank You

2/28/12

1

J E F F R E Y B R E N T , M . D . , P H . D . T O X I C O L O G Y A S S O C I A T E S

U N I V E R S I T Y O F C O L O R A D O S C H O O L O F M E D I C I N E

The use and abuse of chelation therapy in patients with autism

spectrum disorders

DISCLAIMER

I have been a consultant to the US National Vaccine program and was a witness, on behalf of the US Government, in the National Omnibus Vaccine Hearings.

4 year old female diagnosed with PDD is referred by her pediatrician because a hair analysis found that she was high on As, Hg, Zn, Th, Te and her mother wanted her chelated. No environmental source of unusual exposure to any of these elements could be found. Work up was negative.

Chelate?

2/28/12

2

A typical hair analysis report

PT: 6 yr old autistic male – parents want him chelated because on a post-chelation urine sample he was high on:

Cadmium Lead Tin Uranium

Exam normal except for autistic behavior

Environmental history unremarkable

Work up: Cadmium: Blood and urine within ref range Beta-2-microglobulin normal No microalbuminuria Lead: Blood lead 69 ug/dl Tin: Blood within ref range Uranium: Urine within ref range

Chelate?

2/28/12

3

The prevalence of the diagnosis of Autism Spectrum Disorder has been increasing

  The increased prevalence temporally correlates with the increase in the number of vaccinations

  The increase is in ASD, the rates of classical autism are largely unchanged

Two Hypothesis have emerged linking vaccinations to autism/ASD

 MMR

 Thimerosal

US FDA’s Analysis of Thimerosal in vaccines

(Ball LK et al, Pediatrics 107, 1147-1154, 2001)

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It was possible to exceed the US EPA’s Reference Dose for methyl mercury from the ethyl mercury in vaccines

RfD = daily dose determined by US EPA To be acceptably safe when averaged over a lifetime

Ball, 2001

Blood mercury levels before and after receipt of vaccines that contained thimerosal preservative

Pichichero M E et al. Pediatrics 2008;121:e208-e214

Newborns

2 Month olds

6 Month olds

Ethyl mercury poisoning and ASD are completely different diseases

ASD Large head size Lack of social reciprocity Stereotypical behavior Purkinje cells affected Normal renal function No tunnel vision No tremor No paresthesias No ataxia No dysarthria Associated with relatively

normal blood mercury levels (normal approx. 1 ug/L)

Ethylmercury poisoning Small head size No lack of reciprocity No stereotypical behavior Granular cells affected Abnormal renal function Tunnel vision Tremor Paresthesias Ataxia Dysarthria Associated with high blood

mercury levels (> 500 ug/L)

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Is immunization with thimerosal containing vaccines associated with higher rates of

autism or ASD?

The Studies of the Geier’s  Published numerous studies with

positive association between THI exposure and ASD

 Most published in marginal journals  US NAS, IOM: “Geier studies are uninterpetable and

thus non-contributory.”   Criticized methodology,

calculations, conclusions

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Ten human epidemiological studies have found no link between ASD and

Thimerosal Study Design N Publication

Verstraeten, 2003

Cohort 124,170 Pediatrics

Madsen, 2003 Ecological Danish pop Pediatrics

Stehr-Green, 2003

Ecological Danish and Swedish pops

A J Pub Health

Hviid, 2003 Cohort Danish pop JAMA

Andrews, 2004 Cohort 103,043 Pediatrics

Ten human epidemiological studies have found no link between ASD

and Thimerosal Study Design N Publication

Jick, 2004 Case-control 709 NEJM

Heron, 2004 Cohort 12,956 Pediatrics

Fombonne, 2006

Ecological 27,749 Pediatrics

Schecter, 2008 Ecological California Arch Gen Psychiatry

Price, 2010 Case-control 1,008 Pediatrics

PROPONENTS OF THE VACCINE AUTISM THEORY RESPOND BY SAYING THE

EPIDEMIOLOGY IS NON-APPLICABLE BECAUSE

THERE IS A HYPOTHESIZED SMALL

SUSCEPTIBLE POPULATION

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The syllogism that does not work

  Proponents of an ASD-thimerosal link: 1.   The large increase is ASD is due to

thimerosal 2.   The epi studies do not show a

relationship btw thimerosal and ASD 3.   That is because it is only the few

susceptible cases that are caused by thimerosal

4.   ?

There are many reasons for the increase in ASD

  Broadening of the concept of ASD   Changes in diagnostic criteria   Diagnostic substitution

  Inverse relationship between incidence of mental retardation and ASD

  Educational advantages for students diagnosed with ASD

  Increased awareness   Promotion by organizations favoring expensive

but ineffective therapies (e.g. Doctors Against Autism) and attorneys

4 year old female diagnosed with PDD is referred by her pediatrician because a hair analysis found that she was high on As, Hg, Zn, Th, Te and her mother wanted her chelated. No environmental source of unusual exposure to any of these elements could be found. Work up was negative.

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PT: 6 yr old autistic male – parents want him chelated because on a post-chelation urine sample he was high on:

Cadmium Lead Tin Uranium

Exam normal except for autistic behavior

Environmental history unremarkable

Work up: Cadmium: Blood and urine within ref range Beta-2-microglobulin normal No microalbuminuria Lead: Blood lead 69 ug/dl Tin: Blood within ref range Uranium: Urine within ref range

Chelate?

“To evaluate net retention, one compares the levels of metals in urine before and after the administration of a pharmaceutical metal detoxification agent such as EDTA, DMSA or DMPS”

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Thanks for your attention, I hope this was interesting

If you would like to have a copy of these slides in PowerPoint format please e-mail me at: [email protected]

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Moderator: Charles McKay MD, FACMT

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•  Jeffrey Brent, MD, PhD, FACMT •  Michael Kosnett, MD, MPH, FACMT •  Charles Lee, MD •  Walter Rogan, MD, MPH •  Silas Smith, MD •  Richard Wang, DO, FACMT •  Paul Wax, MD, FACMT

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•  Apply material from today’s symposium to case examples – We will focus on Pb, As, Hg, U – Framework should be applicable to other metals

•  For each case, identify: – Patient concern – Misinformation – Role of testing – Role for chelation therapy – Systemic issues or information to reduce confusion

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•  4-year-old Pakistani child: blood Pb of 105 µg/dL –  delayed Pb screening at pre-school entry

•  All family members living in the same residence were also identified as having elevated blood Pb levels ranging from 68 to 84 µg/dL

–  Reported symptoms: crampy abdominal pain, constipation, weakness, difficulty concentrating –  One female who had a whole blood Pb of 51 µg/dL recently had a first trimester miscarriage –  Exception of an infant: blood Pb < detection limit of 2 µg/dL

•  Continuing investigation by local and state public health departments identified an orange powder used by the family as a “yellow food coloring” as containing 47% (470,000 µg /g) Pb by weight.

–  The family has not identified the brand name and location of purchase

–  Extended family members: blood Pb ranging from 51 to 84 µg/dL –  Related family in a neighboring state that had shared meals was also

identified: blood Pb ranging from 13 to 36 µg/dL in 5 of 7 members.

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•  Patient concern? •  Misinformation? •  Role of testing? •  Role for chelation therapy? •  Systemic issues or information to reduce

confusion?

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Mercury 0.010 (<0.01 ug/g) 95% percentile

Urine Mercury VERY ELEVATED

Mercury 21 (0-3 ug/g creatinine)

Comment: Post provocative challenge

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confusion?

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•  After seeing a Dr. Oz show, a mother calls the PCC concerned that she may have poisoned her child by serving apple juice

•  Wonders about having her child tested and perhaps treated for “arsenic poisoning”

•  Data: –  5 brands from 3 cities –  1/3 of samples >10ppb(mcg/L)

•  Highest value 36 mcg/L – Subsequent CR study: 10% of samples similar results

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•  Consumer Reports: 88 samples tested for As and Pb – One [As] value: almost 25 ppb – Most of 9 “elevated” measurements ~ 10ppb

•  Pb comparisons to ‘bottled water’ standard – Why?

•  Tap water standard of 15 ppb was ‘exceeded’ once

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confusion?

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This is the greatest case of poisoning in the history of mankind: In Bangladesh, the health of 35 to 80 million people is endangered due to water contaminated by arsenic. The problem was first detected in the early 1980s in the Indian state of Western Bengal, a neighbor of Bangladesh. It quickly became evident that this contamination also existed in Bangladesh. Another ten years would pass, however, before the authorities and the international community mobilized their efforts. The aim is simple: to make sure the people of Bangladesh have safe drinking water. Achieving it, however, is far more complex. There is no miracle solution in sight and, meanwhile, millions of people are slowly becoming poisoned.

VISION, Thursday 25 November 2004; François Turk, Gabrielle Schwab, Philipe Reymond, Xavier Bengoa

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•  Daily exposure to more than 2 liters (hot climate) at amounts as high as 2000ppb – Equivalent to 2 mg/L – U.S. drinking standard

decreased from 50 to 10 mcg/L

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Caller wants help because of testing: •  “found 33 times the limit for aluminum and

uranium and all these things…” •  “Find out where I have been exposed and

how to get rid of these things so I can become a well person again.”

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•  Well water uranium: 100 mcg/L – EPA standard for public drinking water systems:

30 mcg/L (ppb) •  Urinary uranium (post-provocation):

–  0.8 mcg/L (“normal <0.013”) •  Health status:

–  Fear about possible future health effects •  Renal impairment •  Cancer

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confusion?

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•  Not false manipulation of laboratory data •  Not just a drop in measured body

concentrations – Particularly for chronic exposures

•  Combination of demonstrated removal and improvement of causally-related symptoms – Combined with identification and removal of

significant exposure source

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Touchpoints for Metal Chelation Decisions

•  Valid clinical suspicion •  Proper patient and specimen preparation •  Valid comparison groups

–  No role for provoked challenge in screening/diagnosis –  Laboratory normal vs population norms vs toxicity ranges

•  Distinguish and communicate the difference between “individual health effect” and “public health concern” –  Biochemical changes vs organ dysfunction vs clinical

symptoms –  At-risk population vs entire population

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•  Perspective and comparisons •  Reference ranges •  Advocacy

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•  Conflation of numbers •  Argument for special risk for special groups

– Extrapolate small biochemical effects to organ effects to entire being effects •  Discount any feedback, reparative, compensatory

response – Argue from statistical minimums to large effects

for large populations

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•  “Not based on large samples” •  “Consensus opinion” •  Population-based

–  U.S. hair Hg for an “average fish-eating population”: 0.4-7.6 ppm

–  NHANES sampling total blood mercury •  Children (1-5yo, all races): 705 studied

–  25th percentile: <0.14µg/L –  50th percentile: 0.3 µg/L –  95th percentile: 2.3 µg/L

–  Similar results from other population studies of thousands of individuals

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•  Occupational/BEI – <15 µg/L blood inorganic mercury (ACGIH) – <50 µg/g creatinine urinary mercury (BEI-

renal) •  “Clinical effect”

– Methylmercury death Nierenberg et al. NEJM 1998;338:1672

•  Whole blood Hg 4000 µg/L (reference 1-8 µg/L) •  Plasma Hg 600 µg/L •  Urine Hg 234 µg/L (ref 1-5 µg/L) •  Hair Hg 1100 ppm (ref < 0.26 ppm)

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•  Organic Hg – Subsistence fish diet (Faroe Island)

•  22.9 µg/L cord blood (interquartile range 13.4-41.3) •  4.27 µg/g maternal hair (interquartile range 2.6-7.7)

– Polluted Japanese bays (Fukuda et al. Env Res 1999;81:100)

•  RBC Hg 28.5 +/- 11.5 ng/g (equiv. ~40 µg/L whole blood)

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•  Cord blood and/or maternal hair measurements (confounders of nutrition, “heavy” exposure) –  NOAEL – neurocognitive battery (Seychelles)

•  15 ppm maternal hair (equivalent to ~75 µg/L whole blood) –  LOAEL – subtests of neurocognitive battery (Faroe)

•  12 ppm maternal hair –  NOAEL - Delayed walking (Iraq)

•  10 ppm maternal hair –  NOAEL - Obvious neurologic deficits (Iraq)

•  Paresthesias 100 ppm hair •  Dysarthria 300 ppm hair •  Death 800 ppm hair

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•  Is the “abnormal” value: –  Outside that of an

appropriate referent population

–  Abnormal for clinically relevant norms

–  Of any meaning in your patient

•  Contrast individual health risk and public health “concern” for susceptible populations

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Chen Y, Graziano JH, Parvez F, et al. Arsenic exposure from drinking water and mortality from cardiovascular disease in Bangladesh…BMJ 2011. Rahman M, Tondel M, Ahmad SA, Axelson O.

Diabetes mellitus associated with arsenic exposure in Bangladesh. Am J Epidemiol 1998

•  Epidemiologic studies of chronic “low-level” exposures

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•  Promotional – GUNA or others •  American College for the Advancement of Medicine

(ACAM) •  American Academy of Anti-aging Medicine (A4M) •  Foundation for the Advancement of Innovative

Medicine (FAIM) •  International Academy of Oral Medicine and

Toxicology •  British Society for Homotoxicology

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Advocacy Sites: How to respond? •  Absence of scientific basis? •  Harmless placebo effect? •  Misdirection/adverse effects?

black & white slide set, part three · beneﬁt in acute intoxication by inorganic arsenic or...

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