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Consider Zebras -‐ Assessment & Management of Other Problema9c Metals in Clinical Prac9ce
David Quig, PhD
Cool, they don’t see us!
David Quig, PhD
Faculty Disclosure
• David Quig is Vice President, Scien6fic Support, Doctor’s Data, Inc.
• Content has been peer reviewed for balance and evidence based medicine
• The material presented is not intended for the diagnosis, treatment, cure or preven6on of any disease.
• Comment in RED is the opinion of the presenter
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David Quig, PhD
Or could they be Zebras?
I think I hear horses…
Tl, Gd, Mn, Co, Cr6 Hg, Pb, Cd, As
From afar all zebras look the same, but in fact every zebra’s stripe pa9ern is different.
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David Quig, PhD
To be Covered…
• Considera6on of the bioaccumula=on of less commonly encountered, poten6ally problema6c elements Ø Common sources and possible clinical consequences Ø Objec6ve assessment of exposure and bioaccumula6on Ø Clinical management
• The clinical management of the endless release of cobalt and hexavalent chromium from metal-‐on-‐metal total hip replacements.
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David Quig, PhD
Chronic Metal RetenAon
• Knowledge of adverse effects are based primarily on independent studies of a single toxicant (C.D.C)
• Metals [and chemicals]* can elicit independent, addiAve or synergisAc toxic effects (C.D.C.)
• Recall that Gd, Co, Cr6 and Pb are among metals that can impair / inhibit Phases I and II detoxifica6on reac6ons
Environ Hlth Perspect(1995)103:1048 ATSDR/CDC Lead update(2007) Med Clin N Am(2005)89:721 * Int J Environ Res Public Hlth(2011)8:629-‐47
Interdis Toxicol(2013)6:159-‐64 Food & Chem Toxicl(2004)42:1563-‐71
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David Quig, PhD
Thallium (Tl)-‐ AKA RamorTM
• Heavy metal, rare in earth’s crust, Tl1+ is very stable • Pure Tl is odorless and tasteless • Can be combined with halogens (Br, Cl, I, F) and sulfate • Routes of exposure-‐ inges6on, inhala6on (aerosol/dust), skin contact …some depilatories)
• Have recently seen more Tl in urine and hair (lab perspec6ve)
cdc.gov/niosh [7/22/14] Ind J Occup Environ Med(2005)9:53-‐55 atsdr.cdc.gov/toxprofiles/tp54-‐c5 [7/12/14]
Considered as one of the most toxic metals in the world
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David Quig, PhD
Thallium-‐ Sources of Exposure
• Sources-‐ Occupa=onal / environmental Combus6on of coal, smel6ng (Pb, Zn), cement plants (sub-‐micron par6cles), limestone, cadmium refineries, ar6sts’ paints, semiconductors, imita6on gems, fireworks (green), hazardous waste sites/landfills (nearby drinking water); including frackwater waste / flowback from class II injec9on wells (aquifers and soil in CA, ND)
cdc.gov/niosh [7/22/14] atsdr.cdc.gov/toxprofiles/tp54-‐c5 [7/12/14] www.insideclimatenews.org [accessed 12/10/14] www.bunecounty.net [accessed
12/12/14] 7
David Quig, PhD
Thallium Exposure (cont’d) • Nonindustrial-‐ Tl bioconcentra6on in the food chain Primarily contaminated vegetables (greens), CA almonds, fruits, tobacco products, aqua6c plants, fish and shellfish
(NIOSH Interna6onal Safety Card) • Chronic exposure-‐ cabbage grown in Tl contaminated gardens (China)-‐ peripheral neuropathy, hair Tl 22-‐32 ppb (95th % = 5 ppb)…green drinks??
• Pa6ent with persistently elevated urine Tl (unprovoked) Tl in greens (lenuce) from large produce market in Seanle (D Quig and R Overberg, PhD, unpublished 2010)
cdc.gov/niosh [7/22/14] atsdr.cdc/toxprofiles/tp54-‐c2 [7/02/14] www.bunecounty.net [accessed 12/12/14]
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David Quig, PhD
Metabolic Consequences of Tl BioaccumulaAon
• Repeated or long-‐term exposure-‐ considered to be as toxic as lead and mercury, with similar sites of ac6on: Compe==on with K at cell receptors-‐ affects ion pumps Inhibits DNA synthesis Binds sulKydryl groups on proteins (neurons/mitochondria) Concentrates in renal tubules-‐ necrosis
Mayomedicallaboratories.com [11/19/14] Ind J Occup Environ Med(2005)9:53-‐55 atsdr.cdc/toxprofiles/tp54-‐c2 [11/19/14]
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David Quig, PhD
Chronic Tl RetenAon-‐ Symptoms
fa6gue, headaches, depression, sleeplessness, mental aberra6ons, psychoses, peripheral sensory
disturbances, encephali6s, leg pain, gastric antacidity, loss of appe6te/weight, hair loss, disturbances of vision, cardiac arrhythmias, angina-‐like pain,
hypertension, irregular pulse, endocrine disorders, polyneuropathy
"
Ind J Occup Environ Med(2005)9:53-‐55
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David Quig, PhD
Tl-‐ ExcreAon and Assessment of Exposure • Normal Excre6on-‐ Primarily urine , ~ 35% in feces • Assessment of exposure-‐ Hair < 0.001-‐ 0.005 ug/gm; environmental vs. occupa6onal Urine (random, < 0.5 ug/gm) 24-‐hr. or random urine is considered the best (< 1 ug/day)* Urine Tl is elevated up to 2 months aQer exposure Levels in smokers can be about 2X > non-‐smokers
• Fecal metals • Blood-‐ extremely short T1/2, only very recent/ongoing-‐ not
reliable. Normal level < 1 ug/L “significant exposure” > 10 ug/L*
atsdr.cdc.gov/toxprofiles/tp54-‐c5 [7/12/14] atsdr.cdc.gov/phs Tl [7/23/14] *Mayomedicallaboratories.com [11/19/14]
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David Quig, PhD
Tl-‐ Other Laboratory Tests • Elevated urine levels-‐ consider microalbuminuria and hematuria
• Net Reten6on of Tl ?-‐ problema6c EDTA; 3.5 X 106 ( Ca; 5 x 1010) DMPS; ?, no effect on acute Tl poisoning (rats, man) DMSA; ?, 50 mg/kg-‐ indeterminate effect (rat poisoning)
D-‐ penicillamine-‐ appears to redistribute Tl to the CNS • Misconcep6ons may be due to clinicians not doing pre-‐provoked urinalysis prior to provoca6ons
Ind J Occup Environ Med(2005)9:53-‐55 www.cem.msu.edu [3/12/07] HeylTech
Scien6fic Monograph (2008)p.209 Clin Toxicol(2003)41:137-‐42 Toxicol(2000)42:325-‐9 12
David Quig, PhD
Pre-‐Provoca9on
Pb
Tl
2
0 .5
Exposure
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David Quig, PhD
Pb = 130
Tl-‐ same as pre
Post-‐DMSA
X 5
X
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David Quig, PhD
Pre-‐provoca9on Thallium
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David Quig, PhD
Post-‐DMSA
2.25-‐X higher
X
Does not lower brain Tl as does Prussian Blue (rat models)
Thallium
16
Affinity Mass Compe66on
David Quig, PhD
Clinical Management • Tl depura6on efforts should be based upon urine Tl levels, symptoms, exposure history (alopecia is a major clue), and thorough neurological exam.
• Determine and remove the source(s) of exposure. • Goal is to enhance irreversible excre6on by inhibi9ng enterohepa9c circula9on.
• Prussian Blue / Berlin Blue / RadioguardaseTM (ferric hexacyanoferrate II, non-‐absorbable ion exchange ) is far more effec6ve than charcoal Insoluble crystalline layce, FDA approved in 2003 for radioac6ve and cold Tl and cesium (post 9/11/01, “dirty bomb readiness)
J Toxicol Clin Toxicol(1999)37 :833-‐7 Toxicol Rev(2003)22:29-‐40 atsdr.cdc/toxprofiles/tp54-‐c2 [7/02/14]
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David Quig, PhD
Prussian Blue in PracAce
• Administra6on Oral 3 gms 6d (adults), best with food (s6mulates bile secre6on), decrease dose with ↓ urinary Tl
• May bind potassium in the gut-‐ monitor serum electrolytes. • Mild to moderate cons6pa6on-‐ consider fiber-‐based laxa6ve and/or much dietary fiber and good hydra6on
• Use with cau6on with: Chronic cons6pa6on/decreased mo6lity/blockage Electrolyte imbalances Pre-‐exis6ng cardiac arrhythmias
Orphan Drugs: Res & Revs(2012)2:13-‐21 FDA.gov Heyl Chem.-‐pharm. Fabrik GmbH & Co. KG [accessed 7/24/14] 18
David Quig, PhD
Concerns Regarding the Safety of Gadolinium Enhanced MRI
• Gadolinium (Gd3+) improves imaging. • Ionic (free) Gd is very toxic-‐ bound to DTPA (linear) or other
chela6ng agents (macrocyclic) for imaging. • Concern about disassocia6on, especially w/ impaired renal
func9on and acidosis (severe hepa6c necrosis-‐ free Gd) • Numerous cases of Nephrogenic Systemic Fibrosis (NSF) with
mild to moderate renal insufficiency (GFR> 30 to < 89), but most cases with severe renal failure (GFR < 30 ) associated with linear chelates
(ASSESS GFR prior to Gd-‐enhanced MRIs)
Brit J Radiol(2010)83:590-‐5 Neth J Med(2008)66:416-‐22 Magn Reso Imaging(2007)26:1190-‐7
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David Quig, PhD
Nephrogenic Systemic Fibrosis (NSF)
• Severe life-‐threatening, especially with severe renal failure, but also acute renal injury
• ↑ risk with age (>60), diabetes, hypertension, < 1 year of age • Onset 2-‐4 weeks a~er administra6on (linear Gd-‐chelates) • Presenta6on-‐ thickening of skin (especially limbs), fibroblast-‐like cells progressing to muscles, diaphragm, heart and other organs. Ul6mately mul6-‐organ failure and death.
Omniscan Monograph(2013) J am Soc Nephrol(2006)17:2359-‐65 Brit J Radiol(2010)83:590-‐5 Neth J Med(2008)416-‐22
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David Quig, PhD
Toxicological Effects Chronic Excess Gd in the Body
• General-‐ mineral deposits in capillaries (lungs, kidneys), necrosis in liver and spleen, mineraliza6on of gastric mucosa, thrombocytopenia, prolonged prothrombin 6me, blocks calcium channels, inhibits GABA and glutamate receptors
• Hepa6c-‐ GdCl3 inhibits phagocyto=c ac=vity of macrophages and decreases number of Kupffer cells Impedes biotransforma=on of xenobi=cs (CYP 450s) Inhibits glutathione-‐S-‐transferases (Phase II) Inhibits heme biosynthesis and s6mulates heme catabolism
Acta Biochem Polonica(2000)47:1107-‐14 21
David Quig, PhD
Gd-‐DTPA (Gatodiamide)
• Gd-‐diethylene triamino pentaace6c acid • Stability constant-‐ LogK= 16.9 (≈ EDTA-‐ heterocyclic) • 95 +/-‐ 6 % cleared within 24 hrs. (urine, normal GFR) • Time to disassocia6on (T1/2)-‐ Gd-‐DTPA; 35 seconds, macrocyclic; 3 hrs. to > 1 month (Gatoteridol, Gadoterate meglumine, respec6vely)
• Disassocia6on of Gd likely due to Zn and Cu metalla6on
Gd
Cem.msu.edu [2/8/07] Brit J Radiol(2007)8:73-‐6 Neth J Med(2008)66:416-‐22
Zn
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David Quig, PhD
Gd-‐DTPA Pharmacology
• Kine6cs(dogs): T1/2 ~20 min. (renal excre6on; 88% of dose excreted within 3 hrs., 90% by 7 hrs.)
• Tissue reten6on: liver up to 2 ppm; kidney, bone and heart; ~ 0.5 ppm (FREE Gd-‐ not Gd-‐DTPA)*
• Deceiving expression of “insignificant” % reten9on of dose in early studies **
• Released Gd binds to phosphate and prevents “re-‐capture” (bone pool-‐ much like lead-‐ just keeps on “giving”)
*Proc Intl Soc Mag Reson Med(2002)10: **AJR(1984)142:619-‐24 Brit J Radiol(2010)83:590-‐5 23
David Quig, PhD
Urine Gadolinium (Gd) Post MRI
-‐1,000
0
1,000
2,000
3,000
4,000
5,000
6,000
0 50 100 150 200 250
Urin
e Gd (u
g/gm
)
Time (hours)
Quig & Quig, (2011) unpublished observa6ons
5,500
4.1 1.5
7.5 mg Gd-‐chelate injected into hip capsule
(n=1)
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David Quig, PhD
Ca-‐Na2-‐EDTA and Gadolinium 1st AM urine
Gd = 4.1
Post Ca-‐Na2-‐EDTA urine Gd = 51 XX
X
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David Quig, PhD
RetenAon of Gd Post MRI: Normal GFR
Post Ca-‐EDTA Gadolinium
Pre MRI 0.2
55 Days Post MRI
77
111 Days Post MRI
44
• 61 yof, 2nd hyperparathyroidism, mild expressive aphasia
J Sciabbarrasi, (2011) unpublished clinical observa6ons 26
Ongoing chela6on
David Quig, PhD
Clinical Management Before MRI Imaging
• Absolute necessity for use of a Gd-‐enhancing agent? • If required use a macrocyclic Gd-‐chelate (e.g. Gadoteridol) • Encourage a bona fide crea6nine clearance test (prior) -‐at the imaging facility they will only ask the pa=ent if they have kidney problems Post-‐ MRI (Gd enhanced)
• Support endogenous detoxifica6on processes • Consider establishing baseline post-‐Ca-‐Na2-‐EDTA urine Gd • Consider IV chela6on (EDTA)
Neth J Med(2008)66:416-‐22 27
David Quig, PhD
Manganese-‐ Sources • Occupa6onal (inhala6on)-‐ welders, miners, smelters, steel
produc6on, dry-‐cell banery factories, some paints • Non-‐occupa6onal-‐ gasoline fumes (MMT)?, foods (cereals, TEA),
well water, municipal water (potassium permanganate addi6ve), street drugs (cocaine, crystal meth) Infant formulas-‐ soy-‐based up to 20-‐X > Mn than breast milk
Neurotoxicol(2009)30:240-‐48 epa.gov/safewater (2004) [7/30/14]
Nutr(1986)116:395-‐402
Poorly developed biliary excreAon pathway SO
Y
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David Quig, PhD
Manganism-‐ Idiopathic Parkinson’s • Primarily occupa6on related, but can develop manganism with normal
exposure in the presence of liver disease. • Presenta6on-‐ psychological, neurological (Parkinson’s-‐like disease) Phase I Psychiatric Abnormali6es: Hyperirritability, violence, compulsiveness, apathy, somnolence, anorexia, emo=onal instability, headaches, sexual dysfunc=on Phase II (~ 2 months a~er psychiatric symptoms) Neurological Disorder of Extrapyramidal Motor System Tremor, slurred speech, dystonia, high-‐stepping gait, mask-‐like face, hallucina=ons Phase III Bradykinesia, rigidity, paresis, difficulty walking backwards
Int J Occup Environ Hlth(2003)9:153-‐63 Neurotox(2009)30:240-‐48 Env Hlth Perspect(2000)108:429-‐32 Neurology(2005)64:2033-‐39
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David Quig, PhD
Excessive Mn Exposure and RetenAon • Exposure-‐ random or 24 hr. urine, whole blood (T1/2 ~ 40 days),
serum, hair (preferably pubic for occupa6onal) Urine, blood, serum-‐ no Mn supplementa6on 48 hrs. prior
• Es6ma6on of net reten6on (off label use of Na2-‐EDTA) 1.5-‐3 gm Na2-‐ EDTA slow drip, 1 gm/hr. (50 mg/kg) MUST do pre-‐ and post-‐ urinalysis (Toxic and Essen6al Elements)
(EDTA Log K= 1013) Some batches of Ca-‐Na2-‐EDTA contain Mn*, and Ca-‐Na2-‐EDTA increased Mn excre6on about 15-‐X in 14 healthcare workers**
Mayomedicallaboratories.com [8/1/14] www.cem.msu.edu *Bass and Quig, unpublished observa6ons (2006) **Quig and Filidei (2002)
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David Quig, PhD
Welder (pubic hair)
*!
*!
*! *!
*!
Mn Cr
Co
Mo
Fe
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David Quig, PhD
Manganism-‐ Clinical Management
• Check iron status and Ca intake • Assess ongoing exposure-‐ remove the source(s) • Assess liver status-‐ cirrhosis, biliary obstruc6on, failure • Chela6on Therapy-‐ EDTA – limited value Ca-‐Na2-‐EDTA may help in some mild cases-‐ if interven=on is early enough-‐ may see symptom improvement*… or not** Ca-‐Na2-‐EDTA will not have a sustained effect on neurotoxicity with severe/advanced chronic manganism (“relapse”)
*Neuro Toxicol(2006)27:333-‐9 **J Neurol Sci(2002)199:93-‐96 JOEM(2006)48:644-‐49
Neurotoxicol(2009)30:240-‐48 Toxicol(1978)4:379-‐85 32
David Quig, PhD
PAS and Mn
• Para-‐aminosalicylic acid (PAS, Paser™)-‐ off label use • An6bio6c (tuberculosis), an6-‐inflammatory (IBD), chelates Mn (liver/bile, rabbit model), ↓ ROS
• 1992-‐ two cases of successful remedia6on of chronic Mn-‐induced neurotoxicity using PAS (17 yr. follow up) – 6 gm PAS-‐Na (IV drip, 500 ml glucose/day, 4 days on 3 days off, for 3.5 months (15 rounds of treatment)
• 86 addi6onal cases of successful treatment using PAS men6oned in the literature*
J Occup Environ Med(2006)48:644-‐49 *Neurotoxicol(2009)30:240-‐8 AM J Respir Crit Care Med(1999)159:932-‐4 www.rxlist.com/paser
33
David Quig, PhD
PAS and Mn (cont’d)
• Oral Use of PAS? (not available for parenteral use in U.S.) Dosing for tuberculosis-‐ 4 gm 3X/day adults); 4 gm packets Delayed-‐release granules, sprinkled on / in apple sauce, yogurt or juice (acidic)-‐ dura6on for manganism???
• Possible adverse effects-‐ Inhibits B-‐12 absorp9on (monitor B-‐12 status, IM as necessary) gastrointes6nal distress, nausea, diarrhea Very rare-‐ black/bloody stools, severe liver damage (≤ 3 months)
J Occup Environ Med(2006)48:644-‐49 *Neurotoxicol(2009)30:240-‐8 AM J Respir Crit Care Med(1999)159:932-‐4
Paser™ Monograph www.rxlist.com/paser 34
David Quig, PhD 35
David Quig, PhD
Metallosis from Metal-‐on-‐Metal Hip Total Hip Replacement
• Total hip replacement can be a necessary evil-‐ blessing or calamity
• Ivory is not an op6on-‐ polyethylene lining, ceramics • Concerns regarding the release of metals Orthopedic-‐ Failure due to metal-‐induced local damage to so~ 6ssue and periprosthe6c bone loss. CAM health prac66oners-‐ systemic toxic effects as well
36
David Quig, PhD
Metallosis from Metal-‐on-‐Metal (MOM) Total Hip Arthroplasty (THA)
High concentra6ons of Co/Cr with macrophages, inflamma6on, 6ssue
necrosis, and lymphocyte hypersensi6vity
Cobalt-‐chromium implants were heavily used due to their corrosion resistance…
37
David Quig, PhD
Abrasion-‐induced Release of Co3 and Cr6 NanoparAcles
(also electrochemical corrosion → ions)
J Bone Surg Am(2010)92:2847-‐51 38
David Quig, PhD
PotenAal Consequences of MOM THA
• ~ 200,000 MOM THA/yr., over 93,000 manufacturer recalls (2013) • All pa6ents WILL have elevated serum & urine levels of Co and Cr
– Levels vary with prosthe6c device, surgical precision, ac6vity – Consequences are ion concentra6on, and pa6ent specific
• Possible toxic effects (general) Local 6ssue toxicity/necrosis, bone loss, impaired renal func6on, immune dysregula6on , inflamma6on, hypersensi6vity, eczema, chromosomal damage / malignant cellular transforma6ons (ROS)
www.mayomedicallaboratories.com [8/12/14] Acta Orthopaedica(2013)84:229-‐36 J Bone Joint Surg(2010)92:1-‐5 J Orthop Res(2006)24:2029-‐35
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David Quig, PhD
Co Specific Symptoms
Chronic cobalt exposure skin condi6ons, hypothyroidism, headaches, cogni6ve decline,
polyneuropathy, loss of vision/hearing, and possibly cardiomyopathy (extremely high levels due to implant failure)
www.mayomedicallaboratories.com [8/12/14] Acta Orthopaedica(2013)84:229-‐36 J Bone Joint Surg(2010)92:1-‐5 J Orthop Res(2006)24:2029-‐35
40
David Quig, PhD
Assessment of Exposure-‐ Co
• Circula6ng ion levels at which toxici=es are induced remain unknown-‐ “safe” circulaAng levels have not been determined.*
• Adverse reac6ons to metal release [sic bioaccumula6on] can be clinically silent and severe-‐ early detec=on is very important**
• Test THA pa6ents annually-‐ 6 months with mild prosthesis-‐related symptoms** (standard of care-‐ serum, urine)
*J Arthroplasty(2004)19(suppl.3):71-‐7 **www.massgeneral.org/ortho/ [8/22/14]
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David Quig, PhD
Serum and Urine Co Levels • Serum Co-‐ normal; 0-‐0.9 ng/ml MOM implant; < 10 ng/ml, good condi=on; 4-‐10 ng/ml > 10 ng/ml suggests “significant prosthesis wear”
• Urine Co-‐ (random) normal; 0-‐1.9 ug/gm crea9nine MOM implant; 2-‐4 ug/gm (good condi=on), > 5 (wear)? “significant prosthesis wear”; >20 ug/gm
• [Consider high dose B-‐12 (e.g. ASD, sub-‐Q MB-‐12) that can be associated with urine Co levels similar to that seen with occupa6onal exposure]* www.mayomedicallaboratories.com *Quig, unpublished observa6ons
42
David Quig, PhD
Assessment of Cobalt RetenAon • Assess glomerular filtra6on • Pre vs. post urine Co (EDTA, DMPS, DMSA, Ca-‐DTPA)
Primarily Co2+ in vivo-‐ EDTA log K-‐ Co2+; 16, Co3+; 41) DTPA-‐ Co2, log K= 19 DMPS, DMSA-‐ stability constants not available
• Rats-‐ 4 weeks exposure (CoCl2), 5 days chela6on (IP) EDTA, DTPA, DMSA, GSH and N-‐AC increased Co excre6on Tissue levels were decreased most by GSH and N-‐AC
Res Commun Chem Pathol Pharmacol(1988)60:225-‐33 www.cem.msu.edu Clin Toxicol(2012)50:262-‐5 Orthopade(2006)35:860-‐4 Dimaval Scien6fic Monograph www.Heyl-‐berlin.de (2008) Res Commun Chem Pathol Pharmacol(1988)60:225-‐33
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David Quig, PhD
Clinical Management
• “ Chela6on should be restricted to those who are unable to undergo revision arthroplasty (e.g. Co-‐induced cardiomyopathy)”* [MA Dijkman, Netherlands]
• Chela6on (DMPS) gradually resolved all but deafness (n=1, very high Co, Cr and Ti).**
• Assess glomerular filtra6on and oxida6ve DNA damage (8 OH-‐dGuanosine-‐ 1st AM urine collec6on)
* Ned Tijdschr Geneeskd(2012)156:A4983 **Clin Toxicol(2012)50:262-‐5
44
David Quig, PhD
Clinical Management-‐ Let’s Think!
• Ongoing exposure (not removed)-‐ constant release of metals • Periodic chela9on*-‐ EDTA; IV or suppositories?, DMPS; oral or
suppositories) • Glutathione-‐ direct effects, and as a cysteine delivery system. IV GSH & Cys enhance Co excre6on (urine), decrease 6ssue Co, provide an6oxidant protec6on (metal-‐induced ROS), and support redox-‐buffering capacity of cells and 6ssues.
• Efficacies of GSH and cysteine depend on bioavailability "
*Orthopade(2006)35:860-‐4 Hlth Phys(2010)98:53-‐60 Biomaterials(2005)26:4416-‐22 Acta Biochem Polonica(1999)46:567-‐80
45
David Quig, PhD
GSH-‐induced Cobalt DecorporaAon
64%*
47%*
(single IV dose 60Co)
1 dose/day for 5 days
Health Physics(2010)98:53-‐60
IV GSH and IV cysteine were most effec9ve
% Co Removal from Tissues
(day 5)
46
(n = 6, rats)
Liver, brain, kidneys, heart, muscle, bone
David Quig, PhD
Pilot Study-‐ Liposomal GSH and RBC GSH
RBC GSH (umoles/L)*
Baseline 728, 739
2 weeks 925 (26%)
2 months 1,218 (66%)
4 months 1,680 (128%)
57 yof, 14 yrs. Lyme’s disease, moderate Pb and Cd reten6on
1 tsp. each AM w/o food. Blood drawn 24 hrs. a~er last dose. *Reference range-‐ >1,000 umoles/L
Quig, unpublished observa6ons (2013) 47
David Quig, PhD
Hexavalent Chromium (Cr6+) • Strong oxidizing agent, 500-‐1,000 6mes more toxic than Cr3+
• Class I human carcinogen-‐ indirect DNA lesions, Fenton reac6on (ROS), kills osteoblasts, and alters immune func6on
• Oral Cr6 is rapidly reduced to Cr3 in gastric acid. • Enterocytes present high in the small intes6ne have the highest capacity to reduce Cr6 to Cr3
Open Orthopaedic J(2008)2:10-‐18 Curr Med Chem(2005)12:1161-‐1208 IARC Monographs on the Evalua6on of Carcinogenic risks to Humans(1997)49:17-‐33
Biochem Biophys Res Comm(1976)69:672-‐7 Acta Pharmalogica Toxilogica(1982)50:310-‐15
48
David Quig, PhD
Hexavalent Chromium (Cr6+)
• Cr6 imparts strength and smooth surface to prosthe6cs • Released Cr6 is readily taken up by cells and reduced to Cr3 that binds 6ghtly to GSH and proteins-‐ retained in RBCs
• During intracellular reduc6on ROS (.OH, O2. -‐, H2O2) are
produced that elicit the toxic effects. • GSH, vitamin C and NADPH are important reducing agents.
Open Orthopaedic J(2008)2:10-‐18 Curr Med Chem(2005)12:1161-‐1208 IARC Monographs on the Evalua6on of Carcinogenic risks to Humans(1997)49:17-‐33
Biochem Biophys Res Comm(1976)69:672-‐7 Acta Pharmalogica Toxilogica(1982)50:310-‐15 49
David Quig, PhD
Assessment of Cr Exposure • Standard of Care is serum Cr (Cr3+)*
• Random urine (ug/gm crea6nine) No prosthesis; no established reference range* (< 0.03 ug/gm) “Good condi6on”; 8-‐16 ug/gm Significant wear; > 20 ug/gm OccupaAonal exposure: during shi~; <10 ug/gm, end of week; <30 *www.mayomedicallaboritories.com and “White Paper,” [8/31/11]
Orthopedic Status Serum Cr (ng/ml) No Implant < 0.3
Unaffected Implant 1-‐20 Affected Implant 10-‐90 (> 15)
In the context of implant evalua=on
50
David Quig, PhD
Red Blood Cell Cr
• RBC Cr provides a bener indicator of exposure to Cr6 than serum (longer 6me window, much less erra6c).
• Cr6 is ac=vely transported into cells by [SO4]2-‐ & H[PO4]2-‐ anion channels and retained as Cr3 for the life of the cells.
• Cr3 is not directly taken up by RBCs (94-‐99% excluded in vitro)
Open Orthopedics J(2008)2:10-‐18 Sci Total Env(1988)71:561-‐66 Blood Cells Molecules Dis(2012)46:266-‐76
RBC Cr reflects cumulaAve Cr6 exposure-‐ not nutriAonal status of Cr
56 51
David Quig, PhD
Red Blood Cell Cr and Co
• High RBC Cr provides a qualita6ve assessment that the bodies reduc6ve mechanisms have been exceeded* (NIOSH)
• Co2 binds almost irreversibly to RBC hemoglobin-‐ bener indicator of 6me averaged / cumula6ve exposure.
RBC Co and Cr should be the standard of care!
Open Orthopedics J(2008)2:10-‐18 Sci Total Env(1988)71:561-‐66 Blood Cells Molecules Dis(2012)46:266-‐76 *NIOSH Comments to OSHA 29 CFR Part 1910 Docket #
H-‐0054a(2002) 52
David Quig, PhD
Assessment of Cr RetenAon and Clinical Management
• Very high RBC/serum Cr levels-‐ are sugges=ve of prosthe6c failure; with symptoms refer back to the orthopedist for appropriate evalua6on and considera6on of surgical revision.
• Assess glomerular filtra6on, microalbuminuria • Assess oxida6ve DNA damage (urine 8-‐OH-‐ dGuanosine) • Pre-‐ and Post EDTA urine for both Cr and Co (Cr from plas6c bags!) • Management goals-‐ reduc=on of released Cr6 to prevent cellular
uptake and oxida6ve damage – Op6mize plasma GSH levels (rate limi6ng cysteine and induc6on of γ-‐glutamylcysteine ligase), and Mg
Curr Med Chem(2005)12:1161-‐1208 *Toxicol in vitro(2002)16:509-‐16 53
David Quig, PhD
EDTA-‐ DecorporaAon of Cr and Co…Plus • EDTA has good stability constants for Co3, Co2, Cr3 (Cr6 ?) • Cr3 is at elevated levels in blood in THA pa6ents, and should be
the only form present in blood with Cr supplementa6on. • Post-‐EDTA urine Cr was increased with the level of Cr
supplementa6on (pre-‐ vs. post, n= 16 adults). U.S.D.A. • Bojom line-‐ IV EDTA will enhance the excre6on of Cr3 and Co.
– Ongoing research* • PLUS-‐ EDTA w/o vitamin C decreased oxida6ve damage to DNA
(8-‐OHdG), and lipid peroxida6on (n=8 adults, a~er 10th infusion) • What about Ca-‐EDTA suppositories for this purpose?
Biol Tr Elem Res(2001)70:265-‐72 Altern Med Rev(2009)14:56-‐61 *Waters and Quig (2014/15) 54
David Quig, PhD
Consider the “Zebras” when appropriate, and consider them as part of a pa9ent’s total toxicant burden
Dang, they’re on to us!
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