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Anne-Michelle Ruha, M.D., FACMT Department of Medical Toxicology
Banner Good Samaritan Medical Center Phoenix, Arizona
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Greatplainslaboratory.com
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3 of top 4 sites advise challenge test
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Advocates state: ◦ Current and past exposures result in increased body stores ◦ Challenge reveals ‘body burden’
Advocates advise: ◦ Comprehensive search for potential sources of Hg exposure geography, amalgams, fish, high fructose corn syrup, second hand smoke in childhood, exposures of mother prior to conception
Alt Med Review 2009;14(2):103-108.
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What are normal reference ranges for metals in urine after a dose of chelator?
Diagnostic value? ◦ Can toxicity be ruled in or out based on this test?
Is it safe? Does the evidence support use of a challenge test?
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1960s
◦ Fielding proposed a test for measuring ‘chelatable’ iron
◦ A single dose of IV deferoxamine followed by 6 hour urine test
J Clin Path 1965;18:88-9
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◦ Rabbit model (Keberle 1964)
Fe loaded rabbits – 16x increase UFe with red-brown urine
*Normal rabbits – 5x increase UFe
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IM deferoxamine (about 50 mg/kg)
If ‘vin rose urine’ within 4-6 hours this would indicate excretion of ferrioxamine
Imply a toxic level prompting treatment, until urine no longer red
Pediatric Em Med
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No change in urine color in 70% of patients with serum Fe concentrations exceeding expected TIBC
Recommended that the deferoxamine challenge test be abandoned
Proudfoot AT. Tox Let 1995;82/83:770-783.
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Lead mobilization test: ◦ 24 h urine ◦ 3 doses IM CaNa2EDTA Every 8 h ◦ 24 h urine
Study groups: ◦ Control ◦ Suspected Pb
poisoning ◦ Confirmed Pb
poisoning
Pediatrics. 1962;29:384-388.
*All children had increase UPb after challenge Lead poisoned higher UPb than controls
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1980s ◦ Used routinely in children with elevated BPb levels (25-55 ug/dL) to detect ‘mobilizable’ lead
◦ CDC recommended use of lead mobilization test to determine which children would respond to chelation
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Concerns regarding safety ◦ Concern for redistribution of lead ◦ Depletes other metals ◦ Renal toxicity
Difficult to perform in children
Data showing lead initially mobilized mainly from bone
Chisolm JJ. AJDC 1987;141:1256-1257
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Used as an adjunctive test in the diagnosis of Wilson Disease ◦ One recommendation is use in symptomatic children if WD is suspected but basal urinary copper excretion is normal
D-penicillamine 500 mg administered at the onset and 12 hours into a 24 hour urine collection
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Purpose: to re-evaluate conventional diagnostic criteria for WD in children with mild liver disease
Subjects ◦ 40 with diagnosis of WD ◦ 58 controls – other liver disease and siblings of WD
Hepatology. 2010;52:1948-1956.
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Concluded the PCT is of little value for diagnosis in these patients.
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Not recommended: ◦ CaNa2EDTA for lead ◦ Deferoxamine for iron
Unclear role in dx of Wilson Disease ◦ Penicillamine for copper
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DMSA approved in the US in 1990 for treatment of Pb intoxication
DMPS ◦ Not approved in US ◦ Used in Russia since 1950s ◦ Approved in Europe in 1970s
◦ Studied as early as the 1950s in Soviet Union and China for treatment of Pb and Hg toxicity
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19 healthy college and grad students No seafood x 30 days Amalgam score determined by a dentist (10 with amalgams)
FASEB J. 1992;6:2472-2476.
11 hr pre-DMPS urine collection Oral DMPS 300 mg 9 hr post-DMPS urine collection
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• Amalgam group had higher baseline UHg • Both groups had rise in UHg (19 fold vs 25 fold) • Individual cases UHg increased 12- 70 fold
*healthy subjects had up to 70 fold increase in UHg after DMPS
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Adverse effects in healthy subjects
2/19 nausea, one vomited
1 rash a week out
FASEB J. 1992;6:2472-2476.
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To assess change in UHg in healthy people given a DMSA challenge test
UHg correlates with amalgam surfaces
Ann Clin Biochem 2004;41:33-236.
Fasting urine sample Oral DMSA 30 mg/kg 2 h urine sample discarded 3 h urine sample collected
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Mean factor increase = 7 Range = 1 to 27 *healthy subjects had up to 27
fold increase in UHg after DMSA
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Intention to include 20 subjects ◦ study closed after 14 completed
15th developed vomiting, tight chest, urticarial rash 6 minutes after ingestion of DMSA
3 other subjects with nausea and all reported foul smelling urine x 24 h
Ann Clin Biochem 2004;41:33-236.
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DMSA challenge in healthy individuals with varying amounts of fish intake
22 volunteers, 30mg/kg oral DMSA
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Arch Pathol Lab Med. 2008;132:4-9.
4 9.5 10.8 x
UHg rises in everyone after DMSA challenge
Rise is greater with increased fish intake
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All have urinary Hg excretion even without use of a chelator
Urinary Hg excretion rises in everyone after a chelation challenge
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10 dental technicians
5 dentists 13 non-dental personnel
J Pharm and Exp Therapeut 1995;272:264-274
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Controls 35 fold increase Dentists 49 fold increase Dental techs 88 fold increase
Pre-DMPS All groups excrete Hg at baseline. Exposed groups more so than controls.
Post-DMPS All groups have rise in UHg.
Overlapping ranges
*one subject nausea/diarrhea
14-132 45-76 11-335
*Healthy controls with up to 132x rise in UHg after DMPS
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DMPS challenge to:
11 factory workers ◦ (made HgCl - containing skin lotion)
8 lotion users 9 controls
JPET 1996;277:938-944
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Makers: increased 45 x Users: increased 87 x Controls: increased 38 x
All groups excrete Hg before DMPS Large baseline differences in UHg
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Test whether DMPS challenge could provide index of the Hg body burden due to long-term exposure
All healthy subjects with little fish intake
41 men in 4 groups ◦ 10 industrial workers (m exposure =11yrs) ◦ 8 dentists (m = 33 yrs) ◦ 18 occupationally unexposed ◦ 5 occ unexposed and amalgam free
Int Arch Occup Environ Health. 1991;63:187-192.
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• All groups excrete Hg at baseline • Exposed populations have greater baseline UHg • UHg excretion rises in all groups after DMPS
Average increase: 10 x 5.9 x 5.3 x 3.8 x
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Pre-DMPS UHg excretion was associated with post-DMPS UHg excretion in all groups
Authors concluded the challenge test did not reflect long term exposure (body burden)
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Does DMSA challenge reveal increased body burden of Hg with remote occupational exposure to Hg?
Chloralkali plant workers with long-term, high-level exposure; controls
Exposure profiles - based on specific jobs, historical air sampling data ◦ Average, cumulative, and peak exp
Environ Health Perspect 2001;109:167-171
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Authors conclude DMSA challenge not useful in quantifying past mercury exposure
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15 subjects with highest exposure rank
Range for this highest exposure group 3x -114x increase
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Recognize ◦ UHg concentrations reported differently (mcg, mcg/L, mcg/gCr) ◦ Urine collections vary (spot – 24 h) ◦ Dose of chelating agent varies ◦ Results may not be comparable with different chelators
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Baseline urine Hg concentrations are higher in exposed populations than in unexposed populations
DMPS and DMSA challenges produce a rise in urine Hg excretion in all groups
There is great overlap in factor increase between and within exposure groups
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Study Chelator # subjects Hg (mean; upper range)
Aposhian DMPS 10 (no amal) 5±1mcg/9h
10 (amal) 17±3 mcg/9h
Archbold DMSA 14 14 ± 14 mcg/L
Ruha DMSA 22 3/10/13; 33 mcg/gCr
Gonzalez-Ramirez DMPS 13 27 ±3 mcg/6h
OR 37±15 mcg/L
Maiorino DMPS 9 18±7; 54 mcg/6h OR 22±10; 73 mcg/L
Molin DMPS 5 (no amal) 3.2 mcg/24h
18 (no amal) 14; 56 mcg/24h
Frumkin DMSA 101 8±6; 28 mcg/24h
Reference range (post-challenge) in healthy populations?
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µg/gCr
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No randomized, controlled studies comparing use of a challenge test in subjects with metal poisoning to those without metal poisoning
◦ Metal toxicity would have to be diagnosed based on known exposure and clinical findings consistent with and specific for toxicity
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Reports that describe patients with vague symptoms that are non-diagnostic for Hg toxicity who are given a challenge test and diagnosed on the basis of ◦ An increase in metal excretion ◦ Report of symptom improvement
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DMPS challenge test (2 mg/kg IV) to: ◦ 19 without amalgams and healthy ◦ 21 with amalgams and healthy ◦ 20 with amalgams and self-diagnosed Hg poisoning ◦ 20 who had amalgams removed because of self-diagnosed Hg poisoning
J Dent Res 2000;79(3):868-874.
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The amalgam groups excreted 3x as much Hg as the amalgam free groups
No difference between amalgam groups with and without symptoms (the symptomatic group did not have a larger ‘body burden’ detected with challenge test)
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Grandjean P, et al. Placebo response in environmental disease: chelation therapy of patients with symptoms attributed to amalgam fillings.
Double blind RCT
Patients who attributed symptoms to amalgams (no alternative dx)
DMSA 30 mg/kg divided TID x 5 days
Both groups reported improvement
J Occ and Env Med 1997;39(8):707-714.
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Adverse reactions widely reported Potential for mineral deficiencies Other unpleasant side-effects ◦ Foul-smell ◦ Nausea
Cost
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No established reference ranges No evidence for diagnostic value Not universally safe
NO
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