B&W - American College of Medical Toxicology


B&W - American College of Medical Toxicology

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2/27/12 Greatplainslaboratory.com3 of top 4 sites advise challenge test4

2/27/12 Advocates state:◦ Current and past exposures result inincreased body stores◦ Challenge reveals ‘body burden’ Advocates advise:◦ Comprehensive search for potentialsources of Hg exposure geography, amalgams, fish, highfructose corn syrup, second handsmoke in childhood, exposures ofmother prior to conceptionAlt Med Review 2009;14(2):103-108.5

2/27/12 What are normal reference ranges formetals in urine after a dose ofchelator? Diagnostic value?◦ Can toxicity be ruled in or out basedon this test? Is it safe? Does the evidence support use of achallenge test? 1960s◦ Fielding proposed a test formeasuring ‘chelatable’ iron◦ A single dose of IV deferoxaminefollowed by 6 hour urine testJ Clin Path 1965;18:88-96

2/27/12 ◦ Rabbit model (Keberle 1964) Fe loaded rabbits – 16x increaseUFe with red-brown urine *Normal rabbits –5x increase UFe IM deferoxamine (about 50 mg/kg) If ‘vin rose urine’ within 4-6 hours thiswould indicate excretion offerrioxaminePediatric Em Med Imply a toxic level promptingtreatment, until urine no longer red7

2/27/12 No change in urine color in 70% ofpatients with serum Fe concentrationsexceeding expected TIBC Recommended that the deferoxaminechallenge test be abandonedProudfoot AT. Tox Let 1995;82/83:770-783. Lead mobilization test:◦ 24 h urine◦ 3 doses IM CaNa 2 EDTA Every 8 h◦ 24 h urine Study groups:◦ Control◦ Suspected Pbpoisoning◦ Confirmed Pbpoisoning*All children had increase UPb after challengeLead poisoned higher UPb than controlsPediatrics. 1962;29:384-388.8

2/27/12 1980s◦ Used routinely in children withelevated BPb levels (25-55 ug/dL) todetect ‘mobilizable’ lead◦ CDC recommended use of leadmobilization test to determine whichchildren would respond to chelation Concerns regarding safety◦ Concern for redistribution of lead◦ Depletes other metals◦ Renal toxicity Difficult to perform in children Data showing lead initially mobilizedmainly from boneChisolm JJ. AJDC 1987;141:1256-12579

2/27/12 Used as an adjunctive test in thediagnosis of Wilson Disease◦ One recommendation is use insymptomatic children if WD is suspectedbut basal urinary copper excretion isnormal D-penicillamine 500 mg administered atthe onset and 12 hours into a 24 hoururine collection Purpose: to re-evaluate conventionaldiagnostic criteria for WD in childrenwith mild liver disease Subjects◦ 40 with diagnosis of WD◦ 58 controls – other liver disease andsiblings of WDHepatology. 2010;52:1948-1956.10

2/27/12 Concluded the PCT is of little value for diagnosisin these patients. Not recommended:◦ CaNa2EDTA for lead◦ Deferoxamine for iron Unclear role in dx of Wilson Disease◦ Penicillamine for copper11

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2/27/12 DMSA approved in the US in 1990 fortreatment 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 SovietUnion and China for treatment of Pband Hg toxicity 19 healthy college and grad students No seafood x 30 days Amalgam score determined by adentist (10 with amalgams)11 hr pre-DMPS urine collectionOral DMPS 300 mg9 hr post-DMPS urine collectionFASEB J. 1992;6:2472-2476.13

2/27/12 • 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 70fold increase in UHg after DMPSAdverse effects in healthy subjects2/19 nausea, one vomited1 rash a week outFASEB J. 1992;6:2472-2476.14

2/27/12 To assess change in UHg in healthypeople given a DMSA challenge testFasting urine sampleOral DMSA 30 mg/kg2 h urine sample discarded3 h urine sample collected UHg correlates with amalgam surfacesAnn Clin Biochem 2004;41:33-236.Mean factor increase = 7Range = 1 to 27*healthy subjects had up to 27fold increase in UHg after DMSA15

2/27/12 Intention to include 20 subjects◦ study closed after 14 completed 15 th developed vomiting, tight chest,urticarial rash 6 minutes afteringestion of DMSA 3 other subjects with nausea and allreported foul smelling urine x 24 hAnn Clin Biochem 2004;41:33-236. DMSA challenge in healthy individualswith varying amounts of fish intake 22 volunteers, 30mg/kg oral DMSA16

2/27/12 UHg rises ineveryoneafter DMSAchallengeRise isgreater withincreased fishintake4 9.5 10.8 xArch Pathol Lab Med. 2008;132:4-9. All have urinary Hg excretion evenwithout use of a chelator Urinary Hg excretion rises in everyoneafter a chelation challenge17

2/27/12 10 dentaltechnicians 5 dentists 13 non-dentalpersonnelJ Pharm and Exp Therapeut 1995;272:264-274Pre-DMPSAll groups excrete Hg atbaseline. Exposed groupsmore so than controls.Post-DMPSAll groups have rise in UHg.Controls 35 fold increaseDentists 49 fold increaseDental techs 88 fold increaseOverlappingranges14-13245-7611-335*Healthy controls with up to 132xrise in UHg after DMPS*one subject nausea/diarrhea18

2/27/12 DMPS challenge to: 11 factory workers◦ (made HgCl -containing skin lotion) 8 lotion users 9 controlsJPET 1996;277:938-944All groups excrete Hg before DMPSLarge baseline differences in UHgMakers: increased 45 xUsers: increased 87 xControls: increased 38 x19

2/27/12 Test whether DMPS challenge couldprovide index of the Hg body burden dueto 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 freeInt Arch Occup Environ Health. 1991;63:187-192.20

2/27/12 Average increase: 10 x 5.9 x 5.3 x 3.8 x• All groups excrete Hg at baseline• Exposed populations have greater baseline UHg• UHg excretion rises in all groups after DMPS Pre-DMPS UHg excretion wasassociated with post-DMPS UHgexcretion in all groups Authors concluded the challenge testdid not reflect long term exposure(body burden)21

2/27/12 Does DMSA challenge reveal increasedbody burden of Hg with remoteoccupational exposure to Hg? Chloralkali plant workers with longterm,high-level exposure; controls Exposure profiles - based on specificjobs, historical air sampling data◦ Average, cumulative, and peak expEnviron Health Perspect 2001;109:167-171Authors conclude DMSA challenge not usefulin quantifying past mercury exposure22

2/27/12 Recognize◦ UHg concentrations reporteddifferently (mcg, mcg/L, mcg/gCr)◦ Urine collections vary (spot – 24 h)◦ Dose of chelating agent varies◦ Results may not be comparable withdifferent chelators◦ Determination of reference rangesafter challenge not possible Baseline urine Hg concentrations arehigher in exposed populations than inunexposed populations DMPS and DMSA challenges produce arise in urine Hg excretion in all groups There is great overlap in factor increasebetween and within exposure groups23

2/27/12 Reference range (post-challenge) in healthy populations?Study Chelator # subjectsAposhianDMPSHg (mean; upperrange)10 (no amal) 5±1mcg/9h10 (amal) 17±3 mcg/9hArchbold DMSA 14 14 ± 14 mcg/LRuha DMSA 22 3/10/13; 33 mcg/gCrGonzalez-RamirezDMPS 1327 ±3 mcg/6hOR 37±15 mcg/LMaiorino DMPS 9MolinDMPS18±7; 54 mcg/6hOR 22±10; 73 mcg/L5 (no amal) 3.2 mcg/24h18 (amal) 14; 56 mcg/24hFrumkin DMSA 101 8±6; 28 mcg/24hµg/gCr24

2/27/12 No randomized, controlled studiescomparing use of a challenge test insubjects with metal poisoning to thosewithout metal poisoning◦ Metal toxicity would have to bediagnosed based on known exposureand clinical findings consistent withand specific for toxicity Reports that describe patients withvague symptoms that are nondiagnosticfor Hg toxicity who aregiven a challenge test and diagnosedon the basis of◦ An increase in metal excretion◦ Report of symptom improvement25

2/27/12 Double blind RCT Patients who attributed symptoms toamalgams (no alternative dx) DMSA 30 mg/kg divided TID x 5 days Both groups reported improvementJ Occ and Env Med 1997;39(8):707-714. Adverse reactions widely reported Potential for mineral deficiencies Other unpleasant side-effects◦ Foul-smell◦ Nausea Cost26

2/27/12 No established reference ranges No evidence for diagnostic value Not universally safe NO1. Charlton N and Wallace KL. Post-chelator challenge urinary metal testing. AMCTposition statement. http://www.acmt.net/cgi/page.cgi?aid=2999&_id=52&zine=show(accessed19 Jan 2012)2. Risher JF, Amler SN. Mercury exposure: evaluation and intervention The inappropriateuse of chelating agents in the diagnosis and treatment of putative mercury poisoning.NeuroToxicology 2005;26:691-699.3. Keberle H. The biochemistry of desferrioxamine and its relation to iron metabolism.Ann NY Acad Sci 119:758-768, 19644. Fielding J. Differential ferrioxamine test for measuring chelatable body iron. J Clin Path1965;18:88-95. Proudfoot AT. Antidotes: benefits and risks. Tox Let 1995;82/83:770-783.6. Whitaker JA, Austin W, Nelson JD. Edathamil calcium disodium (versenate) diagnostictest for lead poisoning. Pediatrics. 1962;29:384-388.7. Markowitz ME and Rose JF. Need for the lead mobilization test in children with leadpoisoning. J Pediatr 1991;19:305-310.8. Chisolm JJ. Mobilization of lead by calcium disodium edetate. AJDC.1987;141:1256-12579. Nicastro E, Ranucci G, et al. Re-evaluation of the diagnostic criteria for Wilson Diseasein children with mild liver disease. Hepatology. 2010;52:1948-1956.10. Vieira et al. Urinary copper excretion before and after oral intake of D-penicillamine inparents of patients with Wilson’s disease. Digestive and Liver Disease 2011 (E pub)11. Lee Byung-Kook, et al. Provactive chelation with DMSA and EDTA: evidence fordifferential access to lead storage sites. Occup and Environ Med 1995;52:13-1927

2/27/12 12. Archbold GP, McGuckin RM, and Campbell NA. Dimercaptosuccinic acid loading test for assessingmercury burden in healthy individuals. Ann Clin Biochem 2004;41:33-236.13. Ruha AM, Curry SC, Gerkin RD, et al. Urine mercury excretion following DMSA challenge in fisheaters. Arch Pathol Lab Med. 2008;132:4-9.14. Aposhian HV, Bruce DC, Wilfred A, et al. Urinary mercury after administration of 2,3-dimercaptopropane-1-sulfonic acid: correlation with dental amalgam score. FASEB J.1992;6:2472-2476.15. Gonzalez-Ramirez D, Maiorino RM, et al. Sodium 2,3-dimercaptopropane-1-sulfonate challengetest for mercury in humans: II. Urinary mercury, porphyrins, and neurobehavioral changes of dentalworkers in Monterrey, Mexico. The Journal of Pharmacology and Experimental Therapeutics.1995;272:264-27416. Maiorino RM, et al. Sodium 2,3-dimercaptopropane-1-sulfonate challenge test for mercury inhumans. III. Urinary mercury after exposure to mercurous chloride. JPET 1996;277:938-94417. Molin M, Schiitz A, et al. Mobilized mercury in subjects with varying exposure to elementalmercury vapour. Int Arch Occup Environ Health. 1991;63:187-192.18. Frumkin H, et al…Diagnostic Chelation Challenge with DMSA: A biomarker of long-term mercuryexposure? Environ Health Perspect 2001;109:167-17119. Vamnes JS, Eide R, Isrenn R, et al. Diagnostic value of a chelating agent in patients with symptomsallegedly caused by amalgam fillings. J Dent Res 2000;79(3):868-874.20. Grandjean P, Guldager B, Larsen IB, et al. Placebo response in environmental disease: chelaitontherapy of ptients with symptoms attibuted to amalgam fillings. 1997;39(8):707-714.21. Crinnion WJ. The benefit of pre- and post-challenge urine heavy metal testing: part 2. Alt MedReview 2009;14(2):103-108.28

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