DMPS/DMSA Using DMPS and DMSA in safe and effective ways to assess and treat heavy metal burden Walter J. Crinnion ND SpiritMed www.DrCrinnion.com www.CrinnionOpinion.com Copyright WCrinnion 2013

COI and other issues Thanks to Dr. Dan Carter for some of his slide information. Dr. Crinnion has no conflict of interest in regards to any compounds covered in the following slides. Copyright WCrinnion 2013

Who are they? DMSA DMPS Copyright WCrinnion 2013

DMSA Chemical name: meso-2,3-dimercaptosuccinic acid Alt: meso-2,3-bis(sulfanyl)succinate Other drug names Dimercaptosuccinic acid Succimer Chemet™ Captomer™ Copyright WCrinnion 2013

DMSA Kinetics Second generation from British Anti-Lewisite (BAL) Absorbed rapidly after oral administration Approximately 20% absorption Evidence that enterohepatic circulation occurs 95% binds to albumin via disulfide bond with cysteine This leaves the other thiol group free to chelate metals Renal excretion >90% excreted as mixed disulfides of DMSA Disulfides only found in urine, not blood <10% excreted as DMSA Aposhian HV, Maiorino RM, Rivera M, Bruce DC, Dart RC, Hurlbut KM, Levine DJ, Zheng W, Fernando Q, Carter D, et al. Human studies with the chelating agents, DMPS and DMSA. J Toxicol Clin Toxicol. 1992;30(4):505-28. PubMed PMID: 1331491. Maiorino RM, Bruce DC, Aposhian HV. Determination and metabolism of dithiol chelating agents. VI. Isolation and identification of the mixed disulfides of meso-2,3-dimercaptosuccinic acid with L-cysteine in human urine. Toxicol Appl Pharmacol. 1989 Feb;97(2):338-49. PubMed PMID: 2538007. Copyright WCrinnion 2013

DMSA Kinetics Renal excretion (cont’d) Research evidence indicates that the mixed disulfides of cysteine are the active chelating moiety in humans This suggests that chelation occurs principally in the kidney Elimination half-life of total DMSA (parent drug plus oxidized metabolites) Longer in children with lead poisoning (3hours) Adults with or without lead poisoning (1.9 - 2 hours) See notes previous slide, also Aposhian HV, Maiorino RM, Dart RC, Perry DF. Urinary excretion of meso-2,3-dimercaptosuccinic acid in human subjects. Clin Pharmacol Ther. 1989 May;45(5):520-6. PubMed PMID: 2541962. Copyright WCrinnion 2013

DMSA Indications and Usage Succimer is a (FDA approved) lead chelator; it forms water soluble chelates and increases the urinary excretion of lead Succimer is indicated for the treatment of lead poisoning in pediatric patients with blood lead levels above 45 mcg/dL Succimer is not indicated for prophylaxis of lead poisoning in a lead-containing environment the use of Succimer should always be accompanied by identification and removal of the source of the lead exposure DMSA is also clinically useful for chelating Arsenic Cadmium Mercury It has been suggested that DMSA be utilized following EDTA chelation Dart RC, Hurlbut KM, Maiorino RM, Mayersohn M, Aposhian HV, Hassen LV. Pharmacokinetics of meso-2,3-dimercaptosuccinic acid in patients with lead poisoning and in healthy adults. J Pediatr. 1994 Aug;125(2):309-16. PubMed PMID: 8040783. Fournier L, Thomas G, Garnier R, Buisine A, Houze P, Pradier F, Dally S. 2,3-Dimercaptosuccinic acid treatment of heavy metal poisoning in humans. Med Toxicol Adverse Drug Exp. 1988 Nov-Dec;3(6):499-504. PubMed PMID: 2851085. Friedheim E, Corvi C. Meso-dimercaptosuccinic acid, a chelating agent for the treatment of mercury poisoning. J Pharm Pharmacol. 1975 Aug;27(8):624-6. PubMed PMID: 239185. Lenz K, Hruby K, Druml W, Eder A, Gaszner A, Kleinberger G, Pichler M, Weiser M. 2,3-Dimercaptosuccinic acid in human arsenic poisoning. Arch Toxicol. 1981Jun;47(3):241-3. PubMed PMID: 6268016. Crinnion WJ. EDTA redistribution of lead and cadmium into the soft tissues in a human with a high lead burden - should DMSA always be used to follow EDTA in such cases? Altern Med Rev. 2011 Jun;16(2):109-12. PubMed PMID: 21649453. Copyright WCrinnion 2013

Contraindications DMSA should not be administered to patients with a history of allergy to the drug Most typically found in those with a high reactivity to anything containing sulfur If a patient has experienced unexplained adverse reactions, avoid re-exposure to DMSA Copyright WCrinnion 2013

Warnings & Precautions Mild/moderate neutropenia has been observed A causal relationship to succimer has not been absolutely established Neutropenia has been reported drugs in the same chemical class (dithiols) A complete blood count with white blood cell differential and platelet count should be obtained prior to and weekly during treatment with succimer Withhold or discontinue therapy if the absolute neutrophil count (ANC) is below 1200/mcL . Follow patient closely to document recovery of the ANC to above 1500/mcL or to baseline neutrophil count Due to limited experience with re-exposure in patients who have developed neutropenia, such patients should be re-challenged only if the benefit of therapy clearly outweighs the potential risk of another episode of neutropenia and only with careful patient monitoring Instruct patients treated with succimer to promptly report any signs of infection. If infection is suspected laboratory tests should be performed immediately http://www.medicinenet.com/succimer-oral/article.htm (accessed 9/17/2013) http://www.medicinenet.com/succimer-oral/article.htm (accessed 9/17/2013) Copyright WCrinnion 2013

DMSA Warnings & Precautions Pregnancy: Category C Nursing mothers Many drugs and toxic metals are excreted in human milk, nursing mothers needing DMSA therapy should be discouraged from nursing their infants Copyright WCrinnion 2013

Safety of DMSA with children With mercury overload A cluster of pediatric metallic mercury exposure cases treated with meso-2,3-dimercaptosuccinic acid (DMSA) Forman J, et al. Environ Health Perspect 2000;108:575-577 With lead overload Safety and efficacy of meso-2,3-dimercaptosuccinic acid (DMSA) in children with elevated blood lead concentrations. Chisolm JJ. J Toxicol Clinical Toxicology 2000;38(4):365-375 Copyright WCrinnion 2013

DMPS Chemical name: 2,3-dimercapto-1-propanesulfonic acid Sodium 2,3-dimercaptopropane sulfonate Alt: 2,3-bis(sulfanyl)propane-1-sulfonate Other drug names Dimaval Unithiol Copyright WCrinnion 2013

Heyl Dimaval Monograph http://www.scrib d.com/doc/311017 40/Dimaval®- Scientific- Product- Monograph Accessed: 9/17/2013 Dimaval®: Scientific Product Monograph Ruprecht J. Dimaval®: Scientific Product Monograph. 7th Edition. Berlin: HEYL Chem.-pharm. Fabrik, 2008. Copyright WCrinnion 2013

Kinetics DMPS is distributed extracellularly and, to a smaller extent, intracellularly. 80% bound by protein, mainly albumin, in the plasma, highly stable prolonging the heavy metal mobilizing activity This results in the half life extending from 1.8 hours of the parent compound to 20 hours of the altered (bound) drug. Dimaval®: Scientific Product Monograph Ruprecht J. Dimaval®: Scientific Product Monograph. 7th Edition. Berlin: HEYL Chem.-pharm. Fabrik, 2008. Copyright WCrinnion 2013

Kinetics Half-life after intravenous dosing - 20 hours Half-life after oral dose - 9.5 hours DMPS undergoes renal excretion with 46 to 59% of the dose detected in the urine after 24 hours of dosing Dimaval®: Scientific Product Monograph Ruprecht J. Dimaval®: Scientific Product Monograph. 7th Edition. Berlin: HEYL Chem.-pharm. Fabrik, 2008. Copyright WCrinnion 2013

Toxicology No adverse effects on organ systems at therapeutic doses Immune system parameters not effected – no neutropenia Non-Mutagenic, non-teratogenic Pregnancy category C - It is NOT recommended that pregnant women with chronic toxicity undergo mobilization of heavy metals until completion of lactation Dimaval®: Scientific Product Monograph Ruprecht J. Dimaval®: Scientific Product Monograph. 7th Edition. Berlin: HEYL Chem.-pharm. Fabrik, 2008. Copyright WCrinnion 2013

Indications and Usage Currently, it is not FDA approved in the United States Classified by the FDA as a bulk drug substance for pharmacy compounding Dimaval®: Scientific Product Monograph Ruprecht J. Dimaval®: Scientific Product Monograph. 7th Edition. Berlin: HEYL Chem.-pharm. Fabrik, 2008. Copyright WCrinnion 2013

Contraindications DMPS must not be administered to patients who are hypersensitive to DMPS or its salts Not recommended for use in patients with serum creatinine greater than 2.5 or stage 4 chronic kidney disease (CKD) Dimaval®: Scientific Product Monograph Ruprecht J. Dimaval®: Scientific Product Monograph. 7th Edition. Berlin: HEYL Chem.-pharm. Fabrik, 2008. Copyright WCrinnion 2013

Precautions Drug Interactions Pregnancy Pediatric Use None listed Pregnancy Category C: The safety of DMPS administration during pregnancy has not been confirmed in humans Pediatric Use Pediatric doses have not been specified, do not administer to patients less than 12 months of age Patients with mercury amalgam fillings See Aposhian study Dimaval®: Scientific Product Monograph Ruprecht J. Dimaval®: Scientific Product Monograph. 7th Edition. Berlin: HEYL Chem.-pharm. Fabrik, 2008. Copyright WCrinnion 2013

Does DMPS pull Hg from fillings? Urinary mercury after administration of 2,3- dimercaptopropane-1-sulfonic acid: correlation with dental amalgam score Aposhian HV, et al FASEB J 1992;6:2472-2476 10 subjects with amalgams 10 subjects without amalgams Aposhian HV, Bruce DC, Alter W, Dart RC, Hurlbut KM, Aposhian MM. Urinary mercury after administration of 2,3-dimercaptopropane-1-sulfonic acid: correlation with dental amalgam score. FASEB J. 1992 Apr;6(7):2472-6. PubMed PMID: 1563599. Copyright WCrinnion 2013

Aposhian, HV. 1992 300mg DMPS po after 11 hour fast Urine collected 9 hours post DMPS 10 w/ amalgams 0.70 to 17.2 ug Hg 10 w/o amalgams 0.27 to 5.1 ug Hg Aposhian HV, Bruce DC, Alter W, Dart RC, Hurlbut KM, Aposhian MM. Urinary mercury after administration of 2,3-dimercaptopropane-1-sulfonic acid: correlation with dental amalgam score. FASEB J. 1992 Apr;6(7):2472-6. PubMed PMID: 1563599. Copyright WCrinnion 2013

Aposhian conclusion “ A linear relationship exists between the amalgam score and the urinary mercury after DMPS administration” “Two-thirds of the mercury excreted in the urine of those with dental amalgams appears to be derived originally from the mercury vapor released from their amalgams” Aposhian HV, Bruce DC, Alter W, Dart RC, Hurlbut KM, Aposhian MM. Urinary mercury after administration of 2,3-dimercaptopropane-1-sulfonic acid: correlation with dental amalgam score. FASEB J. 1992 Apr;6(7):2472-6. PubMed PMID: 1563599. Copyright WCrinnion 2013

Where did most of the urinary mercury come from? The Kidneys! Aposhian HV, Bruce DC, Alter W, Dart RC, Hurlbut KM, Aposhian MM. Urinary mercury after administration of 2,3-dimercaptopropane-1-sulfonic acid: correlation with dental amalgam score. FASEB J. 1992 Apr;6(7):2472-6. PubMed PMID: 1563599. Copyright WCrinnion 2013

Sulfa allergy & the “Ds” Sulfa drug allergy? Not a contraindication for either DMSA or DMPS There has been no demonstrated cross reactivity from a chemical or pharmacological standpoint Copyright WCrinnion 2013

W. Crinnion, Unpublished case report Copyright WCrinnion 2013

Adverse Reactions Skin General Pruritus, rashes, allergic skin reactions (rare) General Chills, fever, increased transaminases Dimaval®: Scientific Product Monograph Ruprecht J. Dimaval®: Scientific Product Monograph. 7th Edition. Berlin: HEYL Chem.-pharm. Fabrik, 2008. Copyright WCrinnion 2013

Will Transdermal DMPS work? Transdermal (TD-DMPS) is an ineffective metal chelator TD-DMPS is not absorbed, not found in blood samples There was no increase in urine mercury excretion after TD-DMPS. Cohen JP, Ruha AM, Curry SC, Biswas K, Westenberger B, Ye W, Caldwell KL,Lovecchio F, Burkhart K, Samia N. Plasma and urine dimercaptopropanesulfonate concentrations after dermal application of transdermal DMPS (TD-DMPS). J MedToxicol. 2013 Mar;9(1):9-15. doi: 10.1007/s13181-012-0272-9. PubMed PMID:23143832 Copyright WCrinnion 2013

Transdermal DMPS 48yo M Cd <2 0.2 0.9 0.09 0.3 Pb <5 <dl 13 Metal DDI Pre Post EDTA/ DMPS Transdermal DMPS Cd <2 0.2 0.9 0.09 0.3 Pb <5 <dl 13 0.8 Hg <4 1.4 7.2 0.5 Ni <12 3 9.3 2.4 3.4 Crinnion, W. Unpublished research Copyright WCrinnion 2013

Pre-testing Provocation and Chelation Periodic testing during therapy Complete blood count Comprehensive metabolic panel GFR – or creatinine WNL Anti-IgA gliadin antibody – if suspicion of malabsorption is present. 6 hour urine collection for toxic metal assessment Mineral analysis – when indicated Serum RBC RBC glutathione to show available GSH/GSSG 8-OHdG for oxidative damage assessment Copyright WCrinnion 2013

Testing methods Serum – good for acute exposures, keep in mind the t1/2 in serum. Urine – also good for acute exposures, when used with chelating agent will indicate relative level of body store. Hair – excellent for methylmercury Fecal – good method for children Copyright WCrinnion 2013

Provocation Testing Choose a standard & consistent basis for testing Serial test interpretation is only possible with the same drug dose and urine collection time Provocation dose for each test remains constant DMSA (30 mg/kg oral) DMPS (3 mg/kg IV) Ca EDTA (50 mg/kg IV) Urine collection time of 6 hours Copyright WCrinnion 2013

DMSA protocol Rule out potential DMSA sensitivity i.e. reactive to ALL sulfur-containing compounds No shellfish or seaweed for the week prior to testing Avoid high arsenic levels Empty bladder* and stomach Use first morning urine for pre-flush test Body weight DMSA (30 mg/kg up to 2250mg) Collect all urine for 6 hours Food can be consumed after 1 hour. Copyright WCrinnion 2013

Protocol for DMPS challenge test Sensitivity check for DMPS No shellfish or seaweed for 1 week prior Empty bladder* DMPS (3mg/kg up to 250mg) given in a push over 15-20 minutes. 6 hour urine catch – Toxic element analysis. Check serum creatinine. Copyright WCrinnion 2013

Oral DMPS challenge No shellfish for 1 week prior Empty bladder* and empty stomach 10mg/kg oral DMPS 6 hour urine catch sent in for heavy metal UA. Serum creatinine check Copyright WCrinnion 2013

Oral DMPS testing 300 mg oral dose given after 11 hour fast Dental technicians – 4.84 pre to 424.0 post Dentists - 3.28 pre 162.0 post Non-dental persons 0.783 pre 27.3 post Positive association between pre coproporphyrin levels and flushed Hg Pos assoc. Hg and cognitive sx and mood J Pharmacol Exper Therapeutics 1995;272:264-274. PMID: 7815341 Gonzalez-Ramirez D, Maiorino RM, Zuniga-Charles M, Xu Z, Hurlbut KM, Junco-Munoz P, Aposhian MM, Dart RC, Diaz Gama JH, Echeverria D, et al. Sodium 2,3-dimercaptopropane-1-sulfonate challenge test for mercury in humans: II. Urinary mercury, porphyrins and neurobehavioral changes of dental workers in Monterrey, Mexico. J Pharmacol Exp Ther. 1995 Jan;272(1):264-74. PubMed PMID: 7815341. Copyright WCrinnion 2013

EDTA/DMPS Flush protocol Serum creatinine WNL Empty bladder prior to injection* 2,000mg glycine given 2 hours pre if possible CaNa2EDTA 2,000 mg (10cc) with sterile H2O in one syringe. Slow push. 20 min Flush with 3 cc saline DMPS (3 mg/kg) slow push 15 min Collect all urine for the next six hours Copyright WCrinnion 2013

Assessing Kidney Function Creatinine clearance Compliance for 24 hour UA often poor Serum creatinine being WNL Copyright WCrinnion 2013

NO TEST CAN SHOW TOTAL BODY BURDEN OF HEAVY METALS!!!! These tests are measuring the amount LEAVING the body, NOT the total IN the body Copyright WCrinnion 2013

What to expect DMSA flush gives a good representation of Hg and Pb. DMPS gives a much higher dump of Hg and much lower dump of Pb EDTA will give the highest dumps of Cd, Pb and will mobilize Al. It will give VERY POOR dumping of Hg. If GSH is low you may get a deceptively low reading of Hg Pre-treatment with NAC & MSM Copyright WCrinnion 2013

The differences in Pb and Hg between DMPS and DMSA flushing in one adult female Metal Reference Range Pre Post DMSA Post DMPS AS <57 12 17 54 CD <.9 0.3 0.4 0.5 PB <6 13 4.3 HG <7.2 1 6.4 11 Case Study – unpublished research Copyright WCrinnion 2013

Doing initial pre and post testing Helps identify current exposures Helps identify how effective the proposed chelating agent is Can give information about absorptive ability of the person Pre-testing is the ONLY means available to identify toxic levels of Cd Copyright WCrinnion 2013

Recognizing current exposures CDC National reports provide us with ‘normal’ ranges for US residents for the first time. Levels above 75th percentile would typically indicate current exposure. For Hg, this is NOT from dental amalgams Copyright WCrinnion 2013

Trimethylarsine oxide Total Arsenic 8.24 7.04 14.1 30.4 50.4 Compound Geometric mean 50th percentile 75th percentil e 90th percentil e 95th percentile Arsenous (III) acid NA <LOD Arsenic (V) acid 3.04 MMA 1.33 2.22 2.86 DMA 3.69 3.37 5.71 9.09 13.0 Arsenobetaine 1.55 1.00 5.20 16.8 35.0 Arsenocholine Trimethylarsine oxide Total Arsenic 8.24 7.04 14.1 30.4 50.4 http://www.cdc.gov/exposurereport/ (accessed 9/17/2013) Copyright WCrinnion 2013

Compound 50th percentile 75th percentile 90th percentile Geometric Mean 50th percentile 75th percentile 90th percentile 95th percentile Antimony NA .080 .135 .208 .277 Arsenic (total) 8.24 7.04 14.1 30.4 50.4 Barium 1.48 1.41 2.68 4.92 7.10 Cadmium .210 .412 .678 .940 Cesium 4.64 4.42 6.11 8.51 10.6 Cobalt .314 .290 .455 .737 1.02 Lead .632 .622 .979 1.49 1.97 Mercury .443 .447 .909 1.65 2.35 Thallium .154 .153 .214 .286 .350 Uranium .008 .007 .012 .021 .029 http://www.cdc.gov/exposurereport/ (accessed 9/17/2013) Copyright WCrinnion 2013

Hg mostly organic – not elemental Ug/L of Hg in blood Geometric Mean 50th percentile 75th percentile 90th percentile 95th percentile Total Blood Hg .797 .800 1.70 3.30 4.90 Inorganic blood Hg NA <LOD .600 .700 http://www.cdc.gov/exposurereport/ (accessed 9/17/2013) Copyright WCrinnion 2013

Pre and Post Giving Information on Current Exposures Copyright WCrinnion 2013

Levels of Hg ABOVE CDC 75% = CURRENT EXPOSURE AND an expectation of a large dump post DMSA Metal MMX Reference Range CDC 90/95% Pre AS <57 49 CD <.9 .68 / .94 0.4 PB <4.4 1.5 / 2 HG <7.4 1.65 / 2.35 4.2 Crinnion W. Case Study – unpublished research Copyright WCrinnion 2013

Right on both counts Ate tuna 3-4 times weekly Metal CDC 90/95% Pre MMX Reference Range CDC 90/95% Pre Post DMSA AS <57 49 50 CD <.9 .68 /.94 0.4 0.9 PB <4.4 1.5 / 2 14 HG <7.4 1.65 / 2.35 4.2 Right on both counts Ate tuna 3-4 times weekly Crinnion W. Case Study – unpublished research Copyright WCrinnion 2013

Eats Halibut or King Salmon five times weekly Metal MMX Ref CDC 90/95% Pre DMSA Post DMSA Hg <7.4 1.65 / 2.35 2.9 9.4 Case Study – unpublished research Meager Hg levels on post flush would NOT have been reflective on a current exposure WITHOUT the pre! Also look for poor absorption or GSH deficiency! Copyright WCrinnion 2013

No amalgams, no fish intake?? Metal MMX Ref CDC 90/95% Pre DMSA Post DMSA PB <4.4 1.5 / 2 2.2 23 Hg <7.4 1.65 / 2.35 4.7 38 Case Study – unpublished research Copyright WCrinnion 2013

The culprit (s) Possible exposure in some supplements (as yet untested) But, found a broken Hg thermometer in her car, and vacuumed it up with vacuum used regularly inside of home. http://www.epa.gov/epaoswer/hazwaste/mercury/faq/s pills.htm#cleanup Case Study – unpublished research Copyright WCrinnion 2013

Pre and post testing gives information on absorption of DMSA or DMPS oral Copyright WCrinnion 2013

Multiple amalgams in mouth, but no regular fish intake Metal MMX Ref CDC 90/95% Pre DMSA Post DMSA PB <4.4 1.5 / 2 0.3 11 Hg <7.4 1.65 / 2.35 0.7 (CDC mean .4) 1 Case Study – unpublished research Copyright WCrinnion 2013

Why such a small increase in Hg? Positive anti-gliadin IgG Non-positive transglutaminase IgA Copyright WCrinnion 2013

29 yo f with amalgams and history of gluten sensitivity Metal MMX Ref CDC 90/95 Pre DMSA Post DMSA Pb <4.4 1.5 / 2 <dl 6.6 Hg <7.4 1.65 / 2.35 0.8 4.5 Case Study – unpublished research Copyright WCrinnion 2013

29yo f with amalgams and history of gluten sensitivity No gluten in diet. Anti-gliadin IgA of 26!! Gluten in supplements from discount store Copyright WCrinnion 2013

29yo f with amalgams and gluten sensitivity after 6 months clean diet Metal MMX Ref CDC 90/95 Pre DMSA Post DMSA Pb <4.4 1.5 / 2 <dl 6.6 14 Hg <7.4 1.65 / 2.35 0.8 4.5 86 Case Study – unpublished research Copyright WCrinnion 2013

Pre and Post Testing Giving information on the effectiveness (or lack thereof) of your chosen ‘chelating’ agents Copyright WCrinnion 2013

Pre and Post Tests Metal Free and DMSA MMX ref Pre Metal Free Post Metal Free Post DMSA Cd <.9 0.3 Pb <4.4 <dl Hg <7.4 1.9 0.7 Crinnion W. Case Study – unpublished research Copyright WCrinnion 2013

Pre and Post Tests Metal Free and DMSA MMX ref Pre Metal Free Post Metal Free Post DMSA Cd <.9 0.3 0.7 Pb <4.4 <dl 28 Hg <7.4 1.9 33 Crinnion W. Case Study – unpublished research Copyright WCrinnion 2013

Oral EDTA, pt 1(50yo F) Metal MMX ref Pre DMSA Post DMSA Pre EDTA Post EDTA Cd <.9 0.4 Pb <4.4 <dl Hg <7.4 Ni NA Crinnion W. Case Study. Unpublished research Copyright WCrinnion 2013

Oral EDTA, pt 1(50yo F) Metal DDI ref Pre DMSA Post DMSA Pre EDTA Post EDTA Cd <2 0.4 0.6 Pb <5 <dl 6.5 Hg <4 3.1 Ni <12 Copyright WCrinnion 2013 Crinnion, W. Unpublished research

Oral EDTA, pt 1(50yo F) Metal DDI ref Pre DMSA Post DMSA Pre EDTA Post EDTA Cd <2 0.4 0.6 0.2 Pb <5 <dl 6.5 1 Hg <4 3.1 Ni <12 Crinnion, W. Unpublished research Copyright WCrinnion 2013

Oral EDTA, pt 1(50yo F) Metal DDI ref Pre DMSA Post DMSA Pre EDTA Post EDTA Cd <2 0.4 0.6 0.2 0.5 Pb <5 <dl 6.5 1 2.3 Hg <4 3.1 Ni <12 1.3 Crinnion, W. Unpublished research Copyright WCrinnion 2013

Oral EDTA, 28 yo F Metal MMX Ref Pre DMSA Post DMSA Pre oral EDTA Post o –EDTA Pre IV EDTA Post IV EDTA AL <61 Sb <1.72 35 Cd <.9 0.8 Pb <4.4 0.4 Hg <7.4 1.3 Crinnion W. Case Study. Unpublished research Copyright WCrinnion 2013

Oral EDTA, 28 yo F Metal MMX Ref Pre DMSA Post DMSA Pre oral EDTA Post o –EDTA Pre IV EDTA Post IV EDTA AL <61 Sb <1.72 35 38 Cd <.9 0.8 0.6 Pb <4.4 0.4 14 Hg <7.4 1.3 9.8 Crinnion W. Case Study. Unpublished research Copyright WCrinnion 2013

Oral EDTA, 28 yo F Metal MMX Ref Pre DMSA Post DMSA Pre oral EDTA Post o –EDTA Pre IV EDTA Post IV EDTA AL <61 4.6 Sb <1.72 35 38 0.04 Cd <.9 0.8 0.6 0.5 Pb <4.4 0.4 14 0.3 Hg <7.4 1.3 9.8 1 Crinnion W. Case Study. Unpublished research Copyright WCrinnion 2013

Oral EDTA, 28 yo F Metal MMX Ref Pre DMSA Post DMSA Pre oral EDTA Post o –EDTA Pre IV EDTA Post IV EDTA AL <61 4.6 Sb <1.72 35 38 0.04 Cd <.9 0.8 0.6 0.5 0.3 Pb <4.4 0.4 14 0.9 Hg <7.4 1.3 9.8 1 1.1 Crinnion W. Case Study. Unpublished research Copyright WCrinnion 2013

Oral EDTA, 28 yo F Metal MMX Ref Pre DMSA Post DMSA Pre oral EDTA Post o –EDTA Pre IV EDTA Post IV EDTA AL <61 4.6 Sb <1.72 35 38 0.04 12 Cd <.9 0.8 0.6 0.5 0.3 Pb <4.4 0.4 14 0.9 Hg <7.4 1.3 9.8 1 1.1 Crinnion W. Case Study. Unpublished research Copyright WCrinnion 2013

Oral EDTA, 28 yo F Metal MMX Ref Pre DMSA Post DMSA Pre oral EDTA Post o –EDTA Pre IV EDTA Post IV EDTA AL <61 4.6 230 Sb <1.72 35 38 0.04 12 0.06 Cd <.9 0.8 0.6 0.5 0.3 4.1 Pb <4.4 0.4 14 (x35) 0.9 11 Hg <7.4 1.3 9.8 (x7.5) 1 1.1 Crinnion W. Case Study. Unpublished research Copyright WCrinnion 2013

Zeolite 31 yo M– 40 gtt qid Followed protocol from www. ncdtest Zeolite 31 yo M– 40 gtt qid Followed protocol from www.ncdtest.com- Dr. Lyn Hanshew Metal MMX Ref Pre Zeolite Post Zeolite EDTA/ DMPS Cd <.9 0.2 Pb <4.4 1.1 Hg <7.4 0.5 Crinnion W. Case Study. Unpublished research Copyright WCrinnion 2013

Zeolite 31 yo M – 40 gtt qid Metal MMX Ref Pre Zeolite Post Zeolite EDTA/ DMPS Cd <.9 0.2 0.3 Pb <4.4 1.1 0.1 Hg <7.4 0.5 0.6 Crinnion W. Case Study. Unpublished research Copyright WCrinnion 2013

Zeolite 31 yo M – 40 gtt qid Metal MMX Ref Pre Zeolite Post Zeolite EDTA/ DMPS Cd <.9 0.2 0.3 1.3 Pb <4.4 1.1 0.1 18 Hg <7.4 0.5 0.6 5.7 Crinnion W. Case Study. Unpublished research Copyright WCrinnion 2013

Pre and post testing The ONLY means of assessing Cadmium toxicity Copyright WCrinnion 2013

Cd in the CDC 4th Report Mean 50th 75th 90th 95th Blood Cd (ug/L) .304 .300 .500 1.10 1.60 Urinary (ug/g creatinine) .210 .208 .412 .678 .940 Urinary cadmium reflects both cumulative exposure AND the concentration of cadmium in the kidneys http://www.cdc.gov/exposurereport/ (accessed 9/17/2013) Copyright WCrinnion 2013

Cadmium 2-fold increase in urinary cadmium in non- exposed persons correlated with 73% increased risk of fractures in women 60% increased risk of height loss in men (By CDC that would be 0.4 ug/g) Increased urinary cadmium excretion and renal tubular dysfunction were associated with signs of osteoporosis, as measured by bone mineral density, in men and older women. Staessen JA, et al. Lancet 1999; 353:1140–1144. PMID:10209978 Alfven T, et al. J Bone Miner Res 2000;15(8):1579–1586. PMID:10934657 Copyright WCrinnion 2013

Cadmium and the kidneys Kidneys hold the highest burden of Cd Avg. 20 ug/g nonsmokers, 40 ug/g smokers Urinary Cd .5-2.0 µg/g creatinine associated with renal damage (Sweden)* Corresponded to 10-40 mg/kg .6-1.2 ug/g (Japan)** Urinary Cd of 2.5 µg/g creatinine: 4-fold higher risk of tubular damage “Significant effects were already seen at a mean level of 0.6 ug/g” *** *Jarup, et al. Scan J Work Environ Health 1998;24:1-51 PMID: 9569444 ** Uno, et al. Scan J Work Environ Health 2005;31:307-15 PMID: 16161714. ***Akesson, et al. EHP 2005;113:1627-31. PMID: 16263522 Järup L, Berglund M, Elinder CG, Nordberg G, Vahter M. Health effects of cadmium exposure--a review of the literature and a risk estimate. Scand J Work Environ Health. 1998;24 Suppl 1:1-51. PubMed PMID: 9569444 Uno T, Kobayashi E, Suwazono Y, Okubo Y, Miura K, Sakata K, Okayama A, Ueshima H, Nakagawa H, Nogawa K. Health effects of cadmium exposure in the general environment in Japan with special reference to the lower limit of the benchmark dose as the threshold level of urinary cadmium. Scand J Work Environ Health. 2005 Aug;31(4):307-15. PubMed PMID: 16161714. Akesson A, Lundh T, Vahter M, Bjellerup P, Lidfeldt J, Nerbrand C, Samsioe G, Strömberg U, Skerfving S. Tubular and glomerular kidney effects in Swedish women with low environmental cadmium exposure. Environ Health Perspect. 2005 Nov;113(11):1627-31. PubMed PMID: 16263522 Copyright WCrinnion 2013

Cadmium and ….. Increased risk of developing diabetes Increased risk of high blood pressure and cardiovascular disease. Increased risk of obstructive pulmonary disorders Increased risk of breast, bladder and lung cancer. Schwartz GG, Yasova DI, Ivanova A. Urinary cadmium, impaired fasting glucose, and diabetes in the NHANES III. Diabetes Care 2003;26:468-470. Menke A, Muntner P, Silbergeld E, Platz E, Guallar E. Cadmium levels in urine and mortality among U.S. adults. Environ Health Perspect 2009:117:190-196. Gallagher CM, Meliker JR. Blood and urine cadmium, blood pressure, and hypertension: A systematic review and meta-analysis. Environ Health Perspect 2012;118:1676-84. Copyright WCrinnion 2013

Treatment Options Copyright WCrinnion 2013

Treatment Options The Proven and the UnProven DMSA (great for lead and mercury) CaNa2EDTA (great for lead, cadmium, aluminum, nickel) DMPS (oral or IV – great for mercury) Commonly used but not substantiated Chlorella & Cilantro Metal Free & NDF Oral CaEDTA Zeolite Copyright WCrinnion 2013

My Treatment Protocols for the D’s DMPS 3mg/kg IV (up to 250mg) 10mg/kg po Once every 2-4 weeks Bowel Cleansing Mag Sulf. 2 cc after each shot Supportive nutrients DMSA 10 mg/kg tid (up to 2250mg daily) 5 days on, 9 days off**** Bowel Cleansing Mag sulf 2 cc after each week on Supportive nutrients Copyright WCrinnion 2013

DMSA options if cleansing reactions are too intense. 2 days on (weekends) followed by 5 days off. Lower levels of DMSA given every 4 hours (patients does NOT need to wake themselves up at night for this) Copyright WCrinnion 2013

Hg clearing with DMSA 30mg/kg/day in 9 children Forman J, Moline J, Cernichiari E, Sayegh S, Torres JC, Landrigan MM, Hudson J, Adel HN, Landrigan PJ. A cluster of pediatric metallic mercury exposure cases treated with meso-2,3-dimercaptosuccinic acid (DMSA). Environ Health Perspect. 2000 Jun;108(6):575-7. PubMed PMID: 10856034 Copyright WCrinnion 2013

EDTA, DMPS and DMSA Day 1 – EDTA (2,000 – 3,000mg CaNa2EDTA and saline or sterile water) [50mg/kg] - Flush line with 3cc saline - DMPS (body weight) with saline or sterile water Day 2 – 6 - DMSA oral per body weight in 3 divided doses Day 7 – 14 - Heavy metal support - Colonics - Mag sulf Copyright WCrinnion 2013

Relative Affinities of chelators DMPS Mercury Lead Silver Cadmium Nickel Arsenic Antimony Copper Molybdenum Zinc Manganese DMSA Lead Cadmium Mercury Silver Nickel Arsenic Molybdenum Copper Zinc Manganese Iron Tin Copyright WCrinnion 2013

Suppositories DMSA suppositories at 20 mg/kg EDTA (Detoxamin) 750mg nightly Supplement with Zn in daytime 50% decrease in Pb in 3 months Neither seem to work as a flush-test agent D. Quig, personal communication Copyright WCrinnion 2013

The unproven Copyright WCrinnion 2013

Rachel 35 y.o. female wanting to conceive April 5- H/O Hg fillings recently removed 7 months of detox with Metal Free + more from local D.C. Eats fish Blood Hg levels 3/10/04 Hg 10 4/5/04 Hg 11 Copyright WCrinnion 2013

Pre and Post Tests Metal Free and DMSA DDI ref Pre Metal Free Post Metal Free Post DMSA Cd <2 0.3 Pb <5 <dl Hg <4 1.9 0.7 Ni <10 1.5 1.1 Copyright WCrinnion 2013

Pre and Post Tests Metal Free and DMSA DDI ref Pre Metal Free Post Metal Free Post DMSA Cd <2 0.3 0.7 Pb <5 <dl 28 Hg <4 1.9 33 Ni <10 1.5 1.1 2.1 Copyright WCrinnion 2013 Crinnion, W. Unpublished research

Clinical Study : Chlorella and Mercury Excretion Test popular, unsubstantiated belief that “chlorella enhances biliary/fecal excretion of mercury” No published human studies available to date regarding metal detoxification Japanese research pertaining to growth stimulating effects in animals and humans Copyright WCrinnion 2013

Chlorella (pyrensoida) Single celled marine algae (green) Triple cell wall (cellulose microfibrils) High protein and chlorophyll content Metal binding capacity (ponds) Absorption from human gut? Copyright WCrinnion 2013

CONCLUSIONS No effect of 8-10 gm chlorella/day on fecal excretion of Hg in subjects with average intestinal Hg exposure Undesirable GI side effects in all subjects 2/7 subjects exhibited trend for increased urinary Hg excretion (AA deficiencies?) D. Quig, unpublished research Copyright WCrinnion 2013

Contraindications ? Copyright WCrinnion 2013

Length of treatment Standard Protocol at my old clinic Retest urine every ten weeks 20% are cleared by twenty weeks 60% are cleared by 30 – 50 weeks 20% take more than 50 weeks If lead is present repeat as needed. Combination EDTA, DMPS and DMSA are giving very rapid cleansing results And causing some increased LFTs! Copyright WCrinnion 2013

Pros and Cons DMPS Pro Ease of use Great for Hg Con Legality Cannot reduce dose once it is given DMSA Pro Easy manipulation of dose to adverse responses Great for lead Con Amount of capsules Sulfur reaction Copyright WCrinnion 2013

Adverse cleansing effect Generally begin to show up on the third or fourth “round”. Usually begin on day three of taking DMSA. Can be relieved by: Activated charcoal Colonic irrigations Reduction of DMSA intake (no help with DMPS) Mentharil for GI problems with DMSA Copyright WCrinnion 2013

Adverse Effects of Cleansing Sulfur Nausea Diarrhea Belching Arsenic Fatigue Irritability Blistering on mucus mem Bruising on face Hive-like rash Mercury Insomnia Anxiety Depression Anger Copyright WCrinnion 2013 Crinnion, W. Unpublished research

Don’t forget the colonic 70% of methylmercury is recirculated via enterohepatic recirculation! Copyright WCrinnion 2013