evaluation and treatment of chronic metal...
TRANSCRIPT
Evaluation and Treatment of Chronic Metal Toxicity
Dr. Chris Spooner B. Sc. ND
Sunday, 6 May, 12
Exposure Absorption Excretion:
Chronic Retention:
(Absorption – Excretion) = Retention
Retention Over Time = Chronic Retention = Total Body Burden
Sunday, 6 May, 12
Exposure Absorption Excretion:
Chronic Retention:
(Absorption – Excretion) = Retention
Retention Over Time = Chronic Retention = Total Body Burden
Sunday, 6 May, 12
Chronic Metal Retention• “Low-level exposures associated with long-term effects not previously recognized” (NIEHS)
• Knowledge of adverse effects based primarily on independent studies of single toxicants
• Metals can elicit independent, additive or synergistic toxic effects (CDC)
• MRLs for exposures have not considered that humans bioaccumulate metals (CDC)
D.W. Quig, PhD
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D.W. Quig, PhD
Basic Toxicology!
•" Overt toxicity (poisoning) is rare and “accepted”!
•" “Sub clinical” metal toxicity = “body burden” (metal retention)"
D.W. Quig, PhD
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•" “Low-level exposures associated with long-term effects not previously recognized” (NIEHS)!
•" Knowledge of adverse effects based primarily on independent studies of single toxicants!
•" Metals can elicit independent, additive or synergistic toxic effects (CDC)!
•" MRLs for exposures have not considered that humans bioaccumulate metals (CDC)!
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D.W. Quig, PhD
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•" “Individuals vary considerably in their sensitivity to metals and susceptibility to toxicity varies with age, gender, pregnancy status, nutritional status and genetics”. (CDC)!
•" Neonates, infants and children are most vulnerable to most toxicants.!
•" Injury to developing organ systems (e.g. CNS), can cause lifelong disabilities. (Needleman)!
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•" Excretory tissue that binds circulating metals!
•" Concentrates metals cumulatively!•" Hair Me-Hg 200-300X > than blood Hg!•" Useful for recent/ongoing EXPOSURE"
•" NO direct indication of net retention!
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Distribution Endpoint Model
Storage
Metabolite
BiotransformationToxicant
Interaction With Cells Excretion
ABSORPTION
EXPOSURE
TOXICODYNAMIC
TOXICOKINETIC
(A.D.M.E.)
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Cartoon by Nick D Kim
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Metal Complexing Agent Affinity
• Different agents have (higher or lower) affinities for various metal ions
DMPS – high affinity for free and bound MercuryDMSA – high affinity for Mercury and free Lead EDTA – good affinity for Cd & Pb bound in bone stores
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Metal 1st Choice 2nd Choice
Inorganic Hg DMPS DMSA
Organic Hg DMPS/DMSA
Pb DMSA/EDTA DMPS
As DMPS
Cd EDTA DMPS
Sb DMPS/DMSA EDTA
Sn DMPS/DMSA EDTA
Tl Prussian Blue DMSA
Al EDTA
Ni EDTA DMPS
W DMPS/DMSA
Relative Affinities of Chelating Agents for Metals
-‐ Kemper in Aposhian, Toxicol (1990) 97, 23-‐38
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• EDTA, DMPS and DMSA, have been administered p.r. via suppository
• DMPS/DMSA suppositories
– e.g. ASD
• DMPS, and less commonly EDTA, have been used t.d.
Other routes of administration of chelating agents:
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• meso-‐2,3-‐Dimercaptosuccinic acid
• Synonyms: Succimer; Chemet
Because of the two neighboring SH groups, it has a high affinity for many heavy metals that have an
affinity for sulfur and forms stable complexes with them.
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• meso-‐2,3-‐Dimercaptosuccinic acid
• Synonyms: Succimer; Chemet
Because of the two neighboring SH groups, it has a high affinity for many heavy metals that have an
affinity for sulfur and forms stable complexes with them.
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• Indications: FDA approved for the treatment of lead poisoning in pediatric patients with blood lead levels above 45 μg/dL (2.17 μmol/L)*
• Contraindications: Chemet should not be administered to patient with a history of allergy to the drug
• Warnings: Mild neutropenia has been reported in some patients receiving DMSA
•Check CBC with differential prior to starting treatment*U.S Department of Health and Human Services. Succimer approved for severe lead poisoning.
FDA Medical Bulletin 1991; 21:5
DMSA
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• Precautions: Ensure adequate hydration during treatment
• Transient mild elevations of serum transaminases have been observed in <10% of patients.
• Check LFT prior to starting treatment
• Drug Interactions: None
• Pregnancy: Category C
• Nursing mothers: If treatment is necessary, mothers should be discouraged from nursing
• Pediatric Use: Safety in patients <1 yr has not been established
DMSA
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• Rare; transient
• Perhaps some upper-GI upset with oral agents (DMSA; less so with DMPS)
• Often relieved with small amount of food
• Occasional “warm” / “itchy” sensation or redness around i.v. infusion site with EDTA or DMPS
Adverse Reactions (oral / i.v.):
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• Adverse Reactions:
• GI side effects—nausea, vomiting, diarrhea, metallic taste in mouth <10%. Most common: gas/bloating (Peppermint/ginger tea and peppermint tablets often can alleviate GI side effects)
• Skin—mucocutaneous eruption, pruritus, uriticarial rash, erythematous rash
• Neutropenia
• Metabolic—elevated transaminases (ALT, AST),
Alkaline Phosphatase, Cholesterol <10%
DMSA
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• Adverse Reactions:
DMSA
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• Adverse Reactions:
Clinical Toxicology (2009) 47, 617-631
DMSA
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• Can screen for potential adverse rxns with a small “test dose” – 50 to 100 mg p.o. 2-3 days before the larger provocative challenge dose
Assess and treat dysbiosis:
• If dysbiosis present, may exacerbate symptoms (SH groups may enhance proliferation of some bacteria / yeast)
• Imperative to assess for and treat any dysbiosis before initiating a treatment protocol with oral DMPS or DMSA
Adverse Reactions to oral agents:
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Evaluating Toxic Metal Burden
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A comparison of different lead biomarkers in their associations with lead-related symptoms
B. -K. Lee A1, K. -D. Ahn A1, S. -S. Lee A1, G. -S. Lee A1, Y. -B. Kim A1, B. S. Schwartz A2 A1 Institute of Industrial Medicine, Soonchunhyang University, 23-20 Bongmyung-Dong, Chonan, Choongnam 330-100, Republic of KoreaA2 Department of Environmental Health Sciences, Division of Occupational and Environmental Health, Johns Hopkins University School of Hygiene and Public Health, Baltimore, USA
Abstract:
Abstract Objectives: To evaluate whether dimercaptosuccinic acid (DMSA) -chelatable lead, an estimate of current bioavailable lead stores, is a better predictor of lead-related symptoms than are other commonly used lead biomarkers. Conclusions: DMSA-chelatable lead was found to be the best predictor of lead-related symptoms, particularly of both total symptom scores and neuromuscular symptoms, than were the other other lead biomarkers.
International Archives of Occupational and Environmental Health Publisher: Springer-Verlag Heidelberg ISSN: 0340-0131 (Paper) 1432-1246 (Online) DOI: 10.1007/s004200000132 Issue: Volume 73, Number 5Date: June 2000 Pages: 298 - 304
Current Medicinal Chemistry, 2005, 12, 2771-2794 2771
Chelators as Antidotes of Metal Toxicity: Therapeutic and ExperimentalAspects
Maja Blanusa*˘ , Veda M. Varnai, Martina Piasek and Krista Kostial
Mineral Metabolism Unit, Institute for Medical Research and Occupational Health, Ksaverska cesta 2,P.O. Box 291, HR-10001 Zagreb, Republic of Croatia
Abstract: The effects of chelating drugs used clinically as antidotes to metal toxicity are reviewed. Humanexposure to a number of metals such as lead, cadmium, mercury, manganese, aluminum, iron, copper, thallium,arsenic, chromium, nickel and platinum may lead to toxic effects, which are different for each metal. Similarlythe pharmacokinetic data, clinical use and adverse effects of most of the chelating drugs used in human metalpoisoning are also different for each chelating drug. The chelating drugs with worldwide application aredimercaprol (BAL), succimer (meso-DMSA), unithiol (DMPS), D-penicillamine (DPA), N-acetyl-D-penicillamine (NAPA), calcium disodium ethylenediaminetetraacetate (CaNa2EDTA), calcium trisodium or zinctrisodium diethylenetriaminepentaacetate (CaNa3DTPA, ZnNa3DTPA), deferoxamine (DFO), deferiprone (L1),triethylenetetraamine (trientine), N-acetylcysteine (NAC), and Prussian blue (PB). Several new synthetichomologues and experimental chelating agents have been designed and tested in vivo for their metal bindingeffects. These include three groups of synthetic chelators, namely the polyaminopolycarboxylic acids (EDTAand DTPA), the derivatives of BAL (DMPS, DMSA and mono- and dialkylesters of DMSA) and thecarbodithioates. Many factors have been shown to affect the efficacy of the chelation treatment in metalpoisoning. Within this context it has been shown in experiments using young and adult animals that metaltoxicity and chelation effects could be influenced by age. These findings may have a bearing in the design ofnew therapeutic chelation protocols for metal toxicity.
Keywords: Chelating agents, BAL derivatives, carbodithioates, deferiprone, deferoxamine, D-penicillamine,polyaminopolycarboxylic acids, metals, metal toxicity.
1. INTRODUCTION of the most important information on common metalpoisonings and possibilities for their chelating treatment,both by clinical and experimental agents, are listed in Table1. The effects of chelating agents presently applied in humanclinical practice and the metal binding effects of newlysynthesized chelators are described in separate sections.Three groups of chelators are described, namely thepolyaminopolycarboxylic acids, such as ethylenediaminete-traacetic acid (EDTA) and diethylenetriaminepentaacetic acid(DTPA); the derivatives of dimercaprol (British-Anti-Lewisite, BAL), such as 2,3-dimercaptopropane-1-sulfonicacid (DMPS), 2,3-dimercaptosuccinic acid (DMSA), andmono- and dialkylesters of DMSA; and the carbodithioates.Not only are newer agents being sought, but alsocombinations of new or already known chelators are testedfor possible synergistic action. Age-related differences inefficacy of chelation therapy are also included, since thebinding of toxic metals in the very young is an importanttopic presently under investigation.
A chelating agent is a molecule that forms a complexwith a metal ion. The chelating agent molecule has electronsavailable to form a bond with a positively charged transitionmetal ion. Chelators can be attached to the metal ion by twoor more bonds forming a ring, which is called the chelatering [1]. The main goal of chelation treatment is totransform the toxic metal complex with biological ligandsinto a new, non-toxic complex between the metal ion andchelator, which can be excreted from the organism. To fulfillthis purpose chelating agents must possess severalcharacteristics. The profile of a successful chelating drugincludes high affinity for the toxic metal(s) but low affinityfor essential metals, minimal toxicity, lipid solubility, and,preferably, good absorbability from the gastrointestinal tract.These conditions, however, are not easy to fulfill. Forexample, the advantage of lipid soluble substances is thatthey easily cross the cell membrane and bind metals withinthe cell. Unfortunately, such chelators are usually more toxicthan those which are not lipid soluble. Thus, it is achallenging task to find optimal conditions for bindingspecific toxic metal with minimal risk of adverse effects.
The chemical structures of some clinically used andexperimental chelators are presented in Figs. 1 and 2.
2. METAL EXPOSURE AND HEALTH EFFECTSExposure and toxicity of several metals and metalloids
such as lead, cadmium, mercury, manganese, aluminum,iron, copper, thallium, arsenic, chromium, nickel andplatinum, are of major concern to human health. A summary
Metals can disturb organ functions and cause diseasethrough excess, deficiency, or imbalance in the body. Anumber of metal ions regulate a vast array of physiologicalmechanisms that are essential for organ functioning anddevelopment. However, under conditions of metal overload,toxic side effects can occur. Metal overload can be caused by*Address correspondence to this author at the Mineral Metabolism Unit,
Institute for Medical Research and Occupational Health, P.O. Box 291,HR-10001 Zagreb, Republic of Croatia; E-mail: [email protected]
0929-8673/05 $50.00+.00 © 2005 Bentham Science Publishers Ltd.
Occupational and Environmental Medicine 1995;52:13-19
Provocative chelation with DMSA and EDTA:evidence for differential access to lead storagesitesByung-Kook Lee, Brian S Schwartz, Walter Stewart, Kyu-Dong Ahn
Institute of IndustrialMedicine,SoonchunhyangUniversity, Chunan,Republic of KoreaB-K LeeK-D AhnDepartment ofEnvironmental HealthSciences, Division ofOccupational HealthB-K LeeB S SchwartzW StewartDepartment ofEpidemiology, JohnsHopkins School ofHygiene and PublicHealthB S SchwartzW StewartDepartment ofMedicine, JohnsHopkins School ofMedicine, Baltimore,MD, USAB S Schwartz
Correspondence to:Dr Byung-Kook Lee,Institute of IndustrialMedicine, SoonchunhyangUniversity, 23-20Bongmyung-Dong, Chunan,Choongnam 330-100,Republic of Korea.Accepted I September 1994
AbstractObjectives-To validate a provocativechelation test with 2,3-dimercaptosuc-cinic acid (DMSA) by direct comparisonwith the standard ethylene diaminetetraacetic acid (EDTA) test in the samesubjects; and to compare and contrastthe predictors of lead excretion afterDMSA with those after EDTA. A metalchelating agent given orally, DMSA maymobilise and enhance the excretion oflead from the storage sites in the bodythat are most directly relevant to thehealth effects of lead. A provocativechelation test with DMSA could thushave wide potential application in clinicalcare and epidemiological studies.Methods-34 male lead workers in theRepublic of Korea were given a singleoral dose of 10 mglkg DMSA, urine wascollected over the next eight to 24 hours,and urine volume and urinary lead con-centration determined at 0, 2, 4, 6, 8, and24 hours. Either two weeks before or twoweeks after the dose of DMSA 17 of theseworkers also received 1 g intravenousEDTA followed by an eight hour urinecollection with fractionation at 0, 2, 4, 6,and 8 hours.Results-Urinary lead concentrationpeaked at two hours after DMSA and fourhours after EDTA. Lead excretion afterDMSA was less than after EDTA, andcumulative excretion after DMSAplateaued at six to eight hours. The twohour and four hour cumulative leadexcretions after DMSA were highly cor-related with the eight hour total (r = 0-76and 0.95). In multiple linear regressionanalyses, blood lead was found to be animportant predictor of EDTA-chelatablelead, whereas urinary aminolevulinicacid (ALAU) was associated with DMSA-chelatable lead. Notably, lead excretionafter DMSA was greatly increased ifEDTA was given first. An earlier dose ofEDTA also modified the relation betweenALAU and DMSA-chelatable lead in thatworkers who received EDTA beforeDMSA showed a much steeper dose-response relation between these twomeasures.Conclusions-The predictors of leadexcretion after DMSA and EDTA are dif-ferent and an earlier dose of EDTA mayincrease lead excretion after a subse-quent dose of DMSA. The results suggestthat two hour or four hour cumulative
lead excretion after DMSA may providean estimate of lead in storage sites thatare most directly relevant to the healtheffects of lead.
(Occup Environ Med 1995;52:13-19)
Keywords: chelating agents; dimercaptosuccinic acid;lead
Human exposure to lead is ubiquitous and itsabsorption can be assessed by different mea-sures thought to reflect several definable leadstorage compartments.'-3 Blood lead and zincprotoporphyrin (ZPP) are the two most com-mon measures used to identify people at riskof excess exposure or ill health caused by lead.A limitation of both of these measures is thatthey are poor predictors of such ill health, donot necessarily reflect recent exposure, andare generally thought to be inadequate mea-sures of cumulative lead absorption.4 Bloodlead concentrations are influenced by recentexposure, bioavailable internal stores, and dif-ferences between individuals in lead toxico-kinetics.5 The interpretation of ZPP, an earlybiological intermediary in the haematopoieticsystem, is complicated by differences betweenpeople in the kinetics of lead, the kinetics ofthe multiple steps in the haem synthetic path-way, and the kinetics of red blood cells.5
The limitations of blood lead and ZPP haveled to the development of other biologicalmeasures of lead absorption. As 90-95% ofthe total body burden of lead resides in bone,'in at least two definable compartments-a rel-atively inert cortical bone storage pool and amore bioavailable pool in trabecular bone-xray fluorescence has emerged as a techniquefor measurement of bone lead.7-'0 Althoughx ray fluorescence of cortical bone leadprobably best estimates cumulative leadabsorption, few studies have validated this asa predictor of health effects. It can be hypoth-esised that because much of the bone leadcompartment is biologically inert, with leaddeep in cortical bone, x ray fluorescent mea-surements of cortical bone lead may be lessrelevant to long term changes in health thanbiological measures that estimate the bioavail-able lead pool. Such measures may includex ray fluorescence of trabecular bone lead andchelatable lead.
Provocative chelation with 1 g of intra-venous calcium disodium ethylene diaminetetraacetic acid (EDTA) followed by a six to24 hour urine collection for measurement of
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Environmental Health Perspectives • VOLUME 109 | NUMBER 2 | February 2001 167
Diagnostic Chelation Challenge with DMSA: A Biomarker of Long-TermMercury Exposure?Howard Frumkin,1 Claudine C. Manning,2 Phillip L. Williams,3 Amanda Sanders,1 B. Brooks Taylor,4Marsha Pierce,4 Lisa Elon,2 and Vicki S. Hertzberg2
1Department of Environmental and Occupational Health, 2Department of Biostatistics, Rollins School of Public Health, Emory University,Atlanta, Georgia, USA ; 3Department of Environmental Health Science, University of Georgia, Athens, Georgia, USA ; 4Coastal HealthDistrict, Georgia Division of Public Health, Brunsw ick, Georgia, USA
Assessment of biological exposure is a keychallenge in evaluating metal toxicity, forboth clinicians and epidemiologists. Bloodand urine measurements traditionally havebeen used, but these have several shortcom-ings, such as failure to reflect true body bur-den, failure to correlate with biologicaleffects, high interperson variability followingsimilar exposures, and relatively rapid clear-ance (1). X-ray fluorescence is being usedincreasingly to assess exposure to lead but notto other metals (2–5).
Because chelating agents bind metalsand promote their urinary excretion, theo-retically they can be used in challenge teststo assess metal levels. The rationale fordiagnostic chelation challenge is straightfor-ward: If a person has an elevated body bur-den of a metal, then administration of achelating agent should cause a short-termincrease in the urinary excretion of thatmetal. The most commonly used chelationchallenge test has been EDTA administra-t ion following lead exposure (6,7),although British Anti-Lewisite and penicil-lam ine have also been used (8). Morerecently, attention has focused on dimer-captosuccinic acid (DMSA), or succimer, achelating agent approved by the U.S. Foodand Drug Administration (U.S. FDA) in1991 for the treatment of pediatric leadtoxicity.
DMSA is used primarily in the treatmentof metal toxicity, rather than in diagnosis.The most common therapeutic use has beenin treating lead toxicity (9–11), but DMSAhas also been used to treat a variety of othermetal overexposures (12–14). Besides itstreatment role, DMSA offers considerablediagnostic potential as a chelation challengeagent. First, it is convenient: DMSA is anoral agent, whereas EDTA must be adminis-tered parenterally. Second, DMSA has anexcellent safety profile. Third, DMSA hasbeen shown to mobilize a range of metalseffectively in both animals and humans.Fourth, DMSA acts quickly. The blood con-centration of DMSA peaks in 3 hr, and thehalf-life is 3.2 hr (15). DMSA-induced excre-tion of both lead (16) and mercury (17)peaks within 2 hr. In the clinical setting,chelation challenge would therefore requireurinary collection only over several hours.For these reasons, DMSA chelation challengecould be a convenient, safe approach toassessing the biological burden of variousmetals. Indeed, DMSA chelation challengehas been used in several studies (16,18,19)and in clinical settings to assess lead burden.
Another metal that might be assessed inthis way is mercury. DMSA mobilizes mer-cury effectively in both animals (20–25) andin humans (8,17,26–31). However, unlikelead, mercury undergoes relatively little
bioaccumulation. It is excreted with a half-lifeof 1–2 months (17,32–35). This suggests thatthe primary use of DMSA chelation challengefor mercury would occur in the first weeksafter exposure. However, a long terminalelimination phase has been described (36),with mercury retention in nervous system,kidneys, and other soft tissues. Consequently,there could also be a role for DMSA chelationchallenge some time after mercury exposure,especially if exposure had been prolonged andintense. Support for this notion comes fromanimal evidence (37) that DMSA draws mer-cury with special avidity from the kidneys—an important mercury storage site known tohave a relatively slow turnover (38). Indeed,DMSA chelation challenge has been usedclinically on a limited basis following mercuryexposure (15,26,39). A related agent used inEurope, 2,3-dimercaptopropane-1-sulfonicacid (DMPS), has been used in a similarmanner (40,41).
At present the interpretation of DMSAchallenge tests for mercury is difficultbecause we lack reliable data on the normalrange of mercury excretion in unexposedpeople following DMSA, the expected rangeof elevations following mercury exposure,the correlation between DMSA response andother measures of mercury exposure, and theclinical significance of elevations. Such datawould be necessary to validate the DMSAchelation challenge response as a practical,informative biomarker of mercury exposure.
In this paper we report a study of DMSAchelation challenge testing among workerswith long-term, high-level exposure to mer-cury in a chloralkali plant and among a com-parison population of unexposed workers.
MethodsStudy subjects. This study was conducted aspart of a larger study of the health effects of
Address correspondence to H. Frumkin, Departmentof Environmental and Occupational Health, RollinsSchool of Public Health, Emory University, 1518Clifton Road, Atlanta, GA 30322 USA. Telephone:(404) 727-3697. Fax (404) 727-8744. E-mail:[email protected] study was funded by grant 1 RO1 ES08346
from the National Institute of EnvironmentalHealth Sciences.
Received 7 July 2000; accepted 28 September2000.
Art ic les
Chelation challenge testing has been used to assess the body burden of various metals. The best-known example is EDTA challenge in lead-exposed individuals. This study assessed diagnosticchelation challenge with dimercaptosuccinic acid (DMSA) as a measure of mercury body burdenamong mercury-exposed workers. Former employees at a chloralkali plant, for whom detailedexposure histories were available (n = 119), and unexposed controls (n = 101) completed 24-hrurine collections before and after the administration of two doses of DMSA, 10 mg/kg. The uri-nary response to DMSA was measured as both the absolute change and the relative change inmercury excretion. The average 24-hr mercury excretion was 4.3 µg/24 hr before chelation, and7.8 µg/24 hr after chelation. There was no association between past occupational mercury expo-sure and the urinary excretion of mercury either before or after DMSA administration. There wasalso no association between urinary mercury excretion and the number of dental amalgam sur-faces, in contrast to recent published results. We believe the most likely reason that DMSA chela-tion challenge failed to reflect past mercury exposure was the elapsed time (several years) since theexposure had ended. These results provide normative values for urinary mercury excretion bothbefore and after DMSA challenge, and suggest that DMSA chelation challenge is not useful as abiomarker of past mercury exposure. Key words: biomarkers, chelation, chloralkali, DMSA, envi-ronmental diseases, mercury, neurotoxicity, occupational diseases, renal toxicity, succimer.Environ Health Perspect 109:167–171 (2001). [Online 25 January 2001]http://ehpnet1.niehs.nih.gov/docs/2001/109p167-171frumkin/abstract.html
Scand J Work Environ Health 1992;18:113-9
Chelated lead and bone lead
by Inge Tell, MD,1 Lillian J Somervaille, PhD,3 Ulf Nilsson, BSC,2 Inger Bensryd, RN,1Andrejs Schutz, PhD,1 David R Chettle, PhD,3 Malcolm C Scott, PhD,3Staffan Skerfving, MD1
TELL I, SOMERVAILLE LJ , NILSSON U, BENSRYD I, SCHUTZ A, CHETTLE DR, SCOTT MC,SKERFVING S. Chelated lead and bone lead. Scand J Work Environ Health 1992;18:113-9. In thisstudy a close correlation [correlation coefficient (r) = 0.86, P < 0.001) was found between the blood leadlevel of 20 lead workers and their urinary excretion of lead for 24 h after intravenous infusion withI g of the chelating agent calcium disodium edetate, In addition , there were significant associations be-tween lead levels in different bones (tibia /calcaneus: r=0.93, P<O.OOI; tibia /phalanx: r =0.67,P < 0.002; calcaneu s/phalanx: r = 0.80, P < 0.001), as measured by in vivo X-ra y fluorescence. Chelationproduced no significant chang e in the lead level in either tibia or calcaneus. There was a significant corre-lation between chelated lead and bone lead (eg, for calcaneu s, r=0.62) in currently exposed workers .However, there was no significant relation ship when a retired worker and an inactive worker were in-cluded (r = 0.14). It was concluded that chelatable lead mainly reflects the blood and soft-tissue lead pool,which is only partly dependent upon the skeletal lead content that comprises the biggest sha re of the totalbody burden.
Key terms: blood, calcaneus, calcium disodium edetate, finger bone, occupation al, pha lanx, skeleton,tibia, urine, X-ray fluor escence.
Lead is an ubiquitous metal that is still widely usedindustrially. Once inside the body , it can be incorpo-rated into the skeleton, where the turnover is slow com-pared with that in the blood and soft tissues. One meth-od of assessing lead exposure is to use chelation tech-niques. Thus a chelating agent such as penicillamine(PCA) can be administe red orally (1), or the in-travenous administration of calcium disodium edetate(CaNazEDTA) can be used (2). Increased levels of ex-creted urinary lead are then used as an indicator ofan excess body burden (3). In addition, chelation hasbeen used therapeutically in cases of lead poisoning,especially among children (4), for whom it is assumedthat chelation causes an overall reduction of the leadbody burden. However, the relative input s from thebody compartments, such as soft tissue and bone, tothe measured chelated lead output in urine have notbeen established .
Because over 900/0 of the body burden of lead is inthe skeleton (5), a more direct measure of this burdenin vivo is the assessment of skeletal content frommeasurement s of the lead levels of various bone sites,either by biopsy or by the noninvasive technique of
I Department of Occupational and Environmental Medicine,University Hospital, Lund, Sweden.
2 Department of Radiation Physics, Lund University, MalmoGeneral Hospital, Malmo , Sweden.
3 Department of Physics, University of Birmingham, Bir-mingham , United Kingdom .
Reprint request s to: Dr I Tell, Department of Occupationaland Environmental Medicine , University Hosp ital, 5-221 85Lund, Sweden.
X-ray fluorescence. Lead levels in the mainly corticalphalanx were first measured in occupationally ex-posed workers with the use of the gamma-ray source57cobalt to fluoresce the K-shell X rays of lead (61-An alternative method, developed more recently, is touse the gamma rays of l09cadmium to fluoresce theK-shelliead X rays, the initial measurement being onthe cortical midshaft of the tibia (7). Since the lattertechnique is self-normalizing to bone mineral and isindependent of geometry and overlying tissue depth,it is applicable to any superficial bone site and has beenextended to the measurement of lead levels in thetrabecular calcaneus, or heel bone (8), and in the skullfrontal bone. In addition, tibia lead levels have alsobeen measured by fluorescence of the lower energyL-shell X rays (9), which, because of the short attenu-ation length of L-shell X rays, samples the lead in theouter few millimeters of the bone only.
Lead levels in cortical bone , as measured by X-rayfluorescence, have been shown to be a good index ofcumulative past exposure, both in finger bone (10)and in tibia (11). However, the relationship betweenchelatable lead and bone lead levels remains unclear .In recent reports, associations were found betweenCaNazEDTA-chelated lead and tibia lead levelspredicted by L-shell (12)and K-shell (13)X-ray fluores-cence. However, in a similar study, PCA-chelatablelead was not related to the lead levels predicted byK-shell X-ray fluorescence for finger bone, while therewas an association with biopsy specimensfrom the ver-tebra (14). Moreover, there were associations betweenCaNazEDTA-chelated lead and biopsies from theileum (15).
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British Journal of Industrial Medicine 1986; 43:636-641
Mobilisation of heavy metals into the urine byCaEDTA: relation to erythrocyte and plasmaconcentrations and exposure indicatorsS ARAKI, H AONO, K MURATAFrom the Department of Public Health and Hygiene, Medical College of Oita, Hazama-machi, Oita 879-56,Japan
ABSTRACT To investigate the effects of calcium disodium ethylenediamine tetra-acetate (CaEDTA)on the urinary excretion, erythrocyte, and plasma concentrations and exposure indicators of sevenheavy metals, CaEDTA was administered by intravenous infusion to 20 workers exposed to lead,zinc, and copper. The workers' blood lead concentrations ranged from 22 to 59 ig/dl (mean 38 4g/dl(1 8 yumol/l)). The 24 hour urinary excretion of metals after CaEDTA administration (mobilisationyield) was on average 13 times the background excretion for lead, 11 times for zinc, 3-8 times formanganese, 3*4 times for cadmium, 1 3 times for copper, and I 1 times for chromium; no significantincrease was found for mercury. The mobilisation yield of lead (MPb) was significantly correlatedwith whole blood and erythrocyte concentrations and the urinary excretion of lead but not with itsplasma concentration; similarly, the mobilisation yield of cadmium was significantly correlated withits erythrocyte concentration. In addition, MPb was significantly correlated with intra-erythrocyticenzyme 5-aminolaevulinic acid dehydratase activity and urinary coproporphyrin excretion. Therelation between the mobilisation yield of heavy metals and their body burden (and toxic signs) isdiscussed in the light of these findings.
It has recently been shown that plasma lead (PPb)concentration and urinary lead excretion areincreased after the intravenous infusion of calciumdisodium ethylenediamine tetra-acetate (CaEDTA)without a significant alteration in the lead concen-tration in either erythrocytes (EPb) or whole blood(BPb).' This finding suggests that urinary lead ismobilised for the most part from organs other thanperipheral blood. The I)Pb concentration, on theother hand, is associated closely with the mobilisationyield of lead in urine by CaEDTA (MPb) in workersexposed to lead,2 5 indicating that BPb directlyreflects the body burden of chelatable lead. As morethan 90% of BPb exists in the erythrocytes, the EPbmay also provide a better reflection of the lead bodyburden (as estimated by MPb)6 than the PPb.
The behaviour of zinc in plasma and erythrocytes(PZn and EZn) after CaEDTA infusion was entirely
Accepted 16 January 1986
different from that of lead; the PZn concentration fellrapidly, followed by a gradual rise in the EZn concen-tration during the first five hours after the infusionhad begun.' 7 This observation suggests that chelat-able zinc is mobilised mainly from the plasma into theurine shortly after CaEDTA infusion. The depletedPZn, however, was mostly compensated for by aredistribution of zinc from other organs during a 24hour period.' It must be pointed out that the bodyburden of chelatable zinc is extremely large and only0-1% of the body burden is excreted in the urine byCaEDTA per day.8 Our previous study has alsoshown that copper is mobilised into urine without achange in its concentration in either plasma (PCu) orerythrocytes (ECu) after CaEDTA infusion.7
In the present study we administered CaEDTAintravenously to workers exposed to lead, zinc, andcopper; measured the mobilisation yields of thesemetals as well as four other toxic and essential heavymetals; and estimated their relation to erythrocyteand plasma concentrations and exposure indicators.
636
Environmental Health PerspectivesVol. 91, pp. 57-62, 1991
Sequential Measurements of Bone LeadContent by L X-Ray Fluorescence inCaNa2EDTA-Treated Lead-Toxic Childrenby John F. Rosen,* Morri E. Markowitz,* Polly E.Bijur,* Sarah T. Jenks,* Lucian Wielopolski,tJohn A. Kalef-Ezra,t and Daniel N. Slatkin§
With the development of L X-ray fluorescence (LXRF) to measure cortical bone lead directly, safely,rapidly, and noninvasively, the present study was undertaken to a) evaluate LXRF as a possible re-placement for the CaNa2EDTA test; b) quantify lead in tibial cortical bones of mildly to moderatelylead-toxic children before treatment; and c) quantify lead in tibial cortical bones of lead-toxic chil-dren sequentially following one to two courses of chelation therapy. The clinical research design wasbased upon a longitudinal assessment of 59 untreated lead-toxic children. At enrollment, if the bloodlead (PbB) was 25 to 55 jg/dL and the erythrocyte protoporphyrin (EP) concentration was 2 35 glg/dL,LXRF measurement of tibial bone lead was carried out. One day later, each child underwent aCaNa2EDTA provocative test. If this test was positive, lead-toxic children were admitted to thehospital for 5 days of CaNa2EDTA therapy. These tests were repeated 6 weeks and 6 months afterenrollment. Abatement of lead paint hazards was achieved in most apartments by the time of initialhospital discharge.
The LXRF instrument consists of a low energy X-ray generator with a silver anode, a lithium-dopedsilicon detector, a polarizer of incident photons, and a multichannel X-ray analyzer. Partially polar-ized photons are directed at the subcutaneous, medial mid-tibial cortical bone. The LXRF spectrum,measured 900 from the incident beam, reveals a peak in the 10.5 KeV region, which represents thelead La line. The effective dose equivalent using tissue weighting factors according to guidelines ofthe National Council on Radiation Protection and Measurements (1989), was 2.5 FSv. The reproduci-bility of replicate LXRF measurements, including the day-to-day variation of the instrument, in 26lead-toxic children, after repositioning the instrument within 5 cm of the first LXRF measurements,was ± 9.2 (9 5% confidence limits). For an overlying tibial skin thickness of 5 mm, the minimum detec-tion limit was 7 Ag of lead/g (wet weight) at the 95% confidence interval.
Based upon a discriminant analysis, 90% of lead-toxic children were predicted correctly as beingCaNa2EDTA-positive or CaNa2EDTA-negative. Using LXRF and PbB values to predict CaNa2EDTAoutcomes, the specificity and sensitivity of these two predictors were 86 and 93%, respectively. Ina significant fraction of CaNa2EDTA-positive and CaNa2EDTA-negative children, cortical bone leadvalues were similar to lead concentrations measured via bone biopsy in normal adults and leadworkers in industry. By 24 weeks after enrollment, PbB, EP, and urinary lead/EDTA ratios were simi-lar in all groups. The most dramatic decreases in net corrected photon counts by LXRF occurred inchildren treated twice. Mean values of cortical bone lead by LXRF at 24 weeks in all three groups ofchildren were similar to the mean concentration in untreated CaNa2EDTA-negative children at en-rollment but still three to five times greater than those measured in the tibia or whole teeth ofnormal European children using atomic absorption. In lead-toxic children who did not qualify fortreatment, additional significant accumulation of lead in bone ended once children were removedfrom leaded environments or returned to lead-abated apartments. These data suggest that LXRFmeasurements of lead in tibial cortical bone have considerable promise to replace the CaNa2EDTAtest and to provide a more appropriate end point of chelation therapy than the conventional indicesof PbB and EP. Moreover, markedly elevated bone lead values accumulated during early childhoodmay have an intergenerational impact, as maternal lead stores amassed during childhood cross theplacenta and directly affect the developing fetus.
*Divisions of Pediatric Metabolism and Epidemiology, Albert Ein- School, Ioannina, Greece.stein College of Medicine, Montefiore Medical Center, Bronx, NY §Medical Department, Brookhaven National Laboratory, Upton,10467. NY 11973.
tDepartment of Radiation Oncology, State University of New Address reprint requests to J. F. Rosen, Department of Pediatrics,York, Stony Brook, NY 11794. Albert Einstein College of Medicine, Montefiore Medical Center, 111
tLaboratory of Medical Physics, University of Ioannina Medical East 210th Street, Bronx, NY 10467.
Sunday, 6 May, 12
Lab Test for Metal Toxicology
Metal Poisoning / Acute Toxicity"
• Blood metal concentration
• Urine Porphyrins
Exposure (very recent or ongoing)
• Blood and unprovoked urine
• Hair (longer temporal window)
Net Retention (estimation)
• Pre- vs Post-Provocation
Metal –Induced Allergy / Autoimmunity
• MELISA® Test
Sunday, 6 May, 12
Methods of Evaluating Metal Burden
• 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 levels of tissue deposition
• Hair - excellent for methyl mercury and lead
• Fecal – good method for children
Sunday, 6 May, 12
Non-provoked/Pre-Flush Urine Toxic Metal
Identify current exposures to lead and mercury (whole blood is a better indicator)
Currently the only means of identifying cadmium toxicity. (0.5-‐2.0 μg/g creatinine indicated early renal damage in Swedish cohort, 2.5
μg/creatinine 4-‐fold higher risk of tubular damage )
24-‐hr non-‐provoked urinary test for arsenic toxicity (50μg/24 hours)
Allows the clinician to identify what chelating agent is the most effective for the patient, if oral agents were employed, then possible absorption issues can be identified.
Sunday, 6 May, 12
• Dosage and Administration: (For assessing and treating a toxic heavy metal burden)
• Ensure adequate hydration, normal kidney function, assessment of CBC, and bowel movements are regular (at least daily)
• Serum and provoked heavy metal test prior to starting regimen
• Check serum metals and/or RBC minerals and/or unprovoked urine (first morning void or random spot urine)
DMSA
Sunday, 6 May, 12
• Rule out potential DMSA sensitivity i.e. reactive to ALL sulfur-‐containing compounds
• No shellfish or seaweed for the week prior to testing
• No non-‐essential meds or supplements for 48 hours
• Empty Bladder* and Empty Stomach -‐-‐> Use first morning urine for pre-‐flush test
• Body weight DMSA (30 mg/kg up to 2250mg)
• Collect all urine for 6 hoursFood can be consumed after 1 hour.
• Consider:
• Pre-‐treatment to alkalize urine and adequate nutritional status
• Glycine (oral: 2000 mg the night before challenge test or 40 mg/kg)
DMSA Challenge Protocol
Sunday, 6 May, 12
Test Interpretation
Sunday, 6 May, 12
No test can show the total body burden of Heavy Metals
Provocation tests are measurements of how much is leaving not what is in the
body!!!
Sunday, 6 May, 12
Interpretation of Provoked UTM Results• Rarely a stand alone test.
• Don’t interpret provocation results against unprovoked reference values. (ACMT)! Compare to the patient’s unprovoked results
• Do consider results in context with amounts of all metals excreted, physical exam, history of known exposures and symptoms and, other biomarkers.
• Cannot conclude “metal toxicity” based solely upon higher than average net retention
Sunday, 6 May, 12
Test Interpretation
• Were any of them above lab ranges?
• How many different heavy metals showed up on the first pass? > 7 – “collectors”
• Did the patient experience any change in their metal related symptoms?Subsequent tests typically show increased levels.
Sunday, 6 May, 12
DMSA vs. DMPS Pb and Hg
METALREF
RANGEPRE
POST DMSA
POST DMPS
AS
CD
PB
HG
<57 12 17 54
<0.9 0.3 0.4 0.5
<6 13 4.3
<7.2 1 6.4 11
Sunday, 6 May, 12
The Case for Pre & Post Testing
• Helps Identify Current Exposure
• Helps determine the effectiveness of the proposed chelating agent
• Assesses the level of absorption of the chelating agent which, in turn, may help identify sub-acute malabsorption
Sunday, 6 May, 12
Recognizing Current Exposure
CDC National reports provide us with ‘normal’ ranges for US residents for the first time.
Levels above 75th percentile would typically indicate current exposure.National Report on Human Exposure to Environmental Chemicals, Fourth Report
http://www.cdc.gov/exposurereport/
Sunday, 6 May, 12
National Report on Human Exposure to Environmental Chemicals, Fourth Report
Compound Geometric Mean 50th percentile 75yh percentile 90th percentile 95th percentile
Antimony
Arsenic (total)
Barium
Cadmium
Cobalt
Lead
Mercury
Thallium
Uranium
NA 0.80 0.135 0.208 0.277
8.24 7.04 14.1 30.4 50.4
1.48 1.41 2.68 4.92 7.10
0.210 0.208 0.412 0.678 0.940
0.314 0.290 0.255 0.455 1.02
0.632 0.622 0.979 1.65 2.35
0.443 0.447 0.909 1.65 2.35
0.154 0.153 0.214 0.286 0.350
0.008 0.007 0.012 0.021 0.029
Sunday, 6 May, 12
Assessing Absorption with Pre and Post
Provocation Testing
Sunday, 6 May, 12
29 f with amalgams and hx of gluten sensitivity
METALREF
RANGECDC
90/95%Pre DMSA Post DMSA
Post DSMA 6 months
GF
PB
HG
<4.4 1.5/2 <dl 6.6 14
<7.2 1.65/ 2.35
0.8 4.5 86
+ anti-gliadin IgA of 26
Sunday, 6 May, 12
Testing Cases
Sunday, 6 May, 12
SJSK
• 55 yo wm
• Amyotrophic lateral sclerosis
• Hx. of making lead fishing weights
• DMSA flush UA done
• 30 mg/kg in one dose
• Empty bladder and stomach
Sunday, 6 May, 12
Sunday, 6 May, 12
Protocol
• DMSA – 30mg/kg in three divided daily doses of 10 mg/kg each.
• 5 days on and 9 days off
• Basic Detox Nutrients
• Vitamin C, Fiber, Whey
• Heavy metal support of the 9 days off
• Colonic irrigations weekly
Sunday, 6 May, 12
Sunday, 6 May, 12
Sunday, 6 May, 12
Protocol Change
• Day one: 2,000 mg CaNa2EDTA
• Day two – six: 30mg/kg DMSA
• 8 days off
• Continue colonics and other supplements
Sunday, 6 May, 12
Sunday, 6 May, 12
Metal(ppm)
1GB 4P 2ST 3LT 5TIP
AL 471 1027 3731 60.3 96.1
AS 7.28 .829 99.9 1.53 <dl
CD .487 .442 5.94 0.079 0.076
PB 8.71 7.54 56,185 10.49 1.12
HG 21.9 4.66 6,333 6.81 0.574
Ni 2.79 5.45 11.8 0.269 1.68
Th 0.01 0.017 0.017 <dl <dl
SN 609 0.935 256.4 0.624 0.035
Sunday, 6 May, 12
• 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 spill of Cd, Pb and will mobilized Al. It will give a very poor spill of Hg
• If GH is low you may get a deceptively low reading of Hg
• pre-treatment with NAC & MSM
What to Expect
Sunday, 6 May, 12
Consider:
• Affinity of an agent for the metal in question – e.g. lab result showed ‘normal’ Arsenic but agent administered was EDTA
• ‘spill’ of As might have been higher if DMPS had been used
• Dose of the challenge agent administered – e.g. lab result showed ‘normal’ Mercury but only administered DMPS 5 mg/kg p.o.
• ‘spill’ of Hg might have been higher if 10 mg/kg p.o. had been used
• Length of collection period – e.g. lab result showed ‘normal’ Lead but only collected urine for 2 hours post oral DMSA administration
• ‘spill’ of Pb would have been higher if collection period had been 6 hours as recommended
When Results Go Astray...
Sunday, 6 May, 12
NB – Wide individual variation in tolerance to toxic metals
• Total toxic burden and TILT
• Genetics
• Nutritional status
• Gut function
Significance of Results
Sunday, 6 May, 12
Take Home Message for Testing
• Provocation testing is valid when done correctly and can serve as a component of diagnostic judgement."
• Assess status of liver & glomerular filtration.
• Always do pre- and post provocation urinalysis initially.
• Monitor efficacy of metal clearance: Repeat provocations identically after 5-10 treatments!
Sunday, 6 May, 12
Treatment
Sunday, 6 May, 12
• Treatment
• Start treatment at no greater than 10 mg/kg every 8 hours for five days (for sensitive patients).*
• There are many different dosing regimens:
• 5-‐10 mg/kg every 12 hours for 2 weeks on, then 2 weeks off
• 10 mg/kg every 8 hours for 3 days, then 11 days off
• 100 mg every night M-‐F, skip weekends
• 500 mg 3x/day
• 30 mg/kg divided into three doses/day for 5 days on, then 9 days off
• 10 mg/kg divided into two or three doses/day for 3 days, then 11 days off (extremely sensitive patients do better with a lower dose and with more days off)
• Suppository
• Provide mineral replacement during treatment
*J.Morrison (ACAM)
DMSA
Sunday, 6 May, 12
• Treatment
•Recheck CBC and kidney function and urine toxic metals periodically
• If the patient is on a 30 mg/kg treatment protocol with 5 days on and 9 days off Recheck CBC and kidney function at 5th round and urine toxic metals at the 10th round
•Assess patient’s symptoms during course of treatment.
•Symptom Survey
DMSA
Sunday, 6 May, 12
• Treatment
• Journal of Advancement in Medicine (Vol 10—Number1—Spring 1997)
• 7 days of DMSA at dosages of 10 mg/kg every 8 hours followed by 14 days @ 10 mg/kg in 2 divided doses. No treatment administered for next 21 days. Repeat. (Theodore C. Rozema, MD, FAAFP)
• Chemistry profile after 10 days to check liver function and hemoglobin levels (DMSA can decrease hgb and increase liver enzymes)
• If a skin rash occurs -‐ stop until gone, then lower dose.
• For a patient having mercury amalgam removal: (Godrey and Campbell)
• Oral sodium ascorbate to bowel tolerance (4-‐12 g in divided doses), seleno-‐methionine (200 mcg/day), and specifically prepared multi-‐mineral tablets depending upon results of element analysis
• 500 mg DMSA once a week for 3 months if the pt had high initial Hg levels after DMPS urine Hg challenge. Challenge can be repeated 6 months or a yr laterto check on residual body levels of Hg.
• IV sodium ascorbate to 0.7 g/kg bw (25g/250 ml or 50 g/500 ml sterile water)
DMSA
Sunday, 6 May, 12
• W. Crinnion’s Protocol:
• DMSA—30 mg/kg in 3 divided daily doses of 10 mg/kg each 5 days on & 9 days off or 2 days on & 5 days off for sensitive patients
• If gas/bloating occurs: peppermint tablets or tea
• Adverse reactions: Stop the DMSA. 3 capsules of activated charcoal or colon hydrotherapy
• Retest UTM in 10 weeks/rounds and re-‐check CBC, liver, and kidney function
• Supplementation:
• Basic Detox Nutrients
• Vitamin C, Magnesium citrate, Fiber, Whey, Methionine (if pt has elevated cadmium)
• Heavy Metal Support on the 9 days off
• Constitutional hydrotherapy weekly
• Colonic irrigation weekly (after hydrotherapy yields the best results)
• Magnesium sulfate/nutrient intravenous therapy, if needed
DMSA
Sunday, 6 May, 12
Chelating Agents/Supplements/Procedures Notes
DMSA 100 mg (Dose 30 mg/kg not to exceed 2200 mg) Used for the challenge testing for initial investigation, Rounds 5, 10, 15, 20, 25
DMSA 250 mg (Dose 30 mg/kg not to exceed 2200 mg or 2500 for a very large person) Chelator, oral, usually for 5 days per two week schedule
DMPS IV injection(Dose 5 mg/kg not to exceed 250 mg) Chelator, intravenous once weekly or every other week
Calcium EDTA IV injection(Dose 50 mg/kg not to exceed 3000 mg) Chelator, intravenous once weekly or every other week
Hepatic Support formula LVDX, LIVER GI DETOX Contains Phase 1 and Phase 2 support nutrients. ( NAC, Antioxidants, Cruciferous vegetables etc).
Mineral replacement following chelation – trace metals, magnesium, Taurine. Spectra min, Mercury Amalgam Detox, DMTX
Only used during days off from chelating agent
Fiber formulation containing psyllium Fibre –Plex, Ultra Detox Caps To help bind metals excreted through the bowels, thus preventing their reabsorption
Hydrolysed Whey Protein 17 servings (2 tbsp daily) To raise glutathione levels and aid in moving heavy metals out of the body
Cholagogue and cholerectic herbs (Night prior to a colonic) To support the liver with detoxification. Will promote the production of bile and release if taken the night prior to a colonic.
Vitamin C with Flavinoids 180 caps 6 caps daily Important vitamin for proper adrenal support, an antioxidant. Helps reduce damage of free radicals produced from toxicity. Increases fecal output of mercury
Magnesium Sulphate Injection 2 cc(Usually administered 1 time per round chelation, following the 5 days of DMSA or other chelating agent)
Used when patient not feeling well after several rounds of DMSA. Used to replenish magnesium levels.
Colonic Irrigation (1-5 per week)(Usually following the 5 days of DMSA or other chelating agent)
Promotes release of bile in gallbladder and flush them out of the body, thus helps eliminate metals that were mobilized by chelating agents. Recommendation between 1-5 per week depending on level of toxicity and reaction to chelation therapy. Reduces symptoms of heavy metal cleansing. (Also used effectively for solvent toxicity)
Constitutional Hydrotherapy (0 to 5 per week)
Promotes detoxification. If applied immediately prior to colonic, will increase release of bile from gall bladder. Recommendation between 0 and 2 per week depending on levels of toxicity and reaction to chelation therapy. Increases mobilization of white blood cells.
Sunday, 6 May, 12
Sunday, 6 May, 12
Sunday, 6 May, 12
• Identify sources of heavy metal exposure. Avoid fish/shellfish for about 1 week before challenge test.
• Obtain baseline laboratory values—CBC & ensure adequate kidney function. Consider 24 hr urine creatinine clearance in geriatric patients.
• Conduct a complete physical exam (and heavy metal symptom survey)
• Be flexible with choice of chelating agents
• Ensure good bowel health (at least one bowel movement/day and no GI dybiosis)
• Keep patients expectations for health improvement realistic and conservative
• There is not always an association with a persons symptoms and their heavy metal test.
• Decision to treat requires assessment of risk/benefit potential in view of known adverse side effects, patient’s symptoms, and laboratory assessment
Overview of DMSA & DMPS:Use in Clinical Practice
Sunday, 6 May, 12
Before you wake a tiger…Sunday, 6 May, 12
…Make sure to open the doors and windows before you pinch the tail !
Sunday, 6 May, 12
Metabolism & EHC
Sunday, 6 May, 12
Facilitators ofMetal Mobilization
Sunday, 6 May, 12
• Oral L-Glycine
• Increases the post-provocative release of metals into urine Garrot P. Metabolism and possible health effects of aluminum. Environ Hlth
Perspect 65:363-411, 1986
• Dose – 80 mg/kg body wt BID in divided doses 24 h and 12 h before provocative testing
Sunday, 6 May, 12
Oral L-Glycine:
• Markedly increases urinary spill of toxic metals when used in conjunction with Ca-EDTA, DMSA and/or DMPS
• Facilitates movement of toxic metals from intracellular to extracellular compartment
• Particularly useful with IV Ca-EDTA in the mobilization of retained Al
• May also be useful in mobilizing retained Pb, Hg and Sb when used with DMSA and / or DMPS- Quig DW. Assessment of Toxic Metal Body Burden: Amunition, Hot Topics and Food for Thought. Townsend Letter, Jun 2007
Sunday, 6 May, 12
Glutathione
• The most abundant intracellular thiol- Chouchane S, Snow, ET. In vitro effect of arsenical compounds on glutathione-related enzymes. Chemical Research in Toxicology, 14(5): 517-22, 2001
• Metal exposure depletes Glutathione levels and thus may decrease hepatic detoxification capacity- Sheweita SA. Heavy metal-induced changes in the glutathione levels and glutathione reductase/glutathione s-transferase activities in the liver of male mice. International Journal of Toxicology, 17(4): 383-92, 1998
Sunday, 6 May, 12
Glutathione supplementation:
• Precursors (e.g. oral NAC) may raise glutathione levels- Schaller, Marie-Denise Oxidant-Antioxidant Balance in Granulocytes During ARDS - Effect of N-Acetylcysteine, Chest, 109(1):163-166, Jan 1996
• Oral NAC dose 1200 to 2400 mg/day – typically 500 mg tid
Sunday, 6 May, 12
okanagannaturalmedicine
Dr. Chris Spooner B.Sc. NDOkanagan Natural Medicine
Vernon BC250.275.1672
Sunday, 6 May, 12