Hindawi Publishing Corporation

The Scientific World Journal

Volume 2013, Article ID 219840, 13 pages
http://dx.doi.org/10.1155/2013/219840

Review Article
Chelation: Harnessing and Enhancing Heavy
Metal Detoxification—A Review

Margaret E. Sears
Children’s Hospital of Eastern Ontario Research Institute, 401 Smyth Road, Ottawa, ON, Canada K1H 8L1

Correspondence should be addressed to Margaret E. Sears; megsears@ncf.ca

Received 15 February 2013; Accepted 14 March 2013

Academic Editors: C. Montoliu, J. Pungercar, J.-M. Sabatier, F. Thévenod, and A. Yasutake

Copyright © 2013 Margaret E. Sears. This is an open access article distributed under the Creative Commons Attribution License,
which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Toxic metals such as arsenic, cadmium, lead, and mercury are ubiquitous, have no beneficial role in human homeostasis, and
contribute to noncommunicable chronic diseases. While novel drug targets for chronic disease are eagerly sought, potentially
helpful agents that aid in detoxification of toxic elements, chelators, have largely been restricted to overt acute poisoning. Chelation,
that is multiple coordination bonds between organic molecules and metals, is very common in the body and at the heart of
enzymes with a metal cofactor such as copper or zinc. Peptides glutathione and metallothionein chelate both essential and toxic
elements as they are sequestered, transported, and excreted. Enhancing natural chelation detoxification pathways, as well as use of
pharmaceutical chelators against heavy metals are reviewed. Historical adverse outcomes with chelators, lessons learned in the art
of using them, and successes using chelation to ameliorate renal, cardiovascular, and neurological conditions highlight the need for
renewed attention to simple, safe, inexpensive interventions that offer potential to stem the tide of debilitating, expensive chronic
disease.

1. Introduction are also strongly associated with toxic elements. The Inter-
national Agency for Research on Cancer (IARC) classifies
The living body is full of chelates; metals bound with two or cadmium as a known carcinogen, inorganic lead a probable
more coordination bonds. Metals of oxidation state greater carcinogen, and methylmercury a possible carcinogen [14].
than one (i.e., a charge of +2 or more) are predominantly As research progresses, harms more subtle than acute
bound in tissues by ionic (in skeletal minerals) or coor- poisoning are seen at lower and lower body burdens of heavy
dination bonds (e.g., bound to albumin, enzymes, small metals. For example, early lead exposure is now found to
peptides, and amino acids such as cysteine, methionine, cause IQ decrements at a blood level below 2 𝜇g/dL [15].
and selenomethionine). This was extensively reviewed by The blood lead reference value at which the US Centers
Apostoli et al. [1]. for Disease Control action recommends investigation and
Cadmium [2–5], lead [6–8], and mercury [9–12] have no remediation of a child’s environmental exposures is 5 𝜇g/dL,
essential biochemical roles, but exert diverse, severe toxicities while chelation is recommended at nine times that level above
in multiple organ systems as they bind in tissues, create 45 𝜇g/dL [16].
oxidative stress, affect endocrine function, block aquaporins, Modern mercury and cadmium exposures are frequently
and interfere with functions of essential cations such as via oral routes, prompting advisories regarding fish (e.g.,
magnesium and zinc. Toxic metals pose particular risks to U.S. Environmental Protection Agency [17]), seafood and
the very young, as exposures early in life compromise devel- wildlife consumption (e.g., Canadian Aboriginal Affairs [18]),
opment, with lifelong physical, intellectual, and behavioural as well as cigarette smoke (also noted by Aboriginal Affairs;
impairments. In adults, major chronic diseases [13], including cadmium is but one toxic component). Lead may also
cardiovascular and renal disease, and neurological decline, originate in old drinking water supply pipes.
2 The Scientific World Journal

Toxic metals are ubiquitous in our environment, and chelate moiety during circulation to the kidneys for excretion
thus in ourselves, at higher than historical levels. Exposures in the urine, and to the liver for excretion in the bile. There
[5, 8, 12, 19] include the activities and legacies of mining and are significant concerns related to enterohepatic recirculation
toxic wastes, lead in paint and gasoline, ongoing emissions and reabsorption in the kidney [22].
from industrial and electricity-generating (particularly coal- Another consideration is solubility of the chelate, in
burning) activities, chemicals in everyday products, and water and in lipids. Aqueous solubility facilitates transport
novel technologies such as nanomaterials containing toxic within the blood and excretion via the kidney, while a
elements like cadmium [2]. lipophilic chelator may exhibit greater penetration of cellular
Biological mobility, tissue concentrations, and excretion membranes (including those within the central nervous
of metals are determined by oxidation state, solubility, a system) to chelate intracellular elements. A lipophilic chelator
complex set of equilibria between complexing sites, as well as may also be excreted in greater quantities via the bile.
active transport through membranes [1]. Chelation is central These generalities may be modified by active transport of
to natural detoxification of heavy metals, via formation of intracellular metal complexes via “drug resistance proteins”
complexes, particularly with glutathione and other small [23–26].
molecules, and their excretion [20].
This manuscript stems from a large scoping review
regarding arsenic, cadmium, lead, and mercury, funded by 3. Roles of Chelation in Natural Toxicokinetics
the Canadian Institutes of Health Research. Multiple online
literature searches included a comprehensive list of terms for Metal binding proteins, including metallothioneins, are
the toxic elements and peer-reviewed search strategies, to potent chelators for heavy metals and are central to the
search research publication databases, as well as governmen- natural response of the body to these toxic elements [27, 28].
tal (e.g., Environment Canada, US Environmental Protection Glutathione is another potent chelator involved in cellular
Agency) and nongovernmental (e.g., World Health Organiza- response, transport, and excretion of metal cations and is a
tion) sources, described previously [21]. Expert opinion was biomarker for toxic metal overload [29–31].
solicited via email, during a conference call, and during a Not only animals, but also plants produce chelating
two-day conference in Toronto (February 2011). Clinical tox- compounds [32], and metallothionein content of foods may
icologists at Canadian Poison Control Centres were surveyed affect bioavailability as well as metabolism of toxic metals
to gather information about screening, experiences, and such as cadmium [33].
preferred chelators for each toxic element. Ethics approval Some foods have been suggested to reduce absorption
was obtained from the Children’s Hospital of Eastern Ontario or reabsorption of toxic metals and to support natural
Research Institute, Ottawa, Canada. detoxification pathways.
In this paper, measures to support natural detoxification (i) Dietary fibres from various food products, including
pathways involving chelation, as well as use of pharmaceutical bran from grains as well as fruit, have been evaluated as an
chelators are examined. Historical adverse outcomes, lessons alternative or adjunct to chelation therapy with the aim to
learned in the art of using chelators, and successes using interrupt enterohepatic recirculation [34–36] and to modu-
chelation to ameliorate renal decline, cardiovascular disease, late intestinal flora [37], with findings of reduced levels of
and autism in children are reviewed. mercury in the brain and blood. Caution is merited regarding
soluble fibre; in contrast to protection offered by insoluble
fibre, flax seed resulted in increased intestinal absorption of
2. Chelation Background cadmium [38].
(ii) Other natural polymers have also been gaining atten-
“Chelation,” from “chelos” the Greek word for claw, involves tion as potential adsorbents of heavy metals, such as algal
the incorporation of a mineral ion or cation into a complex polysaccharides alginate [39] and chlorella [40]. Modified
ring structure by an organic molecule, the chelating agent. citrus pectin plus alginate products have been used success-
Typically, electron-donor atoms on the chelating molecule fully to reduce lead and mercury in case studies [39]. Poly(𝛾-
include sulphur, nitrogen, and/or oxygen. glutamic acid), an edible and biodegradable biopolymer,
The strength of the chemical bonds within coordination has been produced extracellularly during fermentation of
complexes that are formed between chelators and metal Bacillus species; its 𝛼-carboxyl groups conjugate a variety of
ions depends upon the elements involved and details of the compounds including metal cations [41].
stereochemistry. With a variety of metal ions that could bind (iii) Given that toxic metals have great affinity for sulphur-
competitively with the chelator (e.g., calcium, magnesium, containing peptides, diets rich in sulphur-containing foods
zinc, copper, manganese, and other metals, that typically such as alliums (e.g. garlic [42]) and brassicas (e.g., broccoli
exceed concentrations of toxic elements), the identity of the [43]) have been suggested for effects on glutathione, with
metal predominately bound by a chelating agent depends hopes for symptomatic improvement and enhanced excre-
both upon accessibility of the chelator to the tissues, how tion. Garlic prevented cadmium-induced kidney damage
strongly the metal is already bound in the tissues, how [44] and decreased the oxidative damage due to lead in rats
strongly the metal binds to the chelator, and to some extent [45].
the relative quantities of various ions [1]. Chelators have the (iv) Cilantro (leaves of Coriandrum sativum), a popular
effect of mobilizing metals from tissues and maintaining the culinary and medicinal herb, gained attention when a soup
The Scientific World Journal 3

was reported to enhance mercury excretion following dental toxicity [2, 33]. This suggests potential for dietary preventive
amalgam removal and remains popular despite limited evi- public health interventions. For example, in animals calcium
dence [46]. In animals, it decreased lead absorption into bone deprivation enhanced absorption of lead and cadmium [69],
and inhibition of the delta-aminolevulinic acid dehydratase while magnesium and zinc supplementation blunted absorp-
(ALAD) enzyme [47]. Less encouragingly, in a recent trial in tion of cadmium [2]. Calcium supplementation reduced lead
3- to 7-year old children exposed to lead, a cilantro extract mobilization from maternal bones during pregnancy and
was as effective as placebo in increasing renal excretion lactation, protecting the newborn and infant [70–72]. In
(improvements across treatment and placebo groups were children, iron supplementation blunted lead accumulation
ascribed to improved diet during the intervention) [48]. [73]; however, mineral supplementation and school meal
Several supplements are also in use to address metal programs should not divert attention from the paramount
toxicities. importance of removal of the sources of exposure [74–76].
(i) Taurine [49–51] and methionine [52] are sulphur-
containing amino acids. They are rich in membranes partic-
ularly of excitable tissues, and they decrease oxidative stress 4. Pharmaceutical Chelators
markers resulting from heavy metal exposure. Practitioners
also report using taurine for 6 weeks or so prior to hair Pharmaceuticals that chelate metal ions in solution are
analyses, to boost levels and improve detection. small organic molecules that typically form coordination
(ii) Alpha lipoic acid is a powerful antioxidant that complexes involving sulphur, oxygen, and/or nitrogen atoms.
regenerates other antioxidants (e.g., vitamins E and C, and Drug information from the US National Library of
reduced glutathione) and has metal-chelating activity. Both Medicine for five chelating agents used most commonly for
fat and water soluble, it is readily absorbed from the gut and the treatment of humans intoxicated with heavy metals and
crosses cellular and blood-brain membrane barriers [22, 53]. metalloids is summarized below, and in Table 1 [56].
Clinical experience is that it must be used carefully as it poses Dimercaprol (British Anti-Lewisite, BAL), the first anti-
particular risks of redistribution of metals. dote to an arsenical nerve gas, is a dithiol prepared in an oil
(iii) N-acetyl-cysteine (NAC), an orally available pre- base and given only by intramuscular injection (painful). It
cursor of cysteine, is a chelator of toxic elements and may has a narrow therapeutic window and is commonly prepared
stimulate glutathione synthesis, particularly in the presence with peanut oil, posing a risk of allergic reaction.
of vitamins C and E [54–56]. BAL has been largely supplanted by dimercaptosuccinic
(iv) Glutathione is not recommended to be administered acid (DMSA or succimer) and dimercaptopropane sulfonate
orally as it undergoes digestion; however novel modes of (DMPS), that were extensively researched in Russia, China,
delivery such as liposomal and prodrug preparations are and Japan, a half century ago [77]. These dithiols, with greater
emerging [57]. It may be administered intravenously, in water solubility, are being administered as oral, intravenous,
creams and via nebulizer. Glutathione is an important physio- suppository, or transdermal preparations. The absorbed dose
logical chelator, and the reduced form of glutathione protects is excreted with a half-life of approximately 3 hours; longer in
cells from reactive oxygen species associated with heavy children and people with mercury toxicity.
metals [58–61]. Oral administration of DMSA may be limited by intesti-
(v) Selenium is an important essential element, that is nal dysbiosis. Oral absorption is approximately 20%, with
present at a broad range of levels across populations. The most DMSA in plasma being protein bound (95%, mainly
selenide ion forms an extremely stable, insoluble compound to albumin); only a very small amount is present as free
with mercury, and provides relief of mercurialism symptoms. drug. DMSA is extensively metabolized in humans to mixed
On the face of it, selenide might not be compatible with disulfides of cysteine. Ten to 25% of an orally administered
chelation, as the two agents may counter the effectiveness of dose of DMSA is excreted in urine; the majority within
one another [62]; however, selenium may be incorporated in 24 hours and most as DMSA-cysteine disulfide conjugates.
organic molecules, and organic selenium/mercury complexes The remainder is largely eliminated in the faeces [77–80].
may be transported through membranes. Selenium depletion DMSA increases urinary excretion of arsenic, cadmium, lead,
in the face of mercury exposures also depletes seleno- methylmercury, and inorganic mercury, with removal from
enzymes. In humans, organic selenium supplementation was animals’ brains of lead and methylmercury. Successful dialy-
beneficial in a controlled trial among 103 mercury-exposed sis of methylmercury-DMSA complexes has been reported.
villagers [63]. A selenium yeast product increased mercury Excretion of essential metals like zinc, iron, calcium, and
excretion and decreased oxidative stress-related biomarkers magnesium is much less than with CaNa2 EDTA, with poten-
urinary malondialdehyde and 8-hydroxy-2-deoxyguanosine tially higher losses of copper in humans. Although frequently
[63]. administered orally, intravenous, rectal, and transdermal
Overall, a number of studies have investigated the effects routes are in clinical use. A rare side effect is mucocutaneous
of micronutrients such as vitamins, sulphur-containing eruptions and toxic epidermal necrosis, that resolves when
amino acids, antioxidants, and essential minerals on kinetics the medication is stopped.
and adverse effects of toxic elements [64–68]. Nutritional DMPS oral absorption is approximately 39%, higher
status affects uptake, as toxic cations are transported by than that of DMSA [81]. Solutions are relatively stable, so
proteins for essential nutrients such as magnesium, zinc, and DMPS is administered intravenously more frequently than
iron, putting those who are malnourished at greater risks for DMSA. DMPS is rapidly converted to a disulphide form
 4

Table 1: Overview of chelation drugs.

Chemical name Coordination
Structure Activation metabolism Elements chelated
(common names, abbreviations) (binding) groups
SH Lead
O
Arsenic
2,3-bis(sulfanyl)butanedioic acid
OH Excretion via urine Mercury
(Dimercaptosuccinic acid; Succimer; Oxygen and
>90% as DMSA—cysteine Cadmium
Dimercaptosuccinic acid; DMSA; Suximer; Tin Salt; HO sulfhydryl
disulfide conjugates. Silver
Succicaptal; Chemet)
O
Tin
SH Copper
Mercury
Arsenic
SH Lead
Sodium 2,3-bis(sulfanyl)propane-1-sulfonate
84% of IV dose excreted Oxygen and Cadmium
(Sodium Dimercaptopropanesulfonate; DMPS;
HS SO3 H through urine sulfhydryl Tin
Unithiol; Dimaval; Unitiol; (+)-DMPS; (−)-DMPS)
Silver
Copper Selenium Zinc
Magnesium
HO
Lead
2-[2-[bis(carboxymethyl)amino]ethyl-
O OH Cadmium
(carboxymethyl)amino]acetic acid
O Not metabolized. Excreted Zinc
(Ethylenediaminetetraacetic acid; Edetic acid; EDTA;
N unchanged, generally (Mercury thought to be
Edathamil; Endrate; Versene acid; Sequestrol; N Oxygen
coordinated with a different too strongly bound in
Titriplex; Havidote; Cheelox; Versene; Calcium
O divalent cation tissues to be mobilized,
Disodium Versenate (edetate calcium disodium
HO O but this is not clinical
injection, USP)
experience)
HO
O
Copper
(2S)-2-amino-3-methyl-3-sulfanylbutanoic acid OH (Wilson’s disease)
Rarely excreted unchanged; Oxygen, hydroxyl,
(3-Sulfanyl-D-valine; Penicillamine; H2 N Arsenic
excreted mainly as sulfhydryl, and
D-Penicillamine; Cuprimine; Depen; Penicillamine; Zinc
SH disulfides amine
Mercaptyl; Artamine; Cuprenil; Perdolat; Trolovol Mercury
Lead
H3 C CH3
HS Arsenic
2,3-bis(sulfanyl)propan-1-ol (Dimercaprol; British Gold
Anti-Lewisite; BAL; 2,3-Dimercaptopropanol; Excreted unchanged in Sulfhydryl and Mercury
Sulfactin; Dicaptol; Dimersol; Antoxol; Panobal; OH urine hydroxyl Lead (BAL in
Dithioglycerine; Dithioglycerol) combination with
HS CaNa2 EDTA)
Information from US National Library of Medicine PubChem: http://pubchem.ncbi.nlm.nih.gov/search/search.cgi.
The Scientific World Journal
The Scientific World Journal 5

and is excreted largely in the urine as acyclic and cyclic Transient increases in hepatic transaminase activity have
disulfide chelates, with an overall half-life of approximately been reported with CaNa2 EDTA, DMSA, and DMPS, but
20 hours following intravenous administration [81]. A sig- hepatic toxicity resolves with discontinuation of the medica-
nificant proportion is also excreted in bile. DMPS increases tion. Skin lesions associated with CaNa2 EDTA may relate to
urinary excretion of arsenic, cadmium, lead, methylmercury, zinc deficiency.
and inorganic mercury. In a study of the DMPS challenge
test there was significantly increased excretion of copper,
selenium, zinc, and magnesium, necessitating replenishment 4.1.2. Chelation Therapy in Children. A single trial published
of these essential minerals orally or intravenously before and in the New England Journal of Medicine (2001) is cited by
after treatment [82]. authorities who recommend that chelation therapy be used
only at highly elevated blood lead levels in children [88].
In comparing the efficacy of the dithiol chelators in
In an early, ambitious trial using DMSA chelation therapy
animals, DMSA was superior in removal of methylmercury,
in 780 children enrolled in the “Cincinnati cohort,” blood
including from animal brains. Although DMPS did not affect
lead levels were temporarily lowered in children receiving
levels in the brain, it was superior at removing methylmer-
the medication compared with the control group; however, at
cury from the kidney [77]. In mice, cadmium was removed
36-month followup blood lead levels in the treated children
more effectively by DMSA than DMPS [83].
had rebounded. At this 3-year mark, there were no significant
CaNa2 EDTA is not metabolized and EDTA chelates differences between treatment and control groups in terms
are rapidly excreted, principally in the urine. With only of blood lead levels nor neurocognitive outcomes [89]. This
oxygen atoms for coordination bonds, EDTA binds lead and trial used a very aggressive protocol, with 26 days of therapy
cadmium strongly, eliminating them in the urine. Clinical for one, two, or three rounds. Currently, chelating agents are
experience is that CaNa2 EDTA will result in increasing typically administered for multiple shorter periods, with time
mercury excretion once other more well bound minerals between courses for the body’s minerals to become repleted.
such as lead and cadmium are depleted. Overall CaNa2 EDTA This aggressive therapy could very well have depleted essen-
causes greater losses of essential minerals than DMSA or tial minerals from this vulnerable population (poor, inner-
DMPS. city, and black/Hispanic children). The vitamin and min-
Penicillamine binds with copper and is used for Wilson’s eral supplementation may have been inadequate and may
disease. It will mobilize arsenic, cadmium, lead, and mercury, have been countered by concomitant administration of the
but it is generally not a drug of choice. It was inferior chelator (doses and adherence to treatment for supplemental
to DMSA and DMPS in removal of methylmercury from minerals were not reported). Shannon et al. have offered
animals, with no effect on levels in the brain [77]. similar criticisms [90].
Canadian clinical toxicologist questionnaire respondents A trial of chelation therapy to treat autism regis-
indicated that their preferences for chelation therapy for tered on the US National Institutes of Health (NIH)
chronic toxicity would be DMPS or DMSA for arsenic; EDTA http://www.clinicaltrials.gov website is indicated as “com-
plus BAL, or as a second line medication penicillamine for pleted,” with the last update October 13, 2009 [91]. When
cadmium; DMSA orally (or possibly EDTA plus BAL for contacted for an update, the NIH representative replied that
acute exposure) for lead; and DMSA or DMPS (or possibly the trial had been cancelled before recruitment, because
BAL for acute exposure) for mercury. some adverse effects were observed in a study of 120 rats
[92]. This study by Stangle et al. clearly demonstrated that
a single three-week course of high dose DMSA treatment
4.1. Roots of Chelation Controversies ameliorated learning, attention, and arousal regulation in rats
exposed to lead during a period from early postpartum to
4.1.1. EDTA Concerns. Three deaths associated with chelation late adolescence. The treatment also reduced lead levels in
therapy have been reported, related to hypocalcemia resulting both the blood and brain. What prompted cancellation of the
in cardiac arrest after use of Na2 EDTA [84]. These were autism trial was detection of a potential adverse drug effect
in fact drug errors and should not reflect on the safety of in the form of adverse cognitive effects among unexposed rats
CaNa2 EDTA, the form generally indicated for chelation of that were treated with DMSA, compared with unexposed,
toxic metals [85]. untreated rats.
CaNa2 EDTA is distributed mainly in the extracellular This pivotal animal study led to cancellation of a large,
fluids and one of its major perceived drawbacks is that of much-publicized trial in children. In assessing the relevance
redistributing lead from other tissues to the brain. In one for the trial cancellation and to clinical practice, several issues
study, treatment with DMSA after exposure to inorganic are pertinent. Adverse effects of drugs are common, which is
mercury caused an elevation of mercury in motor axons, why drugs are not usually given without an indication that
likely due to redistribution of mercury, which was mobilized they are needed. (Pre- and postchelation challenge testing
from nonneural tissues such as the kidneys and liver [86]. to assess excretion of both toxic and essential elements is
Mixed reports indicate that EDTA does not cross the blood- discussed below). In the Stangle et al. study no mineral
brain barrier, but this is in contrast to reports that EDTA may supplementation was provided, and no minerals other than
cause increased symptoms of lead poisoning or mercurialism lead were analysed. DMSA is well known to enhance excre-
[87]. tion of many elements, notably zinc [93]. Zinc deficiency
6 The Scientific World Journal

impairs neurocognitive development in the young [94, 95]. In as disease, trauma, starvation, pregnancy, time of life (e.g.,
addition, Stangle et al.’s rats were treated using an “aggressive” menopause), and extreme emotional impacts. Depending on
protocol, with 50 mg/kg/day DMSA for 21 days; a dose that is a person’s constitution, genetic make-up, diet, lifestyle, and
much higher than the US Food and Drug approved maximum sensitivities, a patient could be suffering from toxic metal
label dose of 30 mg/kg/day [93], that is typically used for effects without having a clear history of exposure. It is a
less than a week at a time in children [96]. It is probable common clinical experience that chronic conditions (e.g.,
that detrimental effects attributed to DMSA resulted from neurological disturbances in a teacher who ate considerable
deficiency of essential elements, an effect that is eminently quantities of tuna [97]) are linked to the causative toxic
avoidable. elements only following a test identifying elevated levels.
In summary, the Stangle et al. study violated important It is difficult to draw conclusions about adverse health
current clinical practices by administering the drug at a high effects of metals without assessing net retention, that is, the
dose, over an extended period of time, when there was no differences between the rates of assimilation and excretion of
indication of need; and failing to assess essential minerals loss metals over the lifetime. In addition, clinicians require infor-
and ensuring that minerals were appropriately supplemented mation to guide therapy. Most commonly, metals are analysed
to avoid health consequences. in urine, whole blood, red blood cells; less commonly hair; or
rarely toenails.
One of the most effective methods to evaluate net reten-
4.2. Chelation in Various Tissues and Redistribution. Chelat-
tion, or at least the biologically readily available metal load,
ing agents are fairly rapidly excreted over a few hours or days.
is to compare the levels of metals in urine before and after
In contrast, toxic elements may have accumulated over long
the administration of a pharmaceutical chelating agent such
periods of time and partitioned into various bodily compart-
as CaNa2 EDTA, DMSA, or DMPS [98]. Variously known
ments, not all being equally accessible to chelating agents.
as “mobilization,” “chelation challenge,” or a “provocation”
Commonly a chelating agent will mobilize the most readily
test, this procedure is not universally accepted as standard of
available metals first, typically in the plasma, kidney, liver and
care. Criticisms have included risks of the chelating drugs,
then to a lesser extent bone and central nervous system. As
and inappropriate comparisons of the provocation results
discussed above, toxic metals in the nervous system are best
with population norms rather than with patient baseline
addressed conservatively, with repeated, modest treatments
concentrations [85]. Indeed, some go so far as to say that any
and the use of multiple agents. With repeated doses the most
testing for metals when the exposure has not been identified;
readily accessed “pools” of toxic elements will be depleted, but
that is, when there is no reason for suspicion based upon
reequilibration slowly replenishes the toxic elements in more
known environmental history that toxins may be elevated,
accessible body compartments. This is evident in the rebound
is inappropriate because of the possibility that false positives
of levels in the blood, following discontinuation of a chelator,
may lead to inappropriate, ineffective therapies and their
which highlights two important facts.
attendant risks [99]. The use of chelation for diagnostic pur-
(i) Blood and urine are poor surrogates to measure the
poses, following dental amalgam removal or in asymptomatic
toxins accrued over the lifetime (body burden). The common
patients with baseline urine or blood levels approximating
laboratory measures of urine, blood, and hair indicate expo-
population norms was deemed inappropriate in 2005 by staff
sures in recent days or months, and to a lesser extent kidney
of the Agency for Toxic Substances and Disease Registry
burden.
[85]. Another criticism of use of a provocation test to
(ii) Toxic elements sequestered in bone and soft tissues
judge net retention is the lack of a standard protocol, and
are not completely immobilized; they migrate back to the
laboratory reference ranges or guidance for interpretation
bloodstream and hence to tissues where they will again exert
of results [100]. Nevertheless, these shortcomings do not
toxic effects. It is important to gain a greater understanding of
fundamentally invalidate the concept; work in this regard has
the quantities of biologically accessible toxic elements within
started. Hansen et al. established such norms for protocol
the body that are not necessarily reflected in baseline blood
involving an oral DMPS test with four hour urine collection,
or urine levels, before chelation provocation.
among 2223 citizens in Luxembourg [101].
(iii) Introduction of a chelating agent into the body
Pre- and postchallenge testing may allow the clinician to
causes shifts of both essential and toxic cations. Increased
identify which chelating agent is the most effective for the
symptoms commonly reported with aggressive initiation of
patient, and if oral agents are employed, possible absorption
chelation therapies are cited as a contraindication to any use
or tolerance problems may be identified. An open research
of chelators. Improvements are nevertheless reported with
question has to do with changes in metals excreted over an
low initial doses and gradual titration according to patient
extended course of chelation treatments; whether in a person
tolerance (characterized as a marathon rather than a sprint).
with high levels of multiple metals, one will be preferentially
chelated initially, with a second then third being excreted
4.3. Testing to Identify Toxic Metals and to Follow Progress of over time with repeated treatments. This research would aid
Therapy. Toxicologically significant levels of toxic elements interpretation of chelation challenge tests, as well as enhance
may not be predictable from exposure history, as relevant knowledge of chelation therapy itself.
exposures may not be queried, recognized, or remembered. Comparison of baseline and provoked urine levels is
Furthermore, mobilization of metals from various compart- entering standard practice and was used to determine inclu-
ments in the body could occur due to certain stressors such sion in a trial of chelation therapy for children with autism
The Scientific World Journal 7

[96]. In this trial, however, a few children experienced wors- of decline among those not treated during followup was
ening symptoms. Such worsening is ascribed to redistribution lower among previously treated patients. Cost of therapy was
of toxic metals, with insufficient excretory mechanisms in approximately $3750 per patient, compared with a cost of
place, leading some practitioners to prefer unprovoked anal- $61,000 for hemodialysis over a similar time frame for end
yses up front, in sensitive, fragile patients. Therapy may be stage renal failure [106]. In a smaller trial in patients with type
guided by parental, caregiver, and patient observations. II diabetes, body lead burden was a strong predictor of rate
of renal function decline. Chelation therapy halved decline
4.4. Therapeutic Benefits. Chelation therapy is established as during three months of treatment but kidney function wors-
an effective treatment for acute and higher exposure poison- ened in both groups during nine months further followup
ing, according to the drug labels. Examples of reports using without treatment [107]. Of note, no other toxic elements
chelation agents for high occupational or environmental were measured during this research, so it is unknown to what
exposures include the following. extent other nephrotoxins such as cadmium or mercury may
have also played roles.
(i) DMSA chelation therapy increased lead excretion on (iii) A 1955 report that patients with ischemic heart
average by a factor of 12 and rapidly reversed lead disease had improvement in angina and other cardiovascular
related symptoms (largely neurological and gastroin- symptoms while undergoing EDTA chelation therapy for lead
testinal) in a case series of 17 lead-poisoned adults poisoning sparked long, ongoing interest in the prevention
[102]; these authors also reviewed effectiveness of and treatment of cardiovascular disease [108]. EDTA chela-
DMSA. tion therapy treatment for atherosclerosis has been a con-
(ii) The same group reported a case of a jeweller with troversial subject of debate. While early anecdotal evidence
extensive neurological symptoms of mercury poison- suggested significant clinical symptomatic improvements,
ing, reversed with DMPS treatment [103]. the five clinical trials identified in a recent meta-analysis
used small populations with different clinical syndromes,
(iii) A trial of oral DMPS therapy in the Philippines
measured different outcomes, and yielded no overall evidence
provided two weeks of treatment in a community
of benefit [109].
highly exposed to mercury used for artisanal gold
The Trial to Assess Chelation Therapy (TACT) [110] was
mining [104]. Most participants experienced multiple
a US National Institutes of Health sponsored, randomized,
significant neurological improvements. This trial was
double blind, placebo-controlled clinical trial, evaluating
remarkable for the extensive testing conducted in this
the benefits and harms of EDTA chelation therapy in 1708
remote location, as well as near-perfect compliance, as
nonsmokers aged 50 and older who had an acute myocardial
the midwife distributed the medication. This report is
infarction more than 6 weeks prior to enrolment and were
high quality, with careful descriptions of the interven-
otherwise medically stable. The protocol was recommended
tion, inclusion, dropouts, and results.
by the American College for Advancement in Medicine,
The effective use of chelation in patients with lower levels the largest physicians’ organization in America practicing
of accumulation of toxic elements is not as widely recognized, chelation. Treatment included 40 3-hour infusions of a
but positive trials are being reported. multicomponent Na2 EDTA solution, plus an oral, high-dose
(i) In a randomized, double-blind controlled trial con- multivitamin/mineral supplement on nonchelation days. The
ducted by Adams et al., reductions in measures of the severity primary endpoint was a composite of all-cause mortality,
of autism were associated with the difference in urinary myocardial infarction, stroke, coronary revascularization,
excretion of toxic metals before and following treatment with and hospitalization for angina [111]. The success of this trial
DMSA, demonstrating both a significant positive association was reported at the American Heart Association meeting
between the severity of autism and the body burden of toxic in November 2012. Three years after treatment, the risk of
metals, and efficacy of reduction of this body burden in the combined endpoint was reduced by 18% in the group
improving symptoms [96]. An inclusion criterion for the trial receiving EDTA (𝑃 = 0.03) compared with placebo. Among
was elevated body burden of one or more toxic elements, participants with diabetes and those who had experienced
determined using chelation challenge testing. The initial three anterior myocardial infarctions, the combined endpoint was
days of treatment for this inclusion screening was sufficient reduced by 39% (𝑃 = 0.002). Of equal importance, there
to improve glutathione and platelet levels in children with was no difference between groups in serious adverse events.
autism [105]. Hypocalcemia and transient renal function impairment, the
(ii) A concern with chelation therapy is that renal insuffi- two complications that had been reported in early studies
ciency may be a contraindication for therapy. The opposite using primitive protocols, did not occur at all. TACT pro-
appears to be the case. In a randomized, controlled study ceeded despite detailed criticisms [112], but unfortunately
of 64 patients with chronic renal insufficiency with elevated excretion of toxic elements was not assessed during this trial.
body burden of lead and without diabetes, three months Thus, participants in whom chelation would potentially have
of CaNa2 EDTA weekly infusions resulted in slowing or been indicated on the basis of higher body burdens of toxic
reversing degeneration in the chelation group. Following 24 elements known to be associated with cardiovascular disease
further months of treatment in 32 patients with elevated body were not identified, and it is unknown if additional benefit
lead burdens, glomerular filtration rate improved among may have accrued with additional treatment, among those
the treatment group and decreased in controls. The rate with remaining significant body burdens of heavy metals.
8 The Scientific World Journal

4.5. Other Potential Pharmaceutical Chelators. Monoisoamyl depleting arsenic from blood and soft tissues compared to
DMSA (MiADMSA) is a potential drug candidate under other treatments [86].
development. In young rats exposed to lead or arsenic, Supplementation with antioxidants and small molecules
MiADMSA was found to potentiate the synthesis of met- containing thiol groups, along with chelating agents may
allothionine in liver and kidneys and glutathione in liver be beneficial in increasing toxic metal mobilization and
and brain, along with significantly reducing the glutathione excretion, with improvement of biochemical variables [118].
disulfide levels in tissues. MiADMSA is capable of mobilizing For example the following.
intracellularly bound cadmium and is seen to provide an
indirect antioxidant effect by removing cadmium from the (i) Taurine, when coadministered with DMSA or
site of deleterious oxidation reactions [86]. MiADMSA, helped to further reduce total body
Analogues of DMSA are capable of crossing biomem- burden of arsenic and lead [119].
branes and are more effective in reducing arsenic burden (ii) NAC forms coordination bonds between metals and
in acute and subchronic intoxication. Monoesters may be its thiol group. The thiol may also reduce free radicals.
preferred over DMSA diesters owing to their higher efficacy Combined administration of NAC and DMSA after
against arsenic intoxication and lower toxicity of the drug arsenic exposure led to a significant reduction of
[86]. oxidative stress biomarkers, as well as to removal of
N-(alpha-L-Arabinofuranos-1-yl)-L-cysteine, stereosele- arsenic from organs [120].
ctively prepared from L-arabinose and L-cysteine, is an (iii) The research group led by Flora has investigated toxic
experimental chelator which has been shown to have good metals extensively in animals, and reviewed combi-
intra- and extracellular mobility as well as little effect on the nations of antioxidants and other agents in addition
level of essential minerals when used in mice [113]. to chelators, including vitamins, NAC, taurine, lipoic
Older drugs known as “metal protein attenuating com- acid [20], and liposomal glutathione [60, 61].
pounds” (MPACs) such as clioquinol are weaker chelators,
thought to modulate copper and zinc in the brain, removing
4.7. Clinical Approaches. Management of patients in whom
it from plaque and tangles. As with the TACT trial focusing
low dose chronic toxic metal exposures are contributing to
on calcium, the focus has been on known physiologically
chronic illnesses presents a significant challenge to the health
essential metals, and little thought and research has been
care provider. Irritable bowel syndrome, fatigue, autism
devoted to possible effects of MPACs on toxic metals. The
spectrum disorders, cognitive impairment, allergies, environ-
hypothesis that MPACs may be acting on toxic as well as
mental sensitivities, or soft neurological signs like tremor,
essential metals merits further investigation, as clioquinol
imbalance or depression may be multifactorial in origin. Such
and vitamin B were found to reduce lead accumulation and
patients’ clinical situations are unique and complex, necessi-
to rescue brain plasticity in rats [114].
tating multiple therapeutic strategies. Individualized therapy
is provided according to the best available evidence, clinical
judgment, and patient preference, in order to maximize
4.6. Combination Therapies. Combination therapy is an benefit and minimize risk [19]. A thorough work-up is used
approach to enhance metal mobilization from the body, to identify underlying factors, such as allergens and gluten
reduce individual doses of chelators, and lessen redistribution intolerance, that are addressed by avoidance, food intolerance
of toxic metals from one site (e.g., bone or liver) to more identification and remediation (rotation and elimination
sensitive sites such as the brain (discussed above). There are diets) and pre- and probiotics for intestinal dysbiosis. As
a large number of possible agents, which are being tested in a result of intestinal malabsorption patients may present
animal research. This is an area ripe for research; here are a with nutritional deficiencies, which can be addressed through
few examples. dietary counselling, oral supplementation with vitamins and
Animals chronically exposed to lead experience redistri- minerals, and intravenous supplementation using a mixture
bution from bone to soft tissues including the brain following such as Myers Cocktail, to which glutathione may be added.
CaNa2 EDTA. This is also seen in humans, leading to the It should be noted that there is concern about endocrine
recommendation that EDTA chelation be followed by a disrupting di (2-ethylhexyl) phthalate (DEHP) leaching from
short course of DMSA [115]. Indeed, the recommendation vinyl intravenous bags and tubing [121].
to combine EDTA with thiol chelators was reported decades An extensive environmental exposure history is used to
ago [116]. In lead-treated rats, a DMSA and CaNa2 EDTA identify xenobiotic exposures [122], so that sources may be
combination was superior to either drug on its own, or recognized (e.g., occupational exposures), remediated (e.g.,
to DMPS alone or in combination with CaNa2 EDTA, in dust from lead-based paint) and avoided (e.g., consumption
depleting organ and bone lead, normalizing lead-sensitive of high-mercury fish, or smoking). Once the sources of toxins
biochemical measures with no redistribution of lead to any are removed from the environment and diet, and if necessary
other organ. DMSA was the only drug that resulted in the natural biochemistry is supported with replenishment of
decreased brain lead levels [117]. essential vitamins, minerals, and microbiota, many patients
Coadministration of DMSA and monoisoamyl DMSA will improve with a healthy diet, exercise, and rest. Sweating
(MiADMSA) at lower doses was most effective not only with exercise or sauna may be of benefit, as toxic metals are
in reducing arsenic-induced oxidative stress but also in excreted in sweat [21].
The Scientific World Journal 9

Toxic elements unfortunately build up over time in soft Acknowledgments

tissues and bone, and even when the external source is
removed the bioaccumulated toxic elements represent an The Toxic Metals in Canadians scoping review was sup-
ongoing endogenous source of exposure, and measures to ported by the Canadian Institutes of Health Research. The
enhance excretion may be helpful. author wishes to thank Dr. Riina Bray for her participation
Overall, during chelation therapy mobilization must and enthusiasm in the Toxic Metals project, the physicians
equal excretion, so adequate hydration and bowel regu- who responded to the questionnaire and participated in
larity are essential. A variety of products may assist in consultation activities, and particularly Dr. Richard Nahas,
interrupting enterohepatic recirculation of toxicants, includ- Dr. Jennifer Armstrong, and Dr. John Coombes for their
ing cholestyramine, charcoal, psyllium, thiolized silica, and generous input into this paper.
others [78]. Pharmaceutical chelating agents may also be
considered, to assist with mobilization and excretion. References
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