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Chelation: Harnessing & Enhancing Heavy Metal Detoxification - a Review
by Margaret E. Sears
Chelation: Harnessing and Enhancing Heavy Metal Detoxification, a Review
(Underlined, bold, italic emphasis by Dr. Michael Roth)
Toxic metals are ubiquitous, and many such as arsenic, cadmium, lead, and mercury have no beneficial role in human homeostasis, and contribute greatly to chronic diseases.
Heavy Metals such as cadmium [2–5], lead [6–8], and mercury [9–12] have no essential biochemical roles, but exert diverse, severe toxicities in multiple organ systems as they bind in tissues, create oxidative stress, affect endocrine function, block aquaporins, and interfere with functions of essential cations such as magnesium and zinc. Toxic metals pose particular risks to the very young, as exposures early in life compromise development, with lifelong physical, intellectual, and behavioural impairments. In adults, major chronic diseases , including cardiovascular and renal disease, and neurological decline, are also strongly associated with toxic elements. The International Agency for Research on Cancer (IARC) classifies cadmium as a known carcinogen, inorganic lead a probable carcinogen, and methylmercury a possible carcinogen .
As research progresses, harms more subtle than acute poisoning are seen at lower and lower body burdens of heavy metals. For example, early lead exposure is now found to cause IQ decrements at a blood level below 2 µg/dL . The blood lead reference value at which the US Centers for Disease Control action recommends investigation and remediation of a child's environmental exposures is 5 µg/dL, while chelation is recommended at nine times that level above 45 µg/dL .
Modern mercury and cadmium exposures are frequently via oral routes, prompting advisories regarding fish (e.g., U.S. Environmental Protection Agency ), seafood and wildlife consumption (e.g., Canadian Aboriginal Affairs ), as well as cigarette smoke (also noted by Aboriginal Affairs; cadmium is but one toxic component). Lead may also originate in old drinking water supply pipes.
Toxic metals are ubiquitous in our environment, and thus in ourselves, at higher than historical levels. Exposures [5, 8, 12, 19] include the activities and legacies of mining and toxic wastes, lead in paint and gasoline, ongoing emissions from industrial and electricity-generating (particularly coal-burning) activities, chemicals in everyday products, and novel technologies such as nanomaterials containing toxic elements like cadmium .
Chelation is central to natural detoxification of heavy metals, via formation of complexes, particularly with glutathione and other small molecules, and their excretion .
This manuscript stems from a large scoping review regarding arsenic, cadmium, lead, and mercury, funded by the Canadian Institutes of Health Research.
Expert opinion was solicited via email, during a conference call, and during a two-day conference in Toronto (February 2011). Clinical toxicologists at Canadian Poison Control Centres were surveyed to gather information about screening, experiences, and preferred chelators for each toxic element.
“Chelation,” from “chelos” the Greek word for claw, involves the incorporation of a mineral ion or cation into a complex ring structure by an organic molecule, the chelating agent.
Chelators have the effect of mobilizing metals from tissues and maintaining the chelate moiety during circulation to the kidneys for excretion in the urine, and to the liver for excretion in the bile. There are significant concerns related to enterohepatic recirculation and reabsorption in the kidney .
Another consideration is solubility of the chelate, in water and in lipids. Aqueous solubility facilitates transport within the blood and excretion via the kidney, while a lipophilic chelator may exhibit greater penetration of cellular membranes (including those within the central nervous system) to chelate intracellular elements. A lipophilic chelator may also be excreted in greater quantities via the bile.
Roles of Chelation in Natural Toxicokinetics
Metal binding proteins, including metallothioneins, are potent chelators for heavy metals and are central to the natural response of the body to these toxic elements [27, 28]. Glutathione is another potent chelator involved in cellular response, transport, and excretion of metal cations and is a biomarker for toxic metal overload [29–31].
Not only animals, but also plants produce chelating compounds , and metallothionein content of foods may affect bioavailability as well as metabolism of toxic metals such as cadmium .
Some foods have been suggested to reduce absorption or reabsorption of toxic metals and to support natural detoxification pathways.
Other natural polymers have also been gaining attention as potential adsorbents of heavy metals, such as algal polysaccharides alginate  and chlorella . Modified citrus pectin plus alginate products have been used successfully to reduce lead and mercury in case studies .
(iii) Given that toxic metals have great affinity for sulphur-containing peptides, diets rich in sulphur-containing foods such as alliums (e.g. garlic ) and brassicas (e.g., broccoli ) have been suggested for effects on glutathione, with hopes for symptomatic improvement and enhanced excretion. Garlic prevented cadmium-induced kidney damage  and decreased the oxidative damage due to lead in rats .
(iv) Cilantro (leaves of Coriandrum sativum), a popular culinary and medicinal herb, gained attention when a soup was reported to enhance mercury excretion following dental amalgam removal and remains popular despite limited evidence . For example, in a recent trial in 3- to 7-year old children exposed to lead, a cilantro extract was as effective as placebo in increasing renal excretion (improvements across treatment and placebo groups were ascribed to improved diet during the intervention) .
Several supplements are also in use to address metal toxicities.
(i) Taurine [49–51] and methionine  are sulphur-containing amino acids. They are rich in membranes particularly of excitable tissues, and they decrease oxidative stress markers resulting from heavy metal exposure.
(ii) Alpha lipoic acid is a powerful antioxidant that regenerates other antioxidants (e.g., vitamins E and C, and reduced glutathione) and has metal-chelating activity. Both fat and water soluble, it is readily absorbed from the gut and crosses cellular and blood-brain membrane barriers [22, 53]. Clinical experience is that it must be used carefully as it poses particular risks of redistribution of metals.
(iii) N-acetyl-cysteine (NAC), an orally available precursor of cysteine, is a chelator of toxic elements and may stimulate glutathione synthesis, particularly in the presence of vitamins C and E [54–56].
(iv) Glutathione is not recommended to be administered orally as it undergoes digestion; however novel modes of delivery such as liposomal and prodrug preparations are emerging . It may be administered intravenously, in creams and via nebulizer. Glutathione is an important physiological chelator, and the reduced form of glutathione protects cells from reactive oxygen species associated with heavy metals [58–61].
(v) Selenium is an important essential element, that is present at a broad range of levels across populations. The selenide ion forms an extremely stable, insoluble compound with mercury, and provides relief of mercurialism symptoms.
Certain vitamins and minerals can enable limited protection against heavy metals. For example, in animals calcium deprivation enhanced absorption of lead and cadmium , while magnesium and zinc supplementation blunted absorption of cadmium . Calcium supplementation reduced lead mobilization from maternal bones during pregnancy and lactation, protecting the newborn and infant [70–72]. In children, iron supplementation blunted lead accumulation .
Drug information from the US National Library of Medicine for five chelating agents used most commonly for the treatment of humans intoxicated with heavy metals and metalloids.
Dimercaprol, the first antidote to an arsenical nerve gas, is given only by intramuscular injection (painful). It has a narrow therapeutic window and is commonly prepared with peanut oil, posing a risk of allergic reaction.
It has been largely supplanted by dimercaptosuccinic acid (DMSA or succimer) and dimercaptopropane sulfonate (DMPS) . These dithiols, with greater water solubility, are being administered as oral, intravenous, suppository, or transdermal preparations.
Oral administration of DMSA may be limited by intestinal dysbiosis. Oral absorption is approximately 20%. Ten to 25% of an orally administered dose of DMSA is excreted in urine; the majority within 24 hours and most as DMSA-cysteine disulfide conjugates. The remainder is largely eliminated in the feces [77–80]. DMSA increases urinary excretion of arsenic, cadmium, lead, methylmercury, and inorganic mercury, with removal from animals' brains of lead and methylmercury. Excretion of essential metals like zinc, iron, calcium, and magnesium is much less than with CaNa2EDTA, therefore mineral supplementation is recommended. Although frequently administered orally, intravenous, rectal, and transdermal routes are in clinical use.
DMPS oral absorption is approximately 39%, higher than that of DMSA . DMPS increases urinary excretion of arsenic, cadmium, lead, methylmercury, and inorganic mercury. In a study of the DMPS challenge test there was significantly increased excretion of copper, selenium, zinc, and magnesium, necessitating replenishment of these essential minerals orally or intravenously before and after treatment .
In comparing the efficacy of the dithiol chelators in animals, DMSA was superior in removal of methylmercury, including from animal brains. Although DMPS did not affect levels in the brain, it was superior at removing methylmercury from the kidney . In mice, cadmium was removed more effectively by DMSA than DMPS .
CaNa2EDTA is not metabolized and EDTA chelates are rapidly excreted, principally in the urine. With only oxygen atoms for coordination bonds, EDTA binds lead and cadmium strongly, eliminating them in the urine. Clinical experience is that CaNa2EDTA (Calcium Disodium EDTA) will result in increasing mercury excretion with the removal of more well-bound minerals such as lead and cadmium. Overall CaNa2EDTA causes greater losses of essential minerals than DMSA or DMPS, and therefore also results in stronger inorganic heavy metal binding and elimination.
Roots of Chelation Controversies
Three deaths associated with chelation therapy have been reported, related to hypocalcemia resulting in cardiac arrest after use of Na2EDTA (Disodium EDTA) . These were in fact drug errors and should not reflect on the safety of CaNa2EDTA, the form generally indicated for chelation of toxic metals .
CaNa2EDTA is distributed mainly in the extracellular fluids and one of its major perceived drawbacks is that of redistributing lead from other tissues to the brain. In one study, treatment with DMSA after exposure to inorganic mercury caused an elevation of mercury in motor axons, likely due to redistribution of mercury, which was mobilized from nonneural tissues such as the kidneys and liver . Mixed reports indicate that EDTA does not cross the blood-brain barrier, but this is in contrast to reports that EDTA in fact is small enough to easily cross the BBB and bind to toxic metals in the brain .
In summary, it appears that any adverse effects of the above for chelation were more likely from violation of important current clinical practices by administering the drug at a high dose, over an extended period of time, when there was no indication of need; and failing to assess essential minerals loss and ensuring that minerals were appropriately supplemented to avoid health consequences.
Chelation in Various Tissues and Redistribution
Chelating agents are fairly rapidly excreted over a few hours or days. In contrast, toxic elements may have accumulated over long periods of time and partitioned into various bodily compartments, not all being equally accessible to chelating agents. Commonly a chelating agent will mobilize the most readily available metals first, typically in the plasma, kidney, liver and then to a lesser extent bone and central nervous system. As discussed above, toxic metals in the nervous system are best addressed conservatively, with repeated, modest treatments and the use of multiple agents. With repeated doses the most readily accessed “pools” of toxic elements will be depleted, but reequilibration slowly replenishes the toxic elements in more accessible body compartments. This is evident in the rebound of levels in the blood, following discontinuation of a chelator, which highlights two important facts.
(i) Blood and urine are poor surrogates to measure the toxins accrued over the lifetime (body burden). The common laboratory measures of urine, blood, and hair indicate exposures in recent days or months, and to a lesser extent kidney burden.
(ii) Toxic elements sequestered in bone and soft tissues are not completely immobilized; they migrate back to the bloodstream and hence to tissues where they will again exert toxic effects.
(iii) Introduction of a chelating agent into the body causes shifts of both essential and toxic cations. Increased symptoms commonly reported with aggressive initiation of chelation therapies are cited as a contraindication to any use of chelators. Improvements are nevertheless reported with low initial doses and gradual titration according to patient tolerance (characterized as a marathon rather than a sprint).
Testing to Identify Toxic Metals and to Follow Progress of Therapy
Mobilization of metals from various compartments in the body could occur due to certain stressors such as disease, trauma, starvation, pregnancy, time of life (e.g., menopause), and extreme emotional impacts. Depending on a person's constitution, genetic make-up, diet, lifestyle, and sensitivities, a patient could be suffering from toxic metal effects without having a clear history of exposure.
One of the most effective methods to evaluate net retention, or at least the biologically readily available metal load, is to compare the levels of metals in urine before and after the administration of a pharmaceutical chelating agent such as CaNa2EDTA, DMSA, or DMPS . Variously known as “mobilization,” “chelation challenge,” or a “provocation” test
Pre- and postchallenge testing may allow the clinician to identify which chelating agent is the most effective for the patient.
The effective use of chelation in patients with lower levels of accumulation of toxic elements is not as widely recognized, but positive trials are being reported.
A concern with chelation therapy is that renal insufficiency may be a contraindication for therapy. The opposite appears to be the case. In a randomized, controlled study of 64 patients with chronic renal insufficiency with elevated body burden of lead and without diabetes, three months of CaNa2EDTA weekly infusions resulted in slowing or reversing degeneration in the chelation group. Following 24 further months of treatment in 32 patients with elevated body lead burdens, glomerular filtration rate improved among the treatment group and decreased in controls. Cost of therapy was approximately $3750 per patient, compared with a cost of $61,000 for hemodialysis over a similar time frame for end stage renal failure .
A 1955 report that patients with ischemic heart disease had improvement in angina and other cardiovascular symptoms while undergoing EDTA chelation therapy for lead poisoning sparked long, ongoing interest in the prevention and treatment of cardiovascular disease .
The Trial to Assess Chelation Therapy (TACT)  was a US National Institutes of Health sponsored, randomized, double blind, placebo-controlled clinical trial, evaluating the benefits and harms of EDTA chelation therapy in 1708 nonsmokers aged 50 and older who had an acute myocardial infarction more than 6 weeks prior to enrolment and were otherwise medically stable. Three years after treatment, the risk of the combined endpoint was reduced by 18% in the group receiving EDTA (P = 0.03) compared with placebo. Among participants with diabetes and those who had experienced anterior myocardial infarctions, the combined endpoint was reduced by 39% (P = 0.002). Of equal importance, there was no difference between groups in serious adverse events. Hypocalcemia and transient renal function impairment, the two complications that had been reported in early studies using primitive protocols, did not occur at all.
Other Potential Pharmaceutical Chelators
Combination therapy is an approach to enhance metal mobilization from the body, reduce individual doses of chelators, and lessen redistribution of toxic metals from one site (e.g., bone or liver) to more sensitive sites such as the brain (discussed above).
Animals chronically exposed to lead experience redistribution from bone to soft tissues including the brain following CaNa2EDTA. This is also seen in humans, leading to the recommendation that EDTA chelation be followed by a short course of DMSA . In lead-treated rats, a DMSA and CaNa2EDTA combination was superior to either drug on its own, or to DMPS alone or in combination with CaNa2EDTA, in depleting organ and bone lead, normalizing lead-sensitive biochemical measures with no redistribution of lead to any other organ. DMSA was the only drug that resulted in decreased brain lead levels .
Supplementation with antioxidants and small molecules containing thiol groups, along with chelating agents may be beneficial in increasing toxic metal mobilization and excretion, with improvement of biochemical variables . For example the following.
Taurine, when coadministered with DMSA or MiADMSA, helped to further reduce total body burden of arsenic and lead .
NAC forms coordination bonds between metals and its thiol group. The thiol may also reduce free radicals. Combined administration of NAC and DMSA after arsenic exposure led to a significant reduction of oxidative stress biomarkers, as well as to removal of arsenic from organs .
The research group led by Flora has investigated toxic metals extensively in animals, and reviewed combinations of antioxidants and other agents in addition to chelators, including vitamins, NAC, taurine, lipoic acid , and liposomal glutathione [60, 61].
Intestinal malabsorption patients may present with nutritional deficiencies, which can be addressed through dietary counseling, oral supplementation with vitamins and minerals, and intravenous supplementation, to which glutathione may be added. It should be noted that there is concern about endocrine disrupting di (2-ethylhexyl) phthalate (DEHP) leaching from vinyl intravenous bags and tubing .
Toxic elements unfortunately build up over time in soft tissues and bone, and even when the external source is removed the bioaccumulated toxic elements represent an ongoing endogenous source of exposure, and measures to enhance excretion may be helpful.
Overall, during chelation therapy mobilization must equal excretion, so adequate hydration and bowel regularity are essential. A variety of products may assist in interrupting enterohepatic recirculation of toxicants, including cholestyramine, charcoal, psyllium, thiolized silica, and others . Pharmaceutical chelating agents may also be considered, to assist with mobilization and excretion.
Chelation therapy, including nonabsorbed agents, should be initiated at a low dose and then gradually titrated to recommended doses according to the individual's response, to avoid the patient's health deteriorating with metal redistribution, other physiological perturbations, or drug intolerance. Mineral status must be monitored during chelation therapy, with panel assays of whole blood or red blood cell essential and toxic minerals, and possibly periodic pre- and postprovocation urinanalyses. Oral or intravenous vitamin and mineral supplementation are important, although mineral supplementation and chelation therapy are antagonistic so are generally not given concomitantly.
Allergy-mediated adverse drug reactions have been reported with DMSA and DMPS, and less commonly with CaNa2EDTA, so allergy testing may precede chelation therapy. In this context, it is interesting that anecdotally risk of allergy increases with frequency and degree of xenobiotic exposure, which adds further complexities to considerations of type, dose, and frequency of administration of a chelating agent. Clinical experience is that allergies decrease with reduction of the body burden of toxic elements.
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