International Board of Clinical Metal Toxicology

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International Board of Clinical Metal Toxicology

Chelation and Detoxification


Clinical Metal Toxicology is the medical concept of “chelating” harmful metals. We use chelating agents in the treatment of pathological conditions. Examples are atherosclerosis and lead intoxication.

The Greek origin of the word chelate signifies the plier-like claws of a crab.

The most widely accepted use of chelation therapy in medicine is for the removal of toxic metals, such as lead, arsenic, cadmium, mercury, iron, copper or aluminum from the body. A more controversial, but clinically useful indication for chelation therapy, and more specifically disodium EDTA chelation therapy, is the treatment of all forms of atherosclerotic diseases, including, coronary, cerebral, and peripheral arterial disease as well as other degenerative conditions.

A chelate is a water-soluble complex between a metal ion and a complexing agent. It may further be defined as: an equilibrium reaction between a metal cation and a complexing agent characterized by the formation of more than one bond between the cation and the complexing agent resulting in a heterocyclic ring structure, incorporating the metal ion. The complex usually does not dissociate easily in solution, but forms an inert complex. In labile complexes, however, the metal ion can be readily exchanged. Metal complexes of transition elements are well known here, chelation occurs within a much wider range of elements. Chelating agents yielding soluble metal complexes are also called sequestering agents. Chelating agents control metal ions by blocking the reactive sites of the ions and preventing them from normal activity. This phenomenon is in effect as long as the chelator is present in the body A chelating agent has at least two functional groups which donate a pair of electrons to the metal, such as = O, -NH2 or -COO¯. Furthermore, these groups must be located so as to allow ring formation with the metal. Chelating agents are widely found in living systems and are of importance in cellular metabolism. For example, chlorophyll is a chelate of magnesium and hemoglobin is a chelate of iron.

Successful in vivo chelation treatment of metal intoxication requires that a significant fraction of the administered chelator in fact chelate the toxic metal. This depends on metal, chelator, and organism-related factors (e.g., ionic diameter, ring size and deformability, hardness/softness of electron donors and acceptors, route of administration, bioavailability, metabolism, organ and intra/extracellular compartmentalization, and excretion). In vivo chelation is not necessarily an equilibrium reaction, determined by the standard stability constant, because rate effects and ligand exchange reactions considerably influence complex formation. Hydrophilic chelators most effectively promote renal metal excretion, but they complex intracellular metal deposits inefficiently. Lipophilic chelators can decrease intracellular stores but may redistribute toxic metals to, for example, the brain. In chronic metal-induced disease, where life-long chelation may be necessary, possible toxicity or side effects of the administered chelator may be limiting. The metal selectivity of chelators is important because of the risk of depletion of the patient's stores of essential metals. DMPS, DMSA, DTPA, Deferoxamine have gained more general acceptance among clinicians, undoubtedly improving the management of many human metal intoxications, including lead, arsenic, and mercury compounds. Deprivation of iron by chelating agents has been proposed as a method of cancer treatment, alongside the well-known mechanism of iron-promoted oxidative damage (e.g., Bleomycin).

Natural Chelators

Water, Carbohydrates, including polysaccharides, Organic acids with more than one, coordination group, Lipids, Steroids, Amino acids and related compounds, Peptides, Phosphates, Nucleotides, Tetrapyrroles, Ferrioxamines, lonophores, such as gramicidin, monensin, valinomycin, phenolics etc.

Synthetic Chelators

BAL. Deferoxamine, Deferiprone, DMPS, DMSA, D-Penicillamine, EDTA, Tetrathiomolybdate, Prussian Blue, DTPA, etc


The aim of Chelation is to relieve the body of toxic metals. Chelated toxic metals need to be eliminated, usually via the urine, occasionally also by the bile and stool. This process of detoxification should be well-understood in order to deliver the proper treatment to a patient. Usually, metal intoxication is not the only intoxication and if the detoxification process is compromised elimination of metal complexes may be compromised as well

The process of detoxification involves two phases.

The body's primary defense against metabolic poisoning is carried out by the liver. The liver has two mechanisms designed to convert fat-soluble chemicals into water soluble chemicals so that they may then be easily excreted from the body via watery fluids such as bile and urine. The two pathways are known as phase I and phase II

Phase I

This pathway converts a toxic chemical into a less harmful chemical. This is achieved by various chemical reactions (such as oxidation, reduction and hydrolysis), and during this process free radicals are produced which, if excessive, can damage the liver cells. Antioxidants (such as vitamin C and E and natural carotenoids) reduce the damage caused by these free radicals. If antioxidants are lacking and toxin exposure is high, toxic chemicals become far more dangerous. Some may be converted from relatively harmless substances into potentially carcinogenic substances. Human liver cells possess the genetic code for many isoenzymes of P-450 whose synthesis can be induced upon exposure to specific chemicals. This provides a mechanism of protection from a wide variety of toxic chemicals. Excessive amounts of toxic chemicals such as pesticides can disrupt the P-450 enzyme system by causing over activity or what is called 'induction' of this pathway. This will result in high levels of damaging free radicals being produced.

Toxins and xenobiotics are converted into a water soluble metabolite or a primary metabolite in the process of biotransformation. Primary metabolites are then cleared later in Phase II of the liver detoxification cycle. Toxins (drugs, pesticides, gut toxins, hormones, metabolic by-products, histamine, etc.) enter into the liver detoxification Phase I and are converted into substances that are water soluble and then excreted via the kidneys, sweat, and bile. This conversion results in the formation of free radicals. There is one molecule of Glutathione used for each molecule of toxin removed. A toxin initially enters phase 1, the p-450 cytochrome system, and is reduced to smaller fragments. These fragments then progress to phase 2, where they are bound to molecules such as glutathione, glycine and sulfate. This process creates a new non-toxic molecule that can be excreted in the bile, urine or stool.

Some substances need further detoxification and must enter Phase II for elimination. These primary metabolites are now more toxic than they were originally before Phase I. These Phase I products can cause tissue damage and can react with a cell protein thus forming a new antigen which may lead to immunological reactions. The more active compounds could bind with the DNA causing mutation which could lead to cancer; many carcinogens are first activated by the liver (e.g. benzopyrene). What should occur is that the primary metabolite reacts with the Phase II enzymes and is rendered harmless. An example of the phase one pathway is the Cytochrome P-450 mixed function oxidase enzyme pathway. These enzymes reside on the membrane system of the hepatocytes. The family of P-450 enzyme systems is quite diverse, with specific enzyme systems being inducible by particular drugs, toxins or metabolites. It is this characteristic that has allowed the development of special tests to check the function of the various pathways the substrate is the substance that is acted upon by the enzyme. Substances that may cause over activity (or induction) of the P- 450 enzymes are: Caffeine, Alcohol, Dioxin, Saturated fats, Organophosphorus pesticides, Paint fumes, Sulfonamides, Exhaust fumes, Barbiturates.           

Phase II.

This is called the conjugation pathway, whereby the liver cells add another substance (e.g. cysteine, glycine or a sulphur molecule) to a toxic chemical or drug, to render it less harmful. This makes the toxin or drug water-soluble, so through conjugation, the liver is able to turn drugs, hormones and various toxins into excretable substances. For efficient phase two detoxification, the liver cells require sulphur-containing amino acids such as taurine and cysteine. The nutrients glycine, glutamine, choline and inositol are also required for efficient phase two detoxification.  Thus, these foods can be considered to have a cleansing action. The phase two enzyme systems include both UDP-glucuronyl transferase (GT) and glutathione-S-transferase (GSH-T). Glutathione is composed of three amino acids (cysteine, glutamic acid, and glycine). Adequate glutathione levels are also dependent on adequate levels of methionine since it is the precursor to cysteine. Glutathione is a powerful antioxidant and is very important because of its dual role as an anticancer agent and antioxidant. Glutathione conjugation is the primary process by which the body removes fat soluble toxins (heavy metals, solvents, pesticides, fertilizers, etc). It can be depleted by large amounts of toxins and/or drugs passing through the liver, as well as starvation or fasting. Phase II reactions may follow Phase I for some molecules or act directly on the toxin or metabolite. During Phase II detoxification the substances are conjugated with a water soluble substance creating a product that is less toxic and water soluble.

Eggs and cruciferous vegetables (e.g. broccoli, cabbage, Brussels sprouts, cauliflower), and raw garlic, onions, leeks and shallots are all good sources of natural sulphur compounds to enhance phase two detoxification.

Provided activation of Phase I and Phase II is simultaneous, this water soluble end product is excreted safely in the bile or in the urine Phase I and Phase II pathways of detoxification need to be in balance. This will determine if the exposure to a xenobiotic will cause toxicity or immune problems. If Phase I reactions are producing primary metabolites faster than Phase II can neutralize them, then toxic consequences will result. Substances that activate Phase I reactions can be undesirable if Phase II can not handle them. The best scenario is simultaneous activation of Phase I and Phase II.
One or both detoxification phases can be inefficient or overloaded. A particularly damaging combination in an ill person is an excessive overload of toxins coming into Phase 1, with an inefficient Phase 2. In some cases this combination is believed to be the cause of marked environmental sensitivities, drug intolerances and interactions that characterize many chronic fatigue and fibromyalgia patients. As patients improve clinically, serial testing of their liver detoxification capacity shows corresponding improvement.

If a patient is very ill with severe toxic symptoms, hepatic detoxification must be performed very slowly and gradually. It is always preferable first to reduce toxin exposure and any liver inflammation. In addition, leaky gut syndrome should be addressed and repaired prior to any liver detoxification.

Lipid Peroxidation

Lipids may also be damaged by free radicals, and often metals, especially copper and iron, are involved. These free radicals products are a major cause in the development of atherosclerosis.

Oxygen-dependent deterioration of lipids, known as rancidity, is a major problem in the storage of oils. The same oxidation process is also considered important today for natural products used in human consumption such as fats, oils, dressings or margarine.

Lipid peroxidation can be defined as the oxidative deterioration of lipids containing any number of carbon-carbon double bonds. Lipid peroxidation is a free radical-related process that in biologic systems may occur under enzymatic control, for instance the generation of lipid-derived inflammatory mediators, or non-enzymatically. This latter form is associated mostly with cellular damage as a result of oxidative stress

During classic rancidification of fats iron and copper complexes can catalyze further radical reactions. Oxygen is seven to eight times more soluble in non-polar media than in polar media. In the plasma membrane there are hydrophobic and hydrophilic substances interdigitated into and interacting with the plasma membrane hydrophobic and ionic forces. This hydrophobic middle zone in the plasma bi-layer is the non-polar medium where oxygen is so soluble. Also, it is the location where for the polyunsaturated fatty acids with their allylic carbon-hydrogen bonds which is susceptible to free radical attack. Thus, the hydrophobic middle zone has the highest concentration of oxygen, with its di-radical potential for doing damage to the plasma membrane’s polyunsaturated fatty acids. In this way the resulting saturate chains become more compacted with the membrane, becoming less fluid and poised for membrane disruption. Cholesterol has a protective antioxidant function in the normal cell membranes. The unsaturated fatty acids tails on the phospholipids are free to wave fluidly around the non-polar end of the cholesterol molecule. Cholesterol’s presence in the hydrophobic middle zone perpendicular to the membrane’s surface is thus poised to accept the di-radical by its allylic bonds. Also the steroid cholesterol thus serves as a physical barrier between the free radical and the allylic bonds of the fatty acids. The steroid rings allow more allylic bonds to suspend the di-radical simultaneously between them and thus become the favorable environment for the di-radical oxygen. Following an incident that causes more free radicals the amount of cholesterol in the membrane is decreased. Thus it appears that that one of cholesterol’s roles to protect normal plasma membranes from free radical attacks. This may be accomplished by maintaining fluidity in the membrane by preserving the polyunsaturated nature of the fatty acid tails on the phospholipids.


The following is certainly not an exhaustive study on the History of Chelation and deals predominantly with the EDTA chelator. It tries to be an incentive to read more about this intriguing story of medicine that was initiated and developed outside universities and medical schools and nevertheless became a remarkable success.

Chelation may be defined as an equilibrium reaction between a metal ion and a complexing agent, characterized by the formation of more than one bond between the metal and a molecule of the complexing agent, resulting in the formation of a ring structure incorporating the metal ion.

The Swiss Alfred Werner proposed the concept of this metal-ligand bonding, with the metal atom as the center of an octahedral ring structure, as early as 1893. At that time it was quite a revolutionary concept, as quantum mechanics was not yet fully understood. At that time it was not yet called “Chelation”.

The word Chelation was first proposed by Morgan and Drew in 1920, because they compared the way a heterocyclic ring structure grabbed the metal with the pincer-like action of a crab.

One chelator, which later became of clinical importance, was EDTA. It was synthesized by a German scientist F. Munz of the Hoechst Farbwerke in Germany. It was developed from nitrile-triacetic acid, which was used to soften water for more uniform dying in the textile industry. A patent for Europe was obtained in 1935.

First synthesis and patent of EDTA in the USA in 1945 In 1933 Frederick Bersworth and William Warren manufactured EDTA from formaldehyde and cyanide, at the Clark University, Worchester Massachusetts.Bersworth applied for a patent in the USA, which was finally granted in 1945 under the name of Versene.

First clinical application of EDTA Chelation.

In 1941 S.Kety employed sodium citrate for the experimental treatment of lead poisoning, because of the complexing action of citrate on the lead ion.

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