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Scientific Rationale for EDTA Chelation Therapy Mechanism of Action

 Elmer M. Cranton, M.D.
James P. Frackelton, M.D.

 This chapter is adapted from A Textbook on EDTA Chelation Therapy, Second Edition, 2001 edited by Elmer M. Cranton, M.D., Hampton Roads Publishing Company, Charlottesville, Virginia.

 Copyright (c) 2001 Elmer M. Cranton, M.D.

[Karl Note:  I have entered in my comments and helpful definitions within the text below -- always in blue, and bold type.]

ABSTRACT: The widely accepted free-radical theory gave us a unified scientific explanation for many diverse benefits following EDTA chelation therapy. Newer concepts of cell-senescence [aging] and apoptosis  [death], together with an insight into homocysteine and cholesterol metabolism expand our knowledge, leading to a broader, more comprehensive understanding. The mechanism of action must explain why full benefit occurs several months after chelation is administered and why that improvement persists for months and years thereafter. EDTA has its effect by binding, redistributing and removing metallic ions. Realignment of essential trace elements with augmentation of vital metalloenzymes may be as important as elimination of free radical catalysts and toxic heavy metals.

INTRODUCTION--RESEARCH SHOWING SAFETY AND EFFECTIVENESS

      The use of chelation therapy with intravenous ethylenediaminetetraacetate (EDTA) for the treatment of atherosclerosis is rapidly increasing worldwide. This practice, which began more than four decades ago, accelerates each year. Dozens clinical studies have been published to document safety and effectiveness of intravenous EDTA for treatment of occlusive atherosclerotic arterial disease and age-related degenerative diseases.(1-89) A very important basis for the scientific rational of this therapy is thus the fact that it has been proven effective over and over again in clinical practice. More than one million patients have received more than twenty million infusions with no serious adverse effects--when administered following the approved Protocol. Many years ago reports of kidney damage and other adverse events resulted from excessive doses of EDTA, infused too rapidly (more than 50 mg/Kg/day or infused more rapidly than 16.6 mg/min).

 Excessive dose-rates of infusion, especially in the presence of preexisting kidney disease or heavy metal toxicity, were responsible for occasional reports of nephrotoxicity.(64-74) No adverse effect on kidneys has been reported when the currently approved protocol has been correctly followed.(72-74)

 Research with laboratory animals provides further support for the effectiveness of EDTA chelation therapy.(77-83)

 There has never been a scientific study of EDTA chelation that did not show effectiveness, although there have been reports in which positive data were erroneously interpreted as negative. Reports of negative or adverse results from EDTA chelation following the currently approved protocol have been either editorial comments and letters to the editor written by opponents of this therapy or seriously flawed attempts to discredit chelation with biased and unscientific interpretation of data--sometimes by cardiovascular surgeons who freely admit their bias.(75,84-89)

In the last ten years, a small cluster of studies has sprouted up in the medical literature purporting to demonstrate that EDTA chelation is not effective in treatment of cardiovascular disease. Although flawed and imperfect, those studies in actuality provide only positive support for chelation. Their negative conclusions are not supported by the data.

The Danish Study

The most controversial and oft cited study of that type was done in Denmark. It was the handiwork of a group of Danish cardiovascular surgeons who freely admitted their opposition to chelation. Results of that study were published in two medical journals, the Journal of Internal Medicine and the American Journal of Surgery.(84-85) Adverse conclusions were also widely publicized in the news media.

The surgeons who conducted that study followed 153 patients suffering from intermittent claudication. The patients had such severely compromised circulation in their lower extremities that walking a city block or less would cause them to stop with pain. An endpoint measured for this study was their maximal walking distance (MWD)--the very longest distance that they could walk before pain of claudication brought them to a halt. Patients were equally divided into an EDTA group and a placebo group. In the pre-treatment phase, the EDTA group averaged walking 119 meters before pain stopped them; the placebo group was less limited at the outset and averaged 157 meters.

Treatment was either 20 intravenous infusions of disodium EDTA or 20 infusions of a simple salt solution, depending on their group. Although the study was alleged to be double-blinded (neither patients nor researchers were supposed to know who received placebo and who received EDTA), the researchers later admitted that they broke the code well before the post-treatment final evaluation

Both groups showed improvement, and the investigators concluded that the improvement was not statistically significant. This Danish study turned many people against chelation; but, in rather short order, the integrity of the study was called into question. It was learned that the researchers had violated their own double-blind protocol. Not only did they themselves know before the end of the study who was receiving EDTA and who placebo, they had also revealed this information to many of the test subjects. Before the study was over more than 64 percent of the subjects were aware of which treatment they had received. This was highly questionable from an ethical and scientific standpoint.

One important aspect of the Danish study is the startling fact that the patients who were given EDTA were much sicker than the patients treated with a placebo. Therefore, the improvements the EDTA group made were harder earned and more significant. The researchers (who candidly admitted that they undertook the study to convince the Danish government's medical insurance NOT TO PAY for chelation) either never noticed that aspect or felt reluctant to reveal it. The evidence is seen in the pre-treatment MWDs, 119 meters for the EDTA group and 157 meters for the placebo group.

Still more significant was the standard deviations The plus or minus 38 meters SD for EDTA patients versus the plus or minus 266 meters SD for the placebo group represents an enormous variation in walking capacity that is heavily biased in favor of the placebo group. Those standard deviations show that some placebo patients must have walked half a mile before stopping. The placebo group’s claudication was therefore markedly less severe, and the EDTA group was much more severely diseased. The design of the study was obviously biased against EDTA chelation from the outset.

Yet, when the six-month study was completed the mean MWD in the EDTA group increased by 51.3 percent, from 119 to 180 meters, while the mean MWD in the placebo group increased only 23.6 percent, from 157 to 194 meters. The chelation group’s improvement was therefore more than twice as great as the placebo group’s, even though the chelation group was significantly sicker at the outset. This is a positive study, supporting the usefulness of EDTA chelation. The authors’ published negative conclusions are not supported by the data.

The New Zealand Study

Another study--also conducted by cardiovascular surgeons--was done at the Otago Medical School in Dunedin, New Zealand, two years after the Danish study. The subjects of this study were also suffering from intermittent claudication. The subjects were divided into two groups, the EDTA group and the control group. The study extended to three months after 20 infusions of either EDTA or a placebo were given. The authors concluded that EDTA chelation had been ineffective. Once again, that conclusion was unsupported by their data.(86-87)

Absolute walking distance in the EDTA group increased by 25.9 percent; while in the placebo group, it increased by 14.8 percent. The difference was not considered statistically significant. The study, however had only 17 subjects in the placebo group. One of the placebo patients was what the statisticians call an “outlier,” whose results differ strikingly from everyone else in the group. This patient’s walking distance increased by almost 500 meters. All of the statistical gain in the placebo group was due to this one individual’s progress. Without him, the placebo group’s distance actually decreased.  

This illustrates the perils of a small study. The 25 percent gain in the EDTA group compared to no gain in the placebo group would have been very significant statistically.  

In addition, the New Zealand researchers did concede that improvement in artery pulsatility (pulse intensity) in the EDTA group’s worse leg improved enough to reach statistical significance (p<0.001).

 A 25.9 percent improvement in walking is by no means minor and would attract notice if the agent had been a patentable drug. Even that level of improvement is not representative of the much greater improvements claudication patients normally experience after chelation. The below expected improvement seen in this study can be explained by smoking. Eighty-six percent of the chelated subjects were smokers. Although they were advised to quit smoking when the study began, how many of them actually complied is not known.

 The Heidelberg Study

 Another study that was carried out with an erroneous negative conclusion is the “Heidelberg Trial,” funded by the German pharmaceutical company Thiemann, AG in the early 1980s. A group of patients with intermittent claudication were given 20 infusions of EDTA and compared with a so-called “placebo” group which was actually given bencyclan, a pharmacologically active vasodilating and antiplatelet agent owned by Thiemann.

From a practical commercial standpoint, Thiemann’s action was bizarre. If EDTA did well in the trial, Thiemann’s well-established drug could only suffer. Nonetheless, the trial went forward and was reported in 1985 at the 7th International Congress on Arteriosclerosis in Melbourne, Australia.(87) Immediately following 20 infusions of EDTA the trial subjects’ pain-free walking distance increased by 70 percent. By contrast, patients receiving bencyclan increased their pain-free walking distance by 76 percent. The difference between these two results was not statistically significant, but another result was. Twelve weeks after the series of infusions was completed, the EDTA patients’ average pain-free walking distance had continued to increase, going up to 182 percent. No further improvement had occurred in the patients receiving bencyclan. Those percentages were never published.(87)

An informal report from Thiemann mentioned only the 70 and 76 percent figures. Press releases stated that chelation was no better than a placebo, but failed to mention that the “placebo” was a drug that had been proven effective in the treatment of intermittent claudication. Thiemann never released the actual data on which the Heidelberg Trial based its conclusions, but some German scientists who had access to it, and who were disturbed at the deception they were witnessing, chose to reveal the complete raw data to members of the American scientific community.

The complete data showed that four patients in the EDTA group experienced more than a 1,000-meter increase in their pain-free walking distance following treatment. That highly significant data from those four patients mysteriously disappeared before the final results were made public. Thiemann had a legal right under terms of their contract to edit the final results and to interpret the data in any way that suited them. A subsequent analysis of the data, with the four deleted patients included, showed an average increase in walking distance of 400 percent in the EDTA treated group--five times the 76 percent increase of the group receiving bencyclan.(89)

The Kitchell-Meltzer Reappraisal

A dark moment for chelation research occurred in 1963, when Drs. J.R. Kitchell and L.E. Meltzer co-authored an article reassessing their support for EDTA chelation.

Although it was hardly in widespread use in 1963, chelation had not been controversial. Beginning in 1953, Norman E. Clarke, Sr., M.D., a prominent cardiologist and Chief of Research at the Providence Hospital in Detroit, began using EDTA chelation to treat coronary artery disease. In 1956 he treated 20 patients suffering from heart disease with angina pectoris. He reported that 19 of the 20 patients who received EDTA had a "remarkable improvement" in symptoms.(1)

Soon other physicians became interested, among them Kitchell and Meltzer, at Presbyterian Hospital in Philadelphia. From 1959 to 1963, Kitchell and Meltzer reported good results treating cardiovascular diseases with EDTA. Their early reports were all very positive.(7,10,14)

In April of 1963, shortly after their last favorable report, Kitchell and Meltzer published a "reappraisal" article in the American Journal of Cardiology that questioned chelation’s value.(75)

In that reappraisal, they reported on ten of the original patients they had treated for cardiovascular disease, plus another 28 patients that were treated subsequently. Patients in their study were all severely ill. The authors state, " . . . we selected ten patients referred to us because of severe angina. The patients had previously been treated with most of the accepted methods, and their inclusion in this study resulted from wholly unsuccessful courses. Each of the patients was considered disabled at the start of therapy." This was therefore a high-risk group of very sick patients, who had not improved with any other form of therapy.

Seventy-one percent of patients treated had subjective improvement of symptoms, 64 percent had objective improvement of measured exercise tolerance three months after receiving 20 chelation treatments, and 46 percent showed improved electrocardiographic patterns. Kitchell and Meltzer concluded that chelation was not effective because some patients eventually regressed long after treatment. However, considering the poor health of the patients, some eventual worsening would be expected with any treatment. Eighteen months following therapy, 46 percent of the patients remained improved. The results were very favorable, even though the authors’ interpretation was not.

Kitchell and Meltzer’s reappraisal article was largely responsible for termination of hospital-based, academic research into chelation as a treatment for cardiovascular disease. Rather than analyzing the data for themselves, many physicians simply accepted the flawed conclusion at face value. We will probably never know what prompted those early researchers to change their position so abruptly. We can only speculate that it was an unrealistic expectation that the emergence of bypass surgery would be a final solution.

EDTA'S ONLY ACTION IS TO ALTER DISTRIBUTION OF METALS IN THE BODY

Intravenous EDTA enters and exits the body very rapidly. In less than one hour, half has been excreted in the urine unchanged except for metal ions it attracts enroute. Half-life in the body with normal renal function is approximately 45 minutes.

[Note:  Whenever an atom has fewer electrons than protons, it's called an ion.  Click for definitions.]

EDTA does not otherwise enter chemically into metabolic pathways. The EDTA molecule is not degraded or altered. Its only action in the body is to rapidly and reversibly attract, chelate and redistribute metal ions, or remove them from the body. When EDTA binds a specific metal, and subsequently encounters another ligand (a metalloenzyme, for example) with stronger affinity, that metal ion is dropped and another is substituted. In that way a shuffling and redistribution may occur without actual removal from the body. To be plausible, a scientific rationale for mechanism of action must be based on that type of activity, and must also explain why full benefit does not occur for several months after therapy.

[Karl Note:  I have more research and writing to do on "ions" but an "ion" is generally an unstable form of an atom -- it has either a negative or a positive charge, and can "do stuff."  Atoms are usually "neutral" -- then not called "ions."  To whatever extent some metal in your body is NOT in the form of an ION, EDTA will not be attracted to it, and it will not be particularly dangerous.]

[Karl Note:  EDTA is a very powerful chelator.  However there are other chelating substances including Cysteine and N Acetyl Cysteine.  These bind to metals in a different way than does EDTA.  For instance, you'll find, below, that EDTA does not remove mercury from the body because the "bindings" which are already attached to mercury are too strong to allow the EDTA to "chelate" it.  However, Cysteine has the peculiar property of 'Unbinding" mercury from its location -- usually the mercury is stuck "like a sliver" into some tissue within the body.  Cysteine "unsticks" (the technical term is "unbinds") the small piece (it could be a few molecules -- these are small items!) of mercury and then continues to chelate it -- meaning to carry it out of the body.  Since Cysteine is a natural amino acid, found in food, it does NOT leave the body as rapidly as does EDTA, but once it is connected to metal, it does leave, and thus a chelation formula that includes several different chelating substances is inherently better than a chelation process that relies on only one substance -- EDTA.

Note also that Dr.  Cranton is one of the foremost "authorities" on the web who claims that when EDTA is taken orally it is useless (even harmful) as a chelating substance.  I, Karl Loren, strongly disagree with this.  Click here to read Dr. Cranton's explanation of why "oral EDTA" is not a valid treatment option.  Click here for the truth of the matter.]

Cellular metabolism relies on 50,000 or more different enzyme catalysts, many of which are metalloenzymes, requiring the presence of a specific metallic trace element for activity. In excess, all essentials trace elements are toxic, poisoning those enzymes. As discussed below, nutritional trace elements can increase to potentially toxic levels in diseased tissues. Realignment of essential trace elements with augmentation of vital metalloenzymes may be as important to benefit as elimination of free radical catalysts and toxic heavy metals.

[Karl Note:  Dr. Cranton uses, here, a phrase I've not been familiar with.  He uses the term "free radical catalyst" to describe the creation of new free radicals because one has hit toxic heavy metal.  He still leaves out of his descriptions, however, that not only is heavy metal a "catalyst" but it accelerates the production of free radicals.]

One nutritional element, iron, accumulates with age to act as a catalyst of oxygen radical proliferation, commonly referred to as free radicals. Free radical pathology is a causative factor in age-related diseases. EDTA has a high affinity for that potentially catalytic form of iron, and removes it from the body.

A number of heavy metals are toxins with no known metabolic function, such as lead and cadmium. They poison enzyme activity directly. EDTA also removes those metals from the body.

It is not yet known which action is most responsible for clinical benefit. Most likely, it is a synergistic combination. In light of recent scientific advances, a number of theoretical possibilities will now be discussed in more detail.

Cell-Senescence Model of Aging and Trace Metals

The cell-senescence model (sometimes called the telomere theory) of aging is hypothesized to underlie almost all aspects of age-related disease, including atherosclerotic cardiovascular disease.(90,91,92) As cells continuously die and are replaced with daughter cells, accuracy of gene expression progressively deteriorates. Replacement cells, produced by cell division and DNA replication, grow increasingly weaker. With each replication, accuracy is lost and subsequent generations of cells reflect that deterioration.

Telomeres on chromosomes shorten with each successive cell division, eventually becoming spent. After 50 divisions, cells reach the so-called Hayflick limit; telomeres become fully depleted and those depleted cells lose their ability to divide further. Without telomere replacement, cell death results.

[Click here for a more simple explanation of the Hayflick Limit, "senescence," "telomere" and related terms.]

There is more to the story that that. Progressive telomere shortening throughout life also correlates with cell senescence, leading to gradual but progressive deterioration through multiple generations of daughter cells. When cell deterioration is sufficient to cause impairment in organ function, age-related disease results. Cells also divide and heal more slowly with each successive division.

It was once thought that only the absolute limit of cell division was important, when telomere length was totally depleted. We now know that as cells divide and telomeres shorten, cumulative inaccuracies in DNA replication cause progressive deterioration of gene expression. This results in cell senescence.

Two types of cells that do not senesce are germ cells and cancer cells, both of which contain telomerase, an enzyme that restores telomeres with each division. They are thus called immortal cells. If other types of cells, such as fibroblasts, are genetically modified in culture to contain telomerase, they also become immortal and do not senesce. Cell senescence is not only reversed, but aging ceases in cells that produce telomerase, even after 400 or more subsequent divisions.(93)

[For a more simple explanation of "telomerase" and related terms, click here.]

Endothelial cells in blood vessel walls, lacking telomerase, therefore deteriorate with each cell division.(94) With progressive telomere shortening, cell division and replacement slows and the healing process is retarded. Replacement endothelium becomes increasingly weaker and defective with each division. Cells subjected to frequent trauma and injury divide more frequently and therefore age more rapidly.

[Endothelial cells are those cells which line the inner surface of the artery (and capillary).]

When endothelial cells are injured and replaced by adjacent cells, daughter cells are produced to fill in the gap. Damage to endothelia occurs with sheer stress at points of bifurcation, from hypertension, infection, toxins, tobacco byproducts, hyperglycemia, oxygen radicals, oxidized LDL cholesterol, and autoimmune processes. Endothelial cells become most disrupted at points of greatest stress, and divide most frequently at precisely those locations where atherosclerosis prevails. The cell senescence model thus accommodates and provides a broadened explanation for all known risk factors of atherosclerosis.

Senescent endothelial cells divide at a progressively slower rate and are progressively less effective at closing breaches in arterial walls. The resulting exposure of denuded subendothelial tissues triggers a cascade of events that encompasses all other theories of causation: monocytes and platelets are attracted and adhere to damaged areas; monocytes transform into macrophages; a variety of trophic factors and mitogenic factors, including cytokines and platelet-derived growth factor, are released locally; smooth muscle cells proliferate; oxidized lipids accumulate in macrophages; and, eventually this enlarging plaque calcifies or ulcerates.

[Karl Note: The word "senescent" means "old."  Click here for an excellent description and for definitions of some of the other words used by Dr. Cranton.]

An underlying cause of this chain of events is now postulated to be the progressive telomere shortening in endothelial cells at points where they are most often called upon to divide. This occurs at arterial sites most subject to damage and therefore to plaque formation.

[Karl Note:  It almost appears that Dr. Cranton is still describing "plaque" as something built up ON the inner lining of the artery, within the inner channel where blood flows -- RATHER than INSIDE the cells he is talking so much about.  It is a very small shift in viewpoint that he requires to see the whole story.]

Cell types that divide frequently throughout life are precisely those cells that show decline with age. Skin cells and cells in hair follicles are frequently replaced throughout life. Resulting deterioration is plainly visible to the naked eye, to the extent that a close estimate of chronological age can be made at a glance. Cell types that divide frequently throughout life and therefore age at predictable rates include chondrocytes, fibroblasts, keratinocytes, microglia, hepatocytes, and lymphocytes. Associated DNA mutations and diminished immune function can act as initiating events in cancer.

Rare or absent division of neuronal cells seems to contradict this theory, since brain function so often declines with age. Astrocytes in the brain, however, continue to divide throughout life and are prominent in the early inflammatory stages of Alzheimer’s dementia. Neurons make up only 10 percent of brain cells.

The cell senescence model supports a conclusion that cell division and telomere shortening are central to cell senescence, and thus to diseases of aging.

To help explain the benefits of EDTA within the cell senescence model, it is only necessary to consider the extensive biochemical pathways involved in cell division and replication require a very large number of metalloenzymes--as many as ten thousand or more different metalloenzymes. For example, DNA-dependent RNA polymerase, an enzyme involved at an early stage of cell replication, is zinc-dependent. Other enzymes needed for cell replication require the entire spectrum of essential nutritional minerals and trace elements. EDTA has its only known effect on those metallic ions--binding, redistributing and removing them.

Frustaci and coworkers in Italy recently published data showing that essential trace elements accumulate to potentially toxic levels in diseased tissues. Essential elements all have the potential to be toxic in excess. Ischemic myocardium accumulates a spectrum of essential, nutritional trace elements to high levels, when compared with myocardial cells of healthy, young control subjects: cobalt increases 500 percent; chromium increases 520 percent; iron increases 400 percent; and zinc increases 280 percent.(95) Metallic trace elements have a narrow margin between normal and toxic levels.

Three- to four-fold intracellular elevations with ischemia may poison cellular metabolism. Toxic metals also increase in ischemic myocardium, but less than the essential elements. It is thus possible that EDTA chelation therapy benefits by restoring a more normal distribution of essential metallic elements within the body. This action may be as important or even more so than enhanced renal excretion of toxic meals. We are still not sure of the most important mechanism of action.

Apoptosis (Programmed Cell Death) and Trace Metals

When intracellular stresses reach a critical threshold, permeability transition pores (PTP) open in mitochondrial membranes and holocytochrome-C is released. The combination of holocytochrome-C with d-ATP then triggers cellular damage and death. That process is termed apoptosis. Cells become increasingly susceptible to apoptosis with each successive DNA replication and cell division, adding support to the cell-senescence model introduced above. When free oxygen radicals reach high enough levels, apoptosis occurs. Formation of a specific protein, called BAX protein, also opens the PTP, and triggers apoptosis.(96,97) Synthesis of BAX protein depends on enzymes that require trace elements as cofactors. Metals in excess can poison metabolism at many different points or trigger apoptosis directly. Every step in the process of apoptosis involves metal-sensitivite enzymes, and it is on those metals that EDTA has its only known action.

Free Radical Causes of Degenerative Disease

The field of free radical biochemistry is as revolutionary and profound in its implications for medicine as the germ theory was for the science of microbiology. It has created a new paradigm for viewing the disease process. Emerging knowledge in this field gives us a compelling scientific rationale for treatment and prevention of major causes of long-term disability and death with EDTA chelation therapy.(98-107)

Detection and direct measurement of free radicals has only recently been possible.(108-110) Although not yet fully understood, recent discoveries in the field of free radical pathology, in combination with the cell senescent model and apoptosis, lead to a coherent and elegant scientific explanation for many of the reported benefits following EDTA chelation therapy.

Properly administered intravenous EDTA, together with a program of applied clinical nutrition and modification of health-destroying habits, act synergistically to prevent free radical damage.

What are Free Radicals?

A free radical is a molecular fragment with an unpaired electron in its outer orbital ring, causing it to be highly oxidative, unstable, and to react instantaneously with other substances in its vicinity.(111,112) The half-life of biologically active free radicals is measured in microseconds.(100) Within a few millionths of a second, free radicals have the potential to react with and damage nearby molecules and cell membranes. Such reactions can then produce an explosive cascade of free radicals in a multiplying effect--a literal chain-reaction of damage.(98,101,102,109,113,114)

Free radicals react aggressively with molecules to create other aberrant compounds. Harmful effects of high-energy ionizing radiation (ultraviolet light, x-rays, gamma rays, nuclear radiation, and cosmic radiation) are similarly caused by the free radicals produced in living tissues when photons of radiation knock electrons out of orbiting pairs.(105,115-119)

In a similar way, free oxygen radicals in cells produce damaging lipid peroxides, oxyarachidonate and oxycholesterol products.(98,119-122) Oxidized cholesterol is toxic and contributes to atherosclerosis. Lipid peroxides can trigger chain reactions, accelerating a further cascade of damaging free radical reactions. Protection against free radicals is achieved from dietary, supplemental and endogenous antioxidants.(98,99,101,102,103,106,121,123,124)

Ongoing free radical reactions in normal cellular metabolism occur continuously in all cells of the body and are necessary for health.(98-103,105-107,125-128) Mitochondrial oxidative phosphorylation produces free radicals during the ongoing production and storage of energy as adenosine triphosphate (ATP) from mitochondrial oxydation. These normal and essential free radical reactions are contained and damage is prevented if adequate antioxidant protection is available. The highly reactive free radicals continuously produced within healthy human cells include hydroxyl radicals, superoxide radicals, and excited or singlet-state oxygen radicals. They are commonly referred to collectively as "free oxygen radicals," or often as simply "free radicals."(99-107)

When free radicals react in the body they in turn produce other highly reactive molecules, including hydrogen peroxide, lipid peroxide, and other peroxides. Peroxides are metastable, highly reactive, corrosive molecules and also react rapidly, producing additional organic radicals in surrounding tissues.(111,112)

To prevent uncontrolled propagation of free radicals, cells normally contain a dozen or more antioxidant control systems that regulate the many necessary and desirable free radicals present.(98-106,109,110,116,121,123,129-134) Those control mechanisms include endogenous enzymes, such as catalase, superoxide dismutase, and glutathione peroxidase. Free radical regulation also depends on nutritional antioxidants such as vitamins C and E, beta-carotene, coenzyme Q-10, and the trace element selenium. In fact, almost all vitamins, including the B vitamins, play a role in antioxidant protection.

[Karl Note:  It seems to me that in the above paragraph Dr. Cranton is revealing somewhat of a blind spot in his work.  He is acknowledging the obvious role of various vitamins in neutralizing free radicals.  This could well have been the spot where he could have also acknowledged that there are "chelating substances" in addition to EDTA, and to at least mention them -- Cysteine and N Acetyl Cysteine.  It would not be "necessary" for the author of a textbook on "EDTA Chelation" to mention the competition, but it would have been the better thing to do, I think.]

When functioning properly, antioxidant systems suppress and control excessive free radical production, allowing oxidative energy metabolism to proceed normally without cellular or molecular damage. When those control systems are weakened, free radicals multiply out of control, much like a nuclear chain reaction, disrupting cell membranes, damaging enzymes, interfering with both active and passive transport across cell membranes, and causing mutagenic damage to nuclear DNA. This is one cause of cancer.(102,109,113,114,120,121,135,136)

[Karl Note: There is a concept of "free radical multiplication" that is not being covered here.  The "chain reaction of free radical creation" is well known.  One free radical hits "something" and is neutralized, but the "something which was hit then becomes a new free radical. This continues. This is the chain reaction so well publicized about free radicals.  Dr. Cranton hints at the speed with which this happens -- indicating that a free radical might well create one new free radical  within One Millionth of a second!  What is NOT mentioned here is the possibility that when ONE free radical hits (rather than "something") some heavy metal, that instead of ONE new free radical being created many, perhaps thousands are then created!  I refer to this as "accelerated multiplication of free radicals" because of the existence of heavy metals in the body.  The role of METALS in free radical multiplication is critical to understanding heart disease since heart disease DID NOT EXIST several hundred years ago, since "normal" free radical multiplication DID EXIST, and since the presence of heavy metals in our bodies is ALSO a new phenomenon.  People did NOT have heavy metals in their bodies several hundred years ago, simply because our environment had not yet contained them.]

Concentration of the free radical control enzyme, superoxide dismutase (SOD), in mammals is directly proportional to life span. Humans have the highest concentrations of SOD. SOD is the fifth most prevalent protein in the human body.(101,102) Elephants, parrots and other long-lived species also have high levels. Thus, life expectancy seems to be highly dependent on effective free radical regulation.

Nonenzymatic free radical scavengers are stoichiometrically consumed on a one-to-one ratio when neutralizing free radicals. These include beta-carotene (provitamin A), vitamin E, vitamin C, glutathione, cysteine, methionine, tyrosine, cholesterol, some corticosteroids, and selenium. Once neutralized, other vitamins and enzymes are necessary to restore antioxidant activity, but they must all be present in adequate amounts.

Enzymes involved in free radical protection are proteins, but also require nutritional metallic trace elements or vitamins as co-enzymes. For example, copper, zinc, and manganese are all essential for superoxide dismutase activity; selenium is essential for glutathione peroxidase; and iron is necessary for catalase and some forms of peroxidase. Tens of thousands of different enzymes in the body depend on vitamins, trace elements and minerals to function. Optimum dietary intake of those nutrients is therefore necessary for protection against free-radical mediated, age related diseases. Recent epidemiological studies show that it is difficult to receive optimal amounts from food alone, without supplementation.

Identifying Free Radicals

Free radicals exist in very low, steady-state concentrations. They rarely reach levels high enough for direct analysis.(98,102) Sophisticated instruments have only recently become available that allow us to recognize the importance and extent of free radical damage in tissues. Electron paramagnetic resonance spectroscopy (EPR) is one type of technology now used.(109,110) Free radicals can be estimated most easily, and perhaps even more accurately, by analyzing end-products of free radical reactions, using gas chromatography, mass spectroscopy, and high-performance liquid chromatography. Cross-linkages between molecules, damaged collagen, lipid peroxides, oxyarachidonate, oxidized cholesterol, lipofuscin, ceroid, and increased pigment can all be caused by free radical reactions. Those substances can more easily be measured.(98,101,102,110,137,138)

By sifting through the molecular wreckage left in the wake of evanescent free oxygen radicals, it thus becomes possible to indirectly estimate the type and extent of ongoing free radical reactions. For example, free radical damage in the brain and central nervous system (CNS) can be assessed by the rate of cholesterol depletion. Cholesterol is not otherwise metabolized in the nervous system. The only way for cholesterol to decrease in the CNS is through oxidation caused by free radicals. Cholesterol acts as an antioxidant and is consumed in the process.(101,102,139,140)

Cholesterol Metabolism

As a free radical scavenger, cholesterol is liberally disbursed throughout cell walls and lipid membranes in the body. Contrary to the popular notion that cholesterol is harmful, it actually protects cell membranes--if it has not previously become oxidized in the process of neutralizing a potentially harmful free radical.(110,139) Unoxidized cholesterol is one of the body's important antioxidant defenses. Some of the cholesterol-derived steroid hormones, including glucocorticosteroids, dehydroepiandrosterone (DHEA), pregnenolone, testosterone, progesterone, and estrogen, can also function as free radical scavengers.(110) Those substances decline steadily with age, inversely related to the incidence of age-associated diseases.

Cholesterol is a precursor to vitamin D. Vitamin D is normally produced in the skin by exposure of cholesterol to ultraviolet radiation from sunlight. Without cholesterol, vitamin D deficiency may occur. Ultraviolet light is a form of ionizing radiation that can also produce free radicals in the skin, leading to sunburn and skin cancer. Unoxidized cholesterol and other antioxidants act to protect the skin.

Total body cholesterol (approximated by measuring blood levels of cholesterol) is derived primarily from cholesterol synthesis within the liver, not from dietary intake.(102) Plasma cholesterol levels increase with free radical stress. Elevation of plasma or serum cholesterol can act as an indicator of exposure to excessive free radicals and increased risk of atherosclerosis and apoptosis. Also, as cholesterol becomes oxidized, in the form of low-density lipoprotein (LDL) cholesterol, LDL receptor sites in the liver and elsewhere are altered, causing increased hepatic synthesis of endogenous cholesterol. An increase in cholesterol thus appears to be a normal physiologic response to free radical stress. Cholesterol is synthesized in the body as needed, and the need is greater to protect those at risk. In Western cultures, where atherosclerosis, cancer, and other free radical mediated diseases are epidemic, blood cholesterol levels commonly increase with age. A problem occurs, however, when the increased cholesterol becomes oxidized, producing its own form of cellular toxicity.

[Karl Note:  The sentence above, in bold type, needs to be shouted from the roof-tops.  I have been saying, for years, that high cholesterol is NOT the cause of heart disease, and that high cholesterol is a sign that something may be wrong.  The artificial suppression of cholesterol with a cholesterol-lowering drug would appear to be very harmful.  Dr. Cranton says all these things, and I do not expect him to do the type of shouting that I do, but I sure would like to see more doctors recognizing the truth of the above, and at least gently mentioning it to their patients, instead of caving in to the misleading and false "cholesterol scare that so much fills our media channels of mis-information.]

After encountering and neutralizing a free radical, cholesterol is oxidized as LDL cholesterol. In oxidized LDL form, cholesterol is toxic to blood vessel walls. If antioxidant protection is diminished, or if free radical production exceeds the threshold of tolerance, oxidized LDL cholesterol thus contributes to atherosclerosis.

A recent multi-country study in Europe, funded by the World Health Organization, showed that low blood levels of vitamin E are statistically 100 times more significant as a predictor of coronary heart disease than are high blood levels of cholesterol.(141). In another report, all published autopsy studies that correlated the extent of atheromatous arterial plaque with levels of blood cholesterol were reviewed. Surgical specimens removed at the time of bypass surgery were also analyzed. After eliminating data from those few individuals with a hereditary form of extremely high cholesterol (above 400 mg/dL), no correlation was found between blood cholesterol levels and the severity of atherosclerosis.(142) The author stated that prior studies falsely concluded that blood cholesterol levels correlated with atherosclerosis because of failure to eliminate those occasional individuals with extremely high cholesterol caused by a lethal genetic mutation.

Less than one half of one percent of the population has a hereditary trait for dangerously high cholesterol. People with that genetic disease have blood cholesterol levels above 400 mg/dL, sometimes much higher. They commonly suffer premature death from atherosclerosis, despite aggressive pharmacological therapy to lower cholesterol. The statements in this section do not apply to people in that group.

Free radicals oxidize cholesterol into a variety of break-down products.(98,100,101,102,110,143,144) Oxidized cholesterol is bound selectively to low-density lipoproteins, referred to as LDL cholesterol, while unoxidized (antioxidant) cholesterol is predominately bound to high density lipoproteins, HDL cholesterol.(101,102) Oxidized cholesterol, bound to small, dense lipoprotein molecules are especially toxic to cells.

Laboratory research at the Cleveland Clinic demonstrated that both EDTA and the antioxidant glutathione prevent LDL cholesterol from becoming toxic.(143)

Oxidized forms of cholesterol possess varying toxicities. (98,102,143-146) Some of those substances have vitamin D activity, which can cause localized vitamin D toxicity in tissues and macrophages.(144) Abnormal calcium deposits in tissues and blood vessel walls may to some extent be caused by localized vitamin D activity at toxic levels.

Free radicals also cause tissue calcification by damaging the integrity of cell membranes, causing leaks in cell walls, and by damaging enzymatic cell-wall transport pumps. If the calcium pump is weakened, or if cell wall integrity is damaged, the calcium pump becomes unable to remove calcium as it leaks in. Intracellular calcium accumulates, causing malfunction and eventually cell death. X-rays of older people commonly show dense calcium deposits in soft tissues that do not normally have that bony appearance. A similar weakening of the sodium pump in cell walls allows an increase of intracellular sodium, leading to swelling of the cell, edema, and eventual cell lysis.

Dietary restrictions of cholesterol and prescription drugs to reduce blood cholesterol have, in some ways, been counterproductive, because the antioxidant role of cholesterol has not been widely recognized. Natural, unoxidized cholesterol is widely dispersed in cell membranes as a protective factor against atherosclerosis, cancer, and other free-radical induced diseases. In this form, cholesterol is not the harmful substance we have been told. Cholesterol is a fat, and dietary cholesterol is consumed in fatty foods. Restriction of dietary cholesterol necessarily results in simultaneous reduction of total dietary fats. Research studies which allegedly show benefit from low-cholesterol diets may have only reflected benefit from reduction in excessive dietary fat and the accompanying lipid peroxides and oxidized cholesterol.

It is not widely known that cholesterol-lowering drugs also have antioxidant and antiplatelet activity.(147) Those drugs also produce significant toxicity and cost much more than antioxidant nutritional supplements.

[Karl Note:  My goodness!   The number ONE selling drug in America is Lipitor -- annual sales in excess of $8 billion!  Isn't it time that people who KNOW the truth speak out a bit more loudly!]

Free radicals cause damage by oxidation. Fats, especially unsaturated fats, are highly susceptible to oxidation, in the same way that cooking fats and oils can easily catch fire on the stove. They ignite (oxidize) easily and burn vigorously. All cells and intracellular organelles are enveloped in easily oxidized layers of unsaturated fat. Damaging oxidation of those fatty cellular and intracellular membranes by free radicals can be prevented in three ways:

 1) By "fire-proofing" lipid membranes with nutritional anti-oxidants;

2) By depriving the fire of fuel by partially restricting dietary fats; and

3) By removing metallic catalysts of free radical proliferation with EDTA chelation therapy (as described in detail below).

These three strategies used together can act synergistically to reverse and slow diseases of aging.

A statistical correlation has been reported between low blood cholesterol and increased risk of cancer.(148) Cancer is caused in part by free radical damage to nuclear material and chromosomes. Free radicals act as both primary initiators and subsequent promoters of malignant change. If adequate unoxidized cholesterol is not present to provide antioxidant activity for nuclear membranes and DNA, an important defense against mutation and cancer can be lost. High fat diets, rich in lipid peroxides, are known to increase the risk of cancer.(98,101,102) However, if antioxidant defenses are reinforced, dietary fats can be protected against and rendered more useful for energy.

[Karl Note:  Almost 100% of the fat that people eat has been heated.  My diet advices suggest that when you eat fat that has never been heated, it is extremely health for you.  RAW butter would be such a fat -- and, of course, raw milk and raw butter have been made illegal in most states.]

Homocysteine Metabolism

Homocysteine can contribute to atherosclerosis in several ways. The higher the homocysteine level, the greater the risk. Free radical production and oxidative stress occur during homocysteine metabolism. (149-153) Homocysteine is a metabolite of methionine, and is normally oxidized by free radicals to become homocysteic acid, a potent stimulator of cell growth and multiplication. (154) In this way, oxidative breakdown of homocysteine can induce proliferation of smooth muscle cells in arterial walls and promote growth of atherosclerotic plaques.(155)

[Karl Note:  My research suggests that high homocysteine is a result of various forms of damage to the system, and not so much a cause of that damage.  I really hesitate to differ with Dr. Cranton -- he obviously has much more technical knowledge than I do!]

Metabolic pathways of homocysteine that cause damage to blood vessel walls involve release of hydrogen peroxide, superoxide radical, and inhibition of glutathione peroxidase.(156) Homocysteine increases the tendency for blood clotting.(157) In addition, homocysteine can speed oxidation of cholesterol, which then becomes bound to small dense LDL particles and is taken up by macrophages to become foam cells in plaque. (158)

Damage to blood vessel walls from elevated homocysteine thus leads to accelerated plaque growth, followed by cholesterol and lipid deposition.(159) Clinical and epidemiological research have shown that atherosclerosis throughout the body correlates directly with blood levels of homocysteine. Elevated homocysteine is a powerful and independent risk factor, as strong or stronger than other well-documented risk factors. (150-152)

[Karl Note: The magic word has been said!  Dr. Cranton refers to "cholesterol and lipid deposition."  That is the traditional view of "plaque," and it is this view which I am contending with in this major article!]

Fortunately, there is an easy solution--vitamin supplementation. Homocysteine is metabolized by enzymes that require vitamins B-6, B-12 and folate as cofactors.(160-161) Increased intake of those vitamins reduces homocysteine levels and atherosclerosis.(162,169) With daily supplementation of B-complex vitamins containing 800 mcg per day of folate, five mg or more of vitamin B-6, and 50 mcg or more of vitamin B-12, even those individuals with a familial trait for excessive homocysteine can correct and prevent potential problems.(162-166)

[Karl Note: Those who are taking my popular oral chelation formula, Life Glow Plus, are getting 400 mcg of Folic Acid, 170 mg of B6 and 165 mcg of B12.  Homocysteine ought not be of any concern to anyone taking Life Glow Plus on a regular basis.]

Essential Free Radical Reactions

Life cannot exist without a balance of carefully regulated free radical reactions. Life in the presence of oxygen requires antioxidant protection--fire proofing, if you will. Cellular respiration involves transfer of electrons across mitochondrial membranes within cells. For every such electron, a superoxide radical is produced. Antioxidants must be present prevent damage to vital intracellular structures during this process. Humans cannot utilize food for fuel without such ongoing oxidation-reduction reactions, which in turn produce free radicals as a byproduct. Oxygen is breathed in through the lungs and transported in the blood to every cell in the body, where oxidation reactions produce life-supporting energy. Red blood cells also produce free radicals during the binding and release of oxygen and carbon dioxide by hemoglobin.

Superoxide radicals are released during oxidative phosphorylation of ATP. Cellular protection from those superoxide radicals is provided by mitochondrial superoxide dismutase(SOD), a manganese-containing enzyme. The average American diet contains suboptimal amounts of manganese.(170) SOD in the cytoplasm of cells requires both zinc and copper for activity. Those trace elements are also marginal to deficient in the average American diet.(170) If the integrity of cell membranes is not protected by adequate SOD, then the activity of other vital enzymes contained within those cell membranes will be compromised.(171)

The metabolic degradation of many chemicals, including most prescription drugs, artificial colorings and flavorings, petrochemicals, and inhaled fumes, takes place in the endoplasmic reticulum of cells, most importantly in the liver. That detoxification process releases hydroxyl free radicals and peroxides.(98,101,102,125-127) Glutathione peroxidase, vitamin C, and a wide variety other antioxidants must be present in adequate supply to prevent chain reactions of damaging free radicals Drugs and other chemical exposures thus cause increased production of free radicals, which may then exceed the threshold of antioxidant protection.(98,101,102) The resulting excess of free radicals can also multiply further, in a chain reaction, magnifying the damage by up to a million times or more.(98,102)

Synthesis of prostaglandins and leukotrienes from unsaturated fatty acids also involves release of free radicals.(102,106,128) Lacking sufficient antioxidant protection, prostaglandin production becomes unbalanced. Thromboxane increases and prostacyclin decreases in the presence of lipid peroxides.(98,101,102) Thromboxane is associated with atherosclerosis while prostacyclin acts to prevent arterial plaque.

Leukocytes and macrophages normally produce free radicals. Disease-causing organisms and foreign material are ingested and destroyed by free radicals during phagocytosis. Leukocytes use free radicals much like "bullets" against an invading army.(172,173) Antioxidants localize and limit the damage caused by those free radicals. If antioxidant protection is exceeded, free radicals migrate into adjacent tissues and produce inflammation, manifested by redness, heat, pain and swelling.

Without antioxidant enzymes, we would die very quickly. And antioxidant defenses decease with age.(98,101,102) An extreme example of accelerated aging is the disease known as progeria, caused by hereditary absence of free-radical protective enzymes. Within ten to fifteen years after birth, a victim of that genetic mutation can experience every aspect of the aging process, including wrinkled, dried, and sagging skin, baldness, bent and frail body, arthritis, and advanced cardiovascular disease. Administration of antioxidant supplementation has successfully slowed one form of progeria. Heredity determines each individual's unique resistance to free radical mediated disease. Familial differences therefore result in a wide variation in tolerance to dietary and life-style stresses that increase free radical production.

Oxygen Toxicity

The process leading to free radical pathology is often referred to as "oxidative stress." Ground state or unexcited atmospheric oxygen has the unique property of being both a free radical generator and a free radical scavenger.(98,102,174,175) Although a liter of normal atmospheric air on a sunny day contains over one billion hydroxyl radicals,(122) oxygen at normal physiologic concentrations in living tissues neutralizes more free radicals than it produces.(176) When oxygen concentration falls below normal, as occurs with diseased arteries and ischemia, oxygen becomes a net contributor to free radical production.(101,102,177)

Oxygen in excessive concentrations for prolonged periods of time can cause toxicity and even death, primarily by free radical damage to the lungs and brain. Under proper conditions, however, intermittent high-pressure oxygen, administered for short periods in a hyperbaric chamber, can stimulate an adaptive increase of intracellular superoxide dismutase, an enzymatic antioxidant.(175,178) Too much or too little oxygen can be equally harmful. Hyperbaric oxygen should be administered in short, pulsitile exposures, to stimulate an adaptive increase in antioxidant defenses without causing harm. Hyperbaric oxygen therapy enhances the benefits of EDTA chelation therapy.

Protection Against Oxygen Free Radicals

Normal oxygenation of tissues strengthens defense against free radicals. Aerobic exercise stimulates blood flow and improves oxygenation. Improved oxygenation during exercise thus acts to protect against free radicals and reduces free radical related disease.

Antioxidant metalloenzymes require trace elements to function. Mitochondrial SOD contains three atoms of manganese. Each molecule of cytoplasmic SOD contains two atoms of zinc and one atom of copper. Each molecule of glutathione peroxidase contains four atoms of selenium. Catalase and peroxidase contain iron. Elemental selenium is an antioxidant, independent of its function as an enzyme co-factor.(102)

The human body lacks an intrinsic defense against a major destructive free radical precursor--excited state singlet oxygen. When superoxide radicals exceed a concentration that can be neutralized by SOD, they spontaneously convert to singlet oxygen. Polynuclear aromatic hydrocarbons and aldehydes, found in tobacco tar and tobacco combustion, produce singlet oxygen. The most important protection against singlet oxygen is dietary intake of beta-carotene; a precursor form of vitamin A.(179-183) Epidemiological evidence correlates increased dietary beta carotene with reduced incidence of cancer. Fully formed retinoid vitamin A lacks that protective activity.(101,102)

When beta-carotene is inactivated by free radicals it must be re-activated by other antioxidants, including vitamin C. Vitamin C is inactivated in the process. Cigarette smoke depletes vitamin C. If smokers are given beta-carotene, the oxidized beta-carotene further depletes vitamin C and other antioxidants. It is therefore important to supplement with a full spectrum of antioxidants and micronutrients simultaneously. In one study, an increase in lung cancer was reported when beta-carotene alone was given to smokers. If beta-carotene and vitamin C are not supplemented simultaneously, beta-carotene alone might worsen a preexisting deficiency of vitamin C. That would explain the seemingly paradoxical report of increased cancer with beta-carotene supplementation. Many different antioxidants work together in harmony. An antioxidant is inactivated when it encounters a free radical, and must in turn be reactivated by the next antioxidant in a cascade--a multi-step process.(184-187) All antioxidants must be present simultaneously for optimal protection.

Vitamin E (tocopherol), vitamin C (ascorbate), beta-carotene, glutathione, selenium-containing glutathione peroxidase, riboflavin, niacin, and a spectrum of other antioxidants are all interrelated in a recycling process that protects against free radicals. If all of those antioxidants are present in optimum amounts, they are continuously recycled back into their active forms, after being inactivated by free radicals.

The process proceeds as follows: vitamin E and beta-carotene neutralize a free radical by becoming oxidized to tocopherol quinone and oxidized beta-carotene. Tocopherol quinone and oxidized beta-carotene are returned to their antioxidant forms of vitamin E (tocopherol) or reduced beta-carotene by vitamin C or co-enzyme Q-10, which are oxidized in the process. Oxidized vitamin C is dehydroascorbate. Interestingly, the ratio of ascorbate to dehydroascorbate diminishes progressively with age and no species survives when that ratio falls below one to one.(102) A protective ratio can be restored and maintained despite advancing age with supplementation.

Inactive vitamin C (dehydroascorbate) is reactivated by reduced glutathione, which in turn is recycled by glutathione peroxidase (containing selenium). Glutathione peroxidase is returned to its active form by the vitamin-B2-dependent (riboflavin-dependent) enzyme, glutathione reductase. Glutathione reductase is reactivated by a vitamin-B3-dependent (niacin-dependent) enzyme, NADH, which is oxidized to become NAD. NAD is then metabolized in an elaborate electron transport system, passed from step to step down the carboxylic acid (Kreb’s) cycle. Potentially destructive energy originating as a free radical is thus redirected to useful metabolism. Subsequent steps in energy metabolism require virtually every nutritional vitamin, mineral and trace element.

This stairstep cascade of oxidation-reduction pathways demonstrates that each component depends on an adequate supp1y of all other components in the chain.(124) A chain is only as strong as its weakest link. This interdependence explains the sometimes-equivocal results reported from clinical trials supplementing just one vitamin or antioxidant. For years medical scientists have been conducting research by supplementing with only vitamin E, beta-carotene, selenium, or vitamin C. Although results were often positive(180-182), benefits would have been much greater had a full spectrum of essential nutrients been supplemented simultaneously.(184-188) When free radical production exceeds the neutralizing capacity of this antioxidant system, serious damage to cell membranes, protein molecules, and nuclear material (DNA) results.(98,101,102,111,119,121,123)

A comprehensive understanding of free radical defenses provides a rationale for nutritional supplementation with a full range of vitamins and trace elements, in safe amounts and in proper physiologic ratios. Although large amounts of water-soluble vitamins are rapidly excreted, transient elevations in tissues are nevertheless achieved following ingestion, which saturate tissues and provide additional.(102)

An 18-year nutritional study involving thousands of adults, published by researchers at the University of California, Los Angeles, showed that daily intake of a multiple vitamin-mineral supplement containing at least 500 mg of vitamin C could extend average life expectancy by up to six years.(189)

Increased Production of Free Radicals

If free radicals in living tissues exceed safe levels, the result is cell destruction, malignant mutation, tumor growth, damage to enzymes, and inflammation, all of which manifest clinically as symptoms of age-related, chronic degenerative diseases. Each uncontrolled free radical has the potential to multiply by up to a million-fold in a chain reaction, much like a nuclear reaction.(98,101,102,111,119,121,123)

Dietary fats, especially polyunsaturated fats, are potential sources of pathological free radicals. Double bonds on unsaturated fatty acids combine very readily with oxygen to produce lipid peroxides. This may occur both within the body after consumption and while exposed to atmospheric oxygen prior to consumption.

Lipid peroxidation begins when fats and oils are exposed to air, and is speeded by heat. That oxidation process is catalyzed and hence accelerated greatly by metallic ions, especially unbound iron. For example, peanuts crushed to make peanut butter are rich in iron, which is released into the oil when the peanut is disrupted. Iron is a potent catalyst of lipid peroxidation and increases the speed of rancidity of peanut oil by up to a million fold. Oxidized fats and oils are commonly called rancid; however, extensive peroxidation can exist in some oils without a detectable rancid odor or taste.(102) Lipid peroxidation commonly occurs during the manufacture of many foods and cooking oils.(102)

The more unsaturated the fatty acids in oil, the more readily peroxidation will occur. The rate of peroxidation is logarithmically proportional to the square of the number of unsaturated bonds in each molecule. Factors that increase the rate of peroxidation include heat, oxygen, light, and presence of unbound catalytic metallic elements.(102,119) Oils prepared in the dark, at low temperatures, in an atmosphere of pure nitrogen, and with added fat-soluble antioxidants such as vitamin E, would be best for nutritional use.(102) Such oils are not commercially feasible. The alternative is to consume oil-containing foods, such as nuts and seeds, in their natural state, without crushing until chewed and swallowed. Dietary supplementation with insurance doses of antioxidants can help to prevent free radical damage in the body, even when oxidized fats and oils are eaten.

Unsaturated vegetable oils commonly contain trace amounts of iron and other catalytic metals. Such oils are routinely subjected to heat and atmospheric oxygen when foods are fried. That creates a perilous combination. Hence, the admonition to limit consumption of fried foods. Oils used in the manufacture of salad dressings, such as mayonnaise, often contain high concentrations of lipid peroxides. The poorest quality oils are commonly used to produce commercial food products of that type because heavy seasoning masks rancidity.(102)

Hydrogenation of vegetable oils during the manufacture of margarine and shortenings used in baking results in cis- to trans-isomerization. Trans-isomerization alters the three-dimensional configuration of dietary fatty acid molecules from their normal "cis" coils to straightened "trans" configurations. Trans-fatty acids are then incorporated into cell membranes in the place of natural cis forms, weakening the membrane structure and impairing function of imbedded phospholipid-dependent enzymes.(101,102,218,219) Substrate recognition by enzymes used to synthesize cell membranes is not able to distinguish between these two forms.(102)

Phospholipids that compose cell membranes are easily damaged by free radicals, as already explained. Dietary intake of peroxidized fats can initiate that process. The prostaglandin precursors, arachidonic and linoleic acids, are depleted when that occurs, as measured by gas chromatography.(101,102) Cell membranes containing trans-fatty acids exhibit impaired fluidity and increased permeability, which interfere with trans-membrane movement of sodium, potassium, calcium, magnesium, and other substances. Receptors on the cell surface for insulin and other hormones are disrupted.(98,101,102) Damage from trans-isomerization of fatty acids is cumulative with lipid peroxidation.(98,101,102)

Very little attention has been paid to the more important qualities of dietary fats and oils. Emphasis has mistakenly been placed on the ratio of saturated to unsaturated fatty acids, irrespective of lipid peroxidation and trans-isomerization. Contrary to conventional wisdom, unsaturated fats are more toxic than saturated fats.(102) Margarine contains far more peroxides and trans-fatty acids than butter. Moderation of intake of all fats and oils is desirable.(102) It has been shown epidemiologically that margarine consumption is a risk factor for heart disease, contrary to advertisements for preventive benefit.(192)

The quantity and quality of dietary fat is as important or more so than the ratio of unsaturated to saturated fatty acids.(98,101,102) If dietary fats and oils are obtained from fresh, whole, unfractionated, and unprocessed foods, they will be minimally oxidized and will produce healthy cell membranes, with normal cis-fatty acid configurations. They will enhance a normal balance of prostaglandins. Although fully saturated fats are not as easily oxidized, all animal fats contain some unsaturated fatty acids and cholesterol, both of which are subject to oxidation. Animal experiments have shown that as little as one percent of dietary cholesterol consumed in oxidized form can contribute to atherosclerosis. Supplemental antioxidants reduce that risk. (144,145,193)

How much dietary fat and oil can one tolerate without risk? Evidence indicates that between 25 to 35 percent of dietary calories as fat can be both safe and nutritious, if attention is paid to the quality and source of the fat, as described above; and if supplemental vitamins, minerals, and trace elements are taken.(101,102) The more oxidized the fats, the less well they are tolerated. In the United States, an average of 45 percent of dietary calories are consumed as fat, mostly of poor quality, with no consideration for rancidity or trans-isomerization. Half the population takes little or nothing in the way of nutritional supplements. Lipid peroxidation occurs much more slowly when foods are frozen.(102)

Free radical damage contributes to senility, dementia, and other nervous system diseases, including Alzheimer’s and Parkinson's syndromes. The brain and spinal cord contain the highest concentration of fats of any organ. The central nervous system is very rich in highly unsaturated arachadonic and