Alternative Pain Treatments

Autism 2002 Mercury, Heavy Metals...Toxicity

Boyd E. Haley, Ph.D.

Boyd E. Haley is Professor and Chair at Department of Chemistry, University of Kentucky, KY. He graduated from Franklin College in 1963 with a BA in Chemistry-Phyrsics, completed an MS in Organic Chemistry at the University of Idaho, and his Ph.D. in Chemistry-Biochemistry at Yale University Medical Center in 1971. In 1985, he was appointed a permanent member of the National Institutes of Health Biomedical Sciences Section. Dr. Haley is the author of over 114 investigational papers. Since 1997, he is Chairman and full Professor in the Department of Chemistry at the University of Kentucky.

PRESENTATION CONTENTS OF BOYD E. HALEY, PROFESSOR AND CHAIR, DEPARTMENT OF CHEMISTRY, UNIVERSITY OF KENTUCKY

In Vitro studies of pure thimerosal and vaccines with and without thimerosal added as a preservative: Comparison to Hg(II) toxicity.

SUMMARY: Data will be presented comparing Hg2+ and thimerosal toxicity as well as that of vaccines with and without thimerosal added. Aspects of the biochemical mechanisms of these toxicants will be addressed. An extensive evaluation of the potential in vitro toxicity of thimerosal and vaccines containing thimerosal as a "preservative" versus those vaccines not containing thimerosal has been the objective of recent research done in my laboratory. In these preliminary studies pure thimerosal has been shown to be more toxic to enzymes of the central nervous system than Hg2+. Further, vaccines with thimerosal added as a preservative consistently demonstrated in vitro enzyme toxicity that was markedly greater than the non-thimerosal or low thimerosal containing vaccines. We also compared the toxicity of thimerosal to solutions of mercury chloride. The data indicate that thimerosal is usually a more potent toxicant to mammalian enzymes and brain tubulin polymerization than is Hg2+. Additionally, the toxicity of thimerosal to pure enzymes is rapid and does not require break down of the released ethylmercury into Hg2+. Also, the inhibitory profile of thimerosal with enzymes of human brain homogenates is very different from the inhibitory profile of Hg2+. This is further proof that the ethylmercury released from thimerosal has its own inhibitory properties independent of any further break down to Hg2+. It seems chemically sensible that ethylmercury ( CH3CH2-Hg+) could exert its toxic effects by disrupting the internal, hydrophobic located, dithiol linkages (-S-S-) of cystine that are necessary for normal enzyme structural conformations as well as binding to the reduced thiol groups of cysteines (-SH). Such data indicate that Hg2+ and ethylmercury could act synergistically to enhance toxicity.

Additional studies on the killing of human neurons in culture show that thimerosal displays toxicities in the nanomolar range. This supports our enzyme/tubulin observations. Also, recent studies on neurons in culture have demonstrated that only Hg2+ at 10-7 to 10-10 molar concentration, of several heavy metals tested, was capable of disrupting neurite structures by causing the abnormal polymerization of tubulin baring the neurofibrils and leaving a body similar to neurofibillary tangles, a diagnostic hallmark of Alzheimer's disease. This is also in agreement with previous research from our laboratory demonstrating that Hg2+, and only Hg2+, under chelation conditions found in brain tissue could cause the abnormal tubulin behavior observed in Alzheimer's disease. The growth of neurite processes is well known to require the presence of two structural proteins, tubulin and actin. Hg2+ appears to be much more toxic to tubulin biochemical properties than to actin. Thimerosal, in contrast, appears to be about equally toxic to both tubulin and actin. This biochemical difference, along with partitioning vectors, may help explain the toxicity differences observed between Hg2+ versus organic mercuricals such as methyl and ethylmercury. Using vaccines with and without thimerosal added to determine their toxicity to human neurons in culture also follows the biochemical observations. Vaccines with out added thimerosal are much less toxic than vaccines containing thimerosal.

With all toxicants one has to consider synergistic toxicities. In the case of thimerosal there was a reported sensitization to this mercurical by the presence of an antibiotic, tetracycline. We have done preliminary studies with tetracycline and ampicillin one the neuron killing capability of thimerosal. Both antibiotics appeared to enhance the toxicity of thimerosal. This may be due to the interactions of these antibiotics with the heavy metal portion of ethylmercury that may enhance delivery of the toxicant to specific sites in the neurons. This area should be of concern as many infants are placed on antibiotics. It would be important to evaluate this aspect of thimerosal toxicity with additional research.

INTRODUCTION: Mercury is a known neurotoxin and its mechanism of neurotoxicity has been studied in our laboratory for the past 10 years. To determine the relative toxicity we used two different biological testing systems: (i) brain homogenates and (ii) a mixture of four purified mammalian enzymes. In human brain homogenates we had earlier observed that mercuric ion rapidly inhibited tubulin viability at low micromolar levels but was less toxic to actin. Both tubulin and actin are polymerizing proteins that are actively involved in neurite growth cone activity. In contrast, vaccines containing thimerosal inhibited both tubulin and actin viability. This would indicate that thimerosal has the potential to be much more damaging to neurite development than equivalent levels of mercuric ion. It is therefore my hypothesis that thimerosal rapidly releases ethyl-mercury which most certainly could interfere directly with neurite growth and neuronal development in infants through inhibition of several dithiol and thiol-sensitive enzymes/proteins. Below I will present my interpretation of this research and that from other laboratories that focus on the potential toxicity of injected thimerosal in the vaccine mixture.

PRESENTATION CONTENTS: Thimerosal, and other compounds containing a similar thiol-organic mercury group, are widely known to be especially potent neurotoxic agents. The toxicity results we obtained were not at all unexpected since our results are very consistent with the previously reported toxicity of thimerosal containing vaccines versus non-thimerosal containing vaccines as observed in cell culture studies reported in 1986. The chemical rationale for the neurotoxicity of thimerosal is that this compound would release ethylmercury as one of its breakdown products. Ethylmercury is a well-known neurotoxin. Further, combining thimerosal with the millimolar levels of aluminum cation plus significant levels of formaldehyde, also found in these vaccines, would make the vaccine mixture of even greater risk as a neurotoxic solution. The synergistic effects of mercury toxicity in the presence of other heavy metalS (Pb, Cd, Zn) is well established in the literature (see below).

Exposing infants who are ill and do not have fully developed bilary (liver) and renal (kidney) systems to a vaccine mixture could greatly increase the toxic effects compared to that observed in healthy adults. The toxic effects of exposure to thimerosal in infants cannot be reasonably compared to those observed in adults made toxic by exposure to similar ethylmercury or methylmercury containing compounds. Mercury is primarily removed through the bilary system and aluminum is removed by the renal system. Inability of the infant to rid the body of these toxicants would greatly increase the damage they are capable of doing.

The necessity of using an anti-microbial "preservative" in vaccines to prevent contamination is obvious and acceptable. However, using a "preservative" that breaks down into a well-known neurotoxin does not appear well thought out. Especially when infants are given multiple thimerosal containing vaccinations during one office visit. Toxicity is determined by units of toxicant per unit body weight. So, if a 10 pound baby was given 4 vaccinations this would result in the equivalent of a 150 pound adult receiving 60 vaccinations in one day. This appears to happen with a great deal of regularity in practice and steps should be taken to recommend against this procedure.

One fact that has become extremely obvious to me during this past 11 years is that it is impossible to determine the exact toxic level of mercury or mercury containing compounds that is safe for all humans. There are several reasons why mercury should not be considered safe for humans at the measurable levels currently reported as "safe" by current government monitoring agencies. First, ethylmercury has its own toxic properties and does not have to break down to Hg2+ to be toxic. Therefore, to evaluate the toxicity of thimerosal delivered mercury levels by comparison to the toxicity levels of elemental mercury is scientifically invalid. Further, each human would likely have a level of toxicity from other mercury and non-mercury containing sources. These environmental toxicants could work synergistically with ethylmercury rendering the ethylmercury much more toxic than it would be in the absence of these other toxicants (e.g., elemental mercury from dental amalgams, cadmium from smoking, lead from paint and drinking water, aluminum, etc.). Humans are not rats in a pristine cage, eating rat chow carefully prepared to eliminate any toxicants. Humans smoke, drink alcohol, have numerous mercury emitting amalgam fillings, eat questionable food, and drink water known to contain other toxicants. Our laboratory has tested the toxicity in vitro of the combination of elemental mercury with some of the other toxicants. The data, not unexpectedly, shows a great increase in toxicity of equally added amounts of mercury. Our results are supported by prior research that demonstrated that a mixture of mercury and lead at LD-1 levels of each metal produced a mixture with an LD-100 effect, at least 50 times the additive effect minimally expected (Schubert, J., Riley, E.J. and Tyler, S.A., Combined Effects in Toxicologyendash;A Rapid Systematic Testing Procedure: Cadmium, Mercury and Lead. J. of Toxicology and Environmental Health, 4:763-776, 1978). Therefore, it is impossible to state the toxic effect of an injection of thimerosal unless one knows the toxic exposure of the individual to other heavy metals or other environmental toxicants, or perhaps the properties of the antibiotic given simultaneously.

The detrimental effect of any specific level of mercury or mercury containing compound would have on any one individual's metabolic system would be directly proportional to both the level of "protective bio-compounds" (e.g., glutathione, APO-E, metallothioine) that exist within that person on the time of exposure and, the ability to physiologically clear such toxicants from the body. The level of the protective compounds would certainly be directly dependent on two factors, age and health. Infants, with their immature physiology and metabolism would not be expected to handle mercury as efficiently as mature adults. The elderly have been shown to have decreased "protective" glutathione and melatonin levels compared to middle aged and young adults. The aged are also more susceptible to oxidative toxicants such as mercury. The elderly also have weakened immune systems and are more susceptible to infections that are known to lower the chemical energy levels needed to remove toxicants. This also reduces their ability to synthesize the proteins that protect them from heavy metals. Infants have their own weaknesses regarding toxic exposures. Infants do not make much bile in their early months of life and are unable to remove mercury through bilary transport, the major route for mercury removal. They also do not have a fully developed renal system that would remove other heavy metals as effectively as adults. Therefore, the age factor must always be considered for response to heavy metal exposure as well as spurious microbial infections.

Genetic susceptibility is of critical importance. For example, other researchers have shown that genetic carriers of the brain protein APO-E2 are protected against Alzheimer's disease (AD) whereas genetic carriers of the APO-E4 genotype are at enhanced risk factor for developing AD. APO-E proteins are synthesized in the brain with the assigned physiological task of carrying waste material from the brain to the cerebrospinal fluid, across the blood-brain barrier into the plasma where the material is cleared by the liver. The biochemical difference between APO-E2 and APO-E4 is that APO-E2 has two additional thiol groups, capable of binding and removing mercury (and ethyl-mercury) that APO-E4 does not have. The second highest concentration of APO-E proteins is in the cerebrospinal fluid. Therefore, it is my opinion that the protective effects of APO-E2 is due to its ability to protect the brain from exposure to oxidants like mercury and ethylmercury by binding these toxicants in the cerebrospinal fluid and keeping them from entering the brain. There are physicians looking at APO-E proteins as a risk factor for autism and early reports indicate that a relationship may exist.

One argument I have heard against thimerosal causing autism is the low number of children getting the disease versus the number receiving vaccinations. I think the same argument could have been made regarding acrodynia (Pinks Disease) being caused by teething powder. Perhaps autism will end up like acrodynia, where the removal of the causative material (i.e. the mercury containing teething powders) lead to cessation of the disease and the identification of the cause.

In my opinion, it is the inability to see the effects of chronic, low level toxicities on human health that is most likely our greatest failing as intelligent beings. For example, within the past year two publications in refereed scientific journals have emerged from major foreign research universities demonstrating that mercury, and only mercury, can induce the formation of the two major pathological diagnostic hallmarks of Alzheimer's disease. Mercury does this at nanomolar concentrations. This near or below the levels of mercury found in most reports where human brains have been tested for mercury levels. First, mercury at 10-9M levels has been shown to induce an increase in amyloid protein secretion (the component of amyloid or senile plaques) and to increase the phosphorylation of a protein called Tau {see Oliveri et al., J. of Neurochemistry,V 74, p231, 2000}, and to produce neurofibillary tangles {Leong et al., NeuroReports V12(4), 733, 2001}. All of this was done with neurons in culture and represent observations found and considered diagnostic of Alzheimer's disease. Further, in a very recent article by Dr. Ashley Bush in the journal Neuron it is implied that Alzheimer's disease may be caused by heavy metal buildup. This article focused on removal of zinc and copper by chelation decreasing amyloid plaque formation in rats---mercury was not studied. However, these metals, along with mercury and silver, are the components of dental amalgams. Most of this work is in agreement with data published earlier from my laboratory in refereed articles and summarized in one single article {Pendergrass and Haley, Metal Ions in Biological Systems V34, Cahpter 16, Mercury and Its Effects on Environment and Biology, Siegel and Sigel EDS., Marcel Dekker, Inc. 1996}. This data basically demonstrated that addition of very low amounts of mercury to normal human brain homogenates inhibited critical enzymes (creatine kinase, glutamine synthetase and tubulin) that were also dramatically inhibited in Alzheimer's diseased brain. The straight-forward conclusion is that any exposure to mercury or mercury containing compounds would exacerbate the medical condition classified as Alzheimer's disease and one would even have to consider low level chronic exposure to mercury as a possible etiology for this disease.

It is very difficult to prove that mercury or organic-mercury compounds cause any specific disease that is identified by its related symptoms. This is mostly due to the high numbers of confounding factors presented in the current human environment. However, since infants get autism and related disorders, and many of our aged are afflicted with AD, we know that they have crossed the thin-red line into the neurologically diseased state. There can be no doubt that the purposeful use of mercury in medicine and dentistry, especially if it was prolonged and excessive, would significantly contribute to the onset of their disease.

Academic medicine has searched long and hard without success to identify vectors that cause many of the neurological diseases such as AD, ALS, MS, Parkinson's, etc. The NIH has spent huge amounts of funds on the study of amyloid protein, tau protein and neuro-fibillary tangles in the search for the cause of AD---now it has been demonstrated that mercury at low concentrations can cause neurons in culture to form these protein abnormalities. Exposure of brain tissue to mercury also specifically inhibits other enzymes/proteins known to be inhibited in AD brain. Yet, there has been a paucity of NIH funds spent to study the potential neuro-toxicity of mercury routinely placed in human contact by medicine and dentistry. Further, our regulatory agencies, such as the FDA, routinely dismiss basic research showing the unique toxicity of mercury at very low concentrations and continue to allow the use of this material without testing. Certain organizations routinely use toxic mercury containing materials without experimental proof of their safety. They then argue that damage by mercury has not been "validly" proven as their defense and the FDA buys into this. Common sense implies that safety should be proven before use of toxicants in medicine and dentistry, not after. Common sense implies that the mere presence of mercury demonstrates toxicity at some level. Nowhere was this lack of common sense more evident than in the exposure of infants to thimerosal without prior testing in the recent past vaccine program.



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