Mercury Amalgam Fillings, Chronic Mercury Poisoning, and Mercury Detoxification: Referenced Scientific Studies with Abstracts
In my ongoing research of mercury amalgam fillings, chronic mercury poisoning, and mercury detoxification I have accumulated a wealth of scientific studies on these subjects. The majority of the information consists of studies and articles obtained from journals and medical reference sites. Each article is referenced and an abstract is provided, and where possible, the PIMD number for PubMedindexed for MEDLINEwill be included with the reference. These references can also be found on other medical search engines but most charge a fee for access. (The URL for the PubMed search page is http://www.ncbi.nlm.nih.gov/entrez/query.fcgi)
A great deal of the information I used to develop the ideas and concepts I present in The Poison in Your Teeth: Mercury Amalgam (Silver) Fillings . . . Hazardous to Your Health! and Mercury Detoxification: The Natual Way to Remove Mercury from Your Body came from the articles I’ve included here. If you are skeptical about mercury amalgam/silver fillings being a health hazard, or the extraordinary toxicity of mercury I suggest you read The Poison in Your Teeth and Mercury Detoxification before you review the studies found in my database. These books will provide solid background information, making it much easier to understand and evaluate any subject you are interested in.
While I believe more definitive studies still need to be done in certain areas, much has been learned. Certainly, in my opinion anyway, there is enough available evidence to support the fact that the mercury released from amalgam fillings is indeed a health hazard and they should be banned from being used in dentistry. If you take nothing else away from reviewing the studies I’m presenting, I can guarantee you it will be how extraordinarily poisonous mercury is. That alone should be cause for extreme concern. (The referenced articles are also available for purchase by researchers by going to my website, https://www.dentalwellness4u.com/Merchant2/merchant.mvc?Screen=CTGY&Store_Code=TDWI&Category_Code=RA, for $225.)
Note: If you are a mecury safe dentist and want more information about how to access new patients by establishing a Prominent Internet Presence please visit my Mercury Safe Dentist Internet Directory Website by Clicking Here. Today over 80% of those searching for a Mercury Safe Dentist will find him or her on the Internet. I have the highest Internet ranking with the major search engines and offer the most cost-effective way to add new patients and increase revenues.
If you want to know more about how you can be certain that your practice is Mercury Safe as possible please go to www.newdirectionsdentistry.com. This is the difinitive guide to Minimizing Occupational Exposure to Mercury at the Dental Office and the only one of its kind available to dentists.
To make searching for a topic of interest easier I’ve included a Table of Contents that lists key topics in alphabetical order. Some of the topics will be further broken down into subheadings. All referenced articles listed under a topic heading are in alphabetical order, followed by the title and author(s) of the article. While this isn’t the standard format used by medical texts and journals, I’m certain you will find that it will make your search for a topic/subject significantly easier. (If you are looking for a particular author or topic you can use the Find Menu. Its use is explained below.)
The article title, related reference information and text is in black, the PIMD reference number for PubMed is in red to make it easier to find. Please note that not every article includes an extensive abstract. This was done to minimize the length yet still address the relevant aspects of the article. In other cases I included more of the abstract because I felt the information was very important and more needed to be included. If you require additional information it can be obtained by going to PubMed, or the source of the article. It has been my experience that using internet search engines to find a title, or author’s name, often yields additional information about the article than can be found on medical reference websites.
Over the years, I’ve researched thousands of articles and websites that have not been included here. Many were left out because they were redundant, some because they they were outdated and others because they weren’t relevant to the subject matter. As much as possible, I included those that I felt were germain to the subjects I was researching regarding mercury amalgam fillings, chronice mercury poisoning, and mercury detoxification
How to Use the Table of Contents
There are two ways to use the Table of Contents to more easily find what you are looking for. The first, and perhaps the most useful, is to click on the subject you are interested in. That will link you to the first article in that subject and from there you can easily scroll through the other articles under that heading. The second is to scroll down from the top, or any place within the database, until you find the page you are looking for. This is just as effective, but it is slower. It does however allow you to start scrolling from the top and browse through the pages.
Using the Find
If you are not familiar with using the Find menu to search pages, you are in for a wonderful surprise. If you go to the Top Row menus and click on the Edit menu and then click Find in the Drop Down menu, it will open a Dialog Box that asks you to Find What. Simply type in what you want to find and each time you click on Find Next the program will search through every one of the pages looking for what you typed in. Keep hitting Find Next until you find what you are looking for. You can type in more than one word and the more selective you can be the better. Play around with it, it’s easy to use and very helpful!
Return to Table of Contents
There are over 1200 referenced articles (180 pages) and to make it easier to get around I’ve added Return to Table of Content links throughout the site. These links will take you back to the Table of Contents and from there you can click on another topic of interest and move quickly around the site.
Comments and Feedback
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Table of Contents
Amount from Amalgam Fillings-vs-Other Sources
Alpha Lipoic Acid
Blood and Body Fluids
DMSA & DMPS
Composite Fillings and Bis-GMA
Dentists and Dental Office
Diseases and Symptoms
Amyotrophic lateral sclerosis (ALS)
Chronic Fatigue Syndrome (CFS)
Multiple Sclerosis (MS)
Factors Affecting Release of Mercury from Amalgam Fillings
Acid conditions in Mouth
Fetus, Baby, and Child
Fish and Food
Galvanic and Corrosion Effects
General Health Genetic/Mutations
Chewing and Grinding
Immune System, Autoimmune, and Allergy
Infertility and Birth Defects
Legal and Political
Relationship to Amalgam Fillings
Release and Absorption
Resistance to Antibiotics
Symptoms Improvement after Amalgam Removal
Mercury Free Dental Association References
Types of Amalgam fillings
WHO: No Safe level of Hg
References & Abstracts: Mercury and Amalgam Fillings
ADA Letter: John W. Stanford, PhD. Secretary CDMIE. May 22, 1986. The ADA has approved a number of them as 'safe and effective,' and I have confidence in that seal of approval. The profession has been using amalgam for more than 150 years, and some of these newer materials have been around for only a decade or less, so we don't have the long-standing history of safety with them that we have with amalgam.
American Dental Asssociation's Special Report. The ADA and CDA Principals of Ethics and Code of Professional Conduct ADA Resolution 42H-1986. Transaction 1986:536. The removal of amalgam restorations from the non-allergic patient for the alleged purpose of removing toxic substances from the body, when such treatment is performed solely at the recommendation or suggestion of the dentist, is improper and unethical.
Code of Professional Conduct Section E: ADA's Special Report The ADA Principals of Ethics. The dentist has the obligation to make known to all the results of his investigations if they have an effect on public health. (This clearly allows the dentists to pass along his or her personal knowledge about a subject that could have a negative affect on his or her patients.)
Journal of the American Dental Association (April, 1990). The strongest and most convincing support we have for the safety of dental amalgam is the fact that each year more than 100 million amalgam fillings are placed in the United States. And since amalgam has been used for more than 150 years, literally billions of amalgam fillings have been successfully used to restore decayed teeth.
The Superior Court of the State of California, Santa Clara County. Case No. 718228, Demurrer (October 22, 1992). “The American Dental Association (ADA) owes no legal duty of care to protect the public form allegedly dangerous products used by dentists. The ADA did not manufacture, design, supply or install the mercury-containing amalgams. The ADA does not control those who do. The ADA's only alleged involvement in the product was to provide information regarding its use. Dissemination of information relating to the practice of dentistry does not create a duty of care to protect the public from potential injury.”
ADA Does Support Mercury-Safe Dentistry
The ADA actually supports Mercury-Safe Dentistry, it just uses a different name. The ADA calls it The ADA's 'Dental Mercury Hygiene Recommendations'. The ADA lists a number of sources of mercury exposure at the dental office, including polishing and removing amalgam. It also recommends that all personnel involved in the handling of mercury and dental amalgam be trained in the potential hazards of mercury vapor and the necessity of observing good mercury hygiene. Although limited in scope the ADA does promote mercury safe dentistry. So while it still may vehemently defend the use of amalgam it encourages dentists to be mercury-safe. Not only does the ADA encourage dentists to be mercury-safe, you should promote the fact that you are to your patients and the public. It also shows that the ADA does not believe that the elemental mercury used in amalgams is somehow safer than elemental mercury used in other products and equipment. The ADA's Dental Mercury Hygiene Recommendations were published in: J AM Dent Assoc, Vol 134, No.11, 1498-1499; © 2003, American Dental Association. You can access the article online at http://jada.ada.org/cgi/content/full/134/11/1498.
Amount from Amalgam fillings versus other sources
World Health Organization: Environmental Health Criteria Series, 1991. The World Health Organization has calculated that the average human daily dose of mercury from various sources are: Dental amalgam = 3.0-17.0 ug/day (Hg vapor); Fish and Seafood = 2.3 ug/day (methylmercury); Other food = 0.3 ug/day(inorganic Hg); Air & Water = Negligible traces. (note: ug = Micrograms).
Antioxidant compounds and Ca(2+) pathway blockers differentially protect against methylmercury and mercuric chloride neurotoxicity. Gasso S, Cristofol RM, Selema G, Rosa R, Rodriguez-Farre E, Sanfeliu C. J Neurosci Res. 2001 Oct 1; 66(1):135-45. 11599010 PubMed. The antioxidants probucol and propyl gallate reduced the HgCl(2) toxicity. Probucol and vitamin E partially inhibited the MeHg toxicity after a 24 hr period, whereas propyl gallate completely prevented this effect. Probucol slightly reduced ROS generation in methylmercury-exposed cultures and decreased mercury-mediated rise of [Ca(2+)](i). Propyl gallate abolished ROS generation and partially inhibited the increase of [Ca(2+)](i) induced by both mercury compounds. Propyl gallate also protected human cerebral cortical neuron cultures from the MeHg effect even after 72 hr of MeHg exposure, thus showing a long-lasting effect. Our data suggest that disruption of redox equilibrium and Ca(2+) homeostasis contribute equally to HgCl(2)-mediated toxicity, whereas oxidative stress is the main cause of MeHg neurotoxicity.
Antioxidants inhibit mercuric chloride-induced early vasculitis. Wu Z, Turner DR, Oliveira DB. Int Immunol. 2002 Mar; 14(3):267-73. 11867563 PubMed. Groups of rats were given HgCl(2) + saline, HgCl(2) + N-acetyl-L-cysteine (NAC), saline + saline or saline + NAC respectively. NAC significantly reduced both HgCl2-induced early vasculitis and HgCl(2)-enhanced IgE expression on mast cells with a trend to a decrease in HgCl(2)-enhanced IL-4 expression in these cells. Our data show that administration of an antioxidant to BN rats reduces HgCl(2)-induced early vasculitis, suggesting that oxidative stress plays a role in the pathogenesis of HgCl(2)-induced early vasculitis.
Antioxidant supplementation and tapering exercise improve exercise-induced antioxidant response. Margaritis I, Palazzetti S, Rousseau AS, Richard MJ, Favier A. J Am Coll Nutr. 2003 Apr; 22(2):147-56. 12672711 PubMed. During TT, antioxidant supplementation at nutritional doses reinforces antioxidant status response to exercise, with an effect on exercise-induced oxidative stress.
Effects of SH-blocking compounds on the energy metabolism in isolated rat hepatocytes. Boot JH. Cell Struct Funct. 1995 Jun; 20(3):233-8. 7586013 PubMed. In conclusion, the results with organic mercury compounds suggest a reaction of these agents with SH-groups in the outer membrane of cells, having an inhibiting effect on the glucose uptake.
Influence of amalgam fillings on Hg levels and total antioxidant activity in plasma of healthy donors. Pizzichini M, Fonzi M, Giannerini F, Mencarelli M, Gasparoni A, Rocchi G, Kaitsas V, Fonzi L. Sci Total Environ. 2003 Jan 1; 301(1-3):43-50. 12493183 PubMed. Hg plasma concentration was found to be correlated with the number of amalgam fillings, suggesting that Hg released from fillings is a source of Hg in non-occupational exposed subjects. P-FRAP correlated negatively with P-Hg suggesting a pro-oxidant role of the Hg released from amalgam fillings.
Influence of exogenous thiols on inorganic mercury-induced injury in renal proximal and distal tubular cells from normal and uninephrectomized rats. Lash LH, Putt DA, Zalups RK. J Pharmacol Exp Ther. 1999 Nov; 291(2):492-502. 10525063 PubMed. Inorganic mercury (Hg(2+)) induced time- and concentration-dependent cellular injury in freshly isolated proximal tubular (PT) and distal tubular (DT) cells from normal (control) rats or uninephrectomized (NPX) rats. PT cells from NPX rats were more susceptible than PT cells from control rats, and DT cells were slightly more susceptible than PT cells to cellular injury induced by Hg(2+) (not bound to a thiol). Preloading cells with glutathione increased Hg(2+)-induced cellular injury in PT cells from control rats. However, coincubation of PT or DT cells from control or NPX rats with Hg(2+) and glutathione (1:4) provided significant protection relative to incubations with Hg(2+) alone. No support was obtained for a role for gamma-glutamyltransferase in glutathione-dependent protection. However, the organic anion carrier does appear to play a role in accumulation and toxicity of mercuric conjugates of cysteine in PT cells from control, but not NPX, rats. Coincubation with Hg(2+) and cysteine (1:4) had little effect on, or slightly enhanced, Hg(2+)-induced cellular injury at low concentrations of Hg(2+) in all cells studied. Coincubation with Hg(2+) and albumin (1:4) markedly protected PT and DT cells from control and NPX rats at all concentrations except the highest concentration of Hg(2+) in DT cells from NPX rats. 2,3-Dimercapto-1-propanesulfonic acid protected cells both when preloaded or added simultaneously with Hg(2+). Thus, renal cells from NPX rats are more susceptible to Hg(2+)-induced injury, PT and DT cells respond differently to exposure to Hg(2+), and thiols can significantly modulate the toxic response to Hg(2+).
Lipid peroxidation and antioxidant enzyme activity in different organs of mice exposed to low level of mercury. Mahboob M, Shireen KF, Atkinson A, Khan AT. J Environ Sci Health B. 2001 Sep; 36(5):687-97. 11599730 PubMed. These results indicated that Hg treatment enhanced LPO in all tissues, but showed significant enhancement only in kidney, testis and epididymus suggesting that these organs were more susceptible to Hg toxicity. The increase in antioxidant enzyme levels in testis could be a mechanism protecting the cells against reactive oxygen species.
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Mercuric chloride-induced reactive oxygen species and its effect on antioxidant enzymes in different regions of rat brain. Hussain S, Rodgers DA, Duhart HM, Ali SF. J Environ Sci Health B. 1997 May; 32(3):395-409. 9177012 PubMed. The present study was undertaken to determine if in vitro exposure to mercuric chloride produces reactive oxygen species (ROS) in the synaptosomes prepared from various regions of rat brain. The effects of in vivo exposure to mercury on antioxidant enzymes such as superoxide dismutase (SOD) and glutathione peroxidase (GPx) activities in different regions of rat brain were also investigated. Adult male Sprague-Dawley (CD) rats were dosed with 0, 1, 2.0 or 4.0 mg HgCl2/kg body weight, for 7 days. One week after the last dose, animals were sacrificed by decapitation, their brains were removed and dissected and frozen in dry ice prior to measuring the activities of these enzymes. The results demonstrated that in vitro exposure to mercury produced a concentration-dependent increase of ROS in different regions of the rat brain. In vivo exposure to mercury produced a significant decrease of total SOD, Cu, Zn-SOD and Mn-SOD activities in the cerebellum of rats treated with different doses of mercury. SOD activity did not vary significantly in cerebral cortex and brain stem. GPx activity declined in a dose-dependent manner in the cerebellum with a significant reduction in animals receiving the 4 mg HgCl2/kg body weight. The activity of GPx increased in the brain stem while unchanged in the cerebral cortex. The results demonstrate that inorganic mercury decreased SOD activity significantly in the cerebellum while GPx activity was affected in both cerebellum and brain stem. Therefore, it can be concluded that oxidative stress may contribute to the development of neurodegenerative disorders caused by mercury intoxication.
Mercury, selenium, and glutathione peroxidase before and after amalgam removal in man. Molin M, Bergman B, Marklund SL, Schutz A, Skerfving S. Acta Odontol Scand. 1990 Jun; 48(3):189-202. 2368614 PubMed. Amalgam fillings considerably contributed to the plasma and urinary mercury levels.
Molecular interactions with mercury in the kidney. Zalups RK. Pharmacol Rev. 2000 Mar; 52(1):113-43. 10699157 PubMed. Mercury is unique among the heavy metals in that it can exist in several physical and chemical forms, including elemental mercury, which is a liquid at room temperature. All forms of mercury have toxic effects in a number of organs, especially in the kidneys. Within the kidney, the pars recta of the proximal tubule is the most vulnerable segment of the nephron to the toxic effects of mercury. The biological and toxicological activity of mercurous and mercuric ions in the kidney can be defined largely by the molecular interactions that occur at critical nucleophilic sites in and around target cells. Because of the high bonding affinity between mercury and sulfur, there is particular interest in the interactions that occur between mercuric ions and the thiol group(s) of proteins, peptides and amino acids. Molecular interactions with sulfhydryl groups in molecules of albumin, metallothionein, glutathione, and cysteine have been implicated in mechanisms involved in the proximal tubular uptake, accumulation, transport, and toxicity of mercuric ions. In addition, the susceptibility of target cells in the kidneys to the injurious effects of mercury is modified by a number of intracellular and extracellular factors relating to several thiol-containing molecules. These very factors are the theoretical basis for most of the currently employed therapeutic strategies. This review provides an update on the current body of knowledge regarding the molecular interactions that occur between mercury and various thiol-containing molecules with respect to the mechanisms involved in the renal cellular uptake, accumulation, elimination, and toxicity of mercury.
Oral succimer decreases the gastrointestinal absorption of lead in juvenile monkeys. Cremin JD Jr, Luck ML, Laughlin NK, Smith DR. Environ Health Perspect. 2001 Jun; 109(6):613-9. 11445516 PubMed. Although succimer (Chemet, meso-2,3-dimercaptosuccinic acid, DMSA) is considered to be a safe and effective chelating agent for the treatment of lead poisoning in humans, there is concern that it may increase the gastrointestinal (GI) absorption and retention of Pb from exposures suffered concurrent with treatment. Succimer also significantly increased the urinary excretion of endogenous Pb by approximately 4-fold over the vehicle treatment, while endogenous fecal Pb excretion was decreased by approximately 33%. Finally, although succimer reduced the whole-body retention of endogenous Pb by approximately 10% compared to vehicle, the majority (77%) of the administered internal dose of Pb tracer was retained in the body when assessed after 5 days of treatment. These data do not support the concern that succimer treatment increases GI Pb absorption.
Relationships between alterations in glutathione metabolism and the disposition of inorganic mercury in rats: effects of biliary ligation and chemically induced modulation of glutathione status. Zalups RK, Barfuss DW, Lash LH. Chem Biol Interact. 1999 Dec 15; 123(3):171-95. 10654838 PubMed. Influences of biliary ligation and systemic depletion of glutathione (GSH) or modulation of GSH status on the disposition of a low, non-nephrotoxic i.v. dose of inorganic mercury were evaluated in rats in the present study. Renal and hepatic disposition, and the urinary and fecal excretion, of inorganic mercury were assessed 24 h after the injection of a 0.5-micromol/kg dose of mercuric chloride in control rats and rats pretreated with acivicin (two 10-mg/kg i.p. doses in 2 ml/kg normal saline, 90 min apart, 60 min before mercuric chloride), buthionine sulfoximine (BSO; 2 mmol/kg i.v. in 4 ml/kg normal saline, 2 h before mercuric chloride) or diethylmaleate (DEM; 3.37 mmol/kg i.p. in 2 ml/kg corn oil, 2 h before mercuric chloride) that either underwent or did not undergo acute biliary ligation prior to the injection of mercury. Among the groups that did not undergo biliary ligation, the pretreatments used to alter GSH status systemically had varying effects on the disposition of inorganic mercury in the kidneys, liver, and blood. Biliary ligation caused the net renal accumulation of mercury to decrease under all pretreatment conditions. By contrast, biliary ligation caused significant increases in the hepatic burden of mercury in all pretreatment groups except in theacivicin-pretreated group. Blood levels of mercury also increased as a result of biliary ligation, regardless of the type of pretreatment used. The present findings indicate that biliary ligation combined with methods used to modulate GSH status systemically have additive effects with respect to causing reductions in the net renal accumulation of mercury. Additionally, the findings indicate that at least some fraction of the renal accumulation of inorganic mercury is linked mechanistically to the hepato-biliary system.
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Alpha Lipoic Acid
Effect of lipoic acid on biliary excretion of glutathione and metals. Gregus Z, Stein AF, Varga F, Klaassen CD. Toxicol Appl Pharmacol. 1992 May; 114(1):88-96. 1585376 PubMed. Several metals are excreted in bile as glutathione complexes, and their biliary excretion is facilitated by increased hepatobiliary transport of glutathione. The present study analyzed the effect of lipoic acid (LA; thioctic acid; 37.5-300 mumol/kg, iv), an endogenous disulfide which can be reduced in vivo to a dithiol, on the hepatobiliary disposition of glutathione-related thiols and the biliary excretion of metals (10 mumol/kg, iv) in rats. Administration of LA enhanced the biliary excretion of reduced glutathione in a dose-dependent fashion. Despite increasing glutathione output, LA (150 mumol/kg, iv) did not increase, but rather decreased, the biliary excretion of methylmercury, cadmium, zinc, and copper, which are transported into bile in a glutathione-dependent manner, as indicated by a marked reduction in their biliary excretion after diethyl maleate-induced glutathione depletion. In contrast, biliary excretion of inorganic mercury, which is minimally affected by glutathione depletion, was dramatically enhanced (12- to 37-fold) by LA administration. Following injection of LA, the concentrations of endogenous disulfides in arterial blood plasma (e.g., cystine, glutathione disulfide, cysteine-glutathione, protein-cysteine, and protein-glutathione mixed disulfides) were considerably diminished, while the levels of endogenous thiols (e.g., glutathione and cysteine) were increased. This finding indicates that LA, probably after enzymatic conversion to dihydrolipoic acid, can reduce endogenous disulfides to thiols. It appears that LA induces the transport of glutathione into bile by the temporary formation of dihydrolipoic acid-glutathione mixed disulfide, which after being translocated into bile is cleaved to LA and reduced glutathione. Because the glutathione molecule thus transported into bile cannot complex metals at the thiol group, this might be the mechanism for the observed failure of the LA-induced increase in biliary excretion of glutathione to enhance the hepatobiliary transport of metals that are transported into bile as glutathione complexes (i.e., methylmercury, cadmium, zinc, and copper). The observations also raise the possibility that endogenous dihydrolipoic acid, by forming a stable complex with mercuric ion, may play the role of a carrier molecule in the hepatobiliary transport of inorganic mercury.
Influence of alpha-lipoic acid on intracellular glutathione in vitro and in vivo. Busse E, Zimmer G, Schopohl B, Kornhuber B. Arzneimittelforschung. 1992 Jun; 42(6):829-31. 1418040 PubMed. The influence of alpha-lipoic acid (CAS 62-46-4) on the amount of intracellular glutathione (GSH) was investigated in vitro and in vivo. Using murine neuroblastoma as well as melanoma cell lines in vitro, a dose-dependent increase of GSH content was observed. Dependent on the source of tumor cells the increase was 30-70% compared to untreated controls. Normal lung tissue of mice also revealed about 50% increase in glutathione upon treatment with lipoic acid. This corresponds with protection from irradiation damage in these in vitro studies. Survival rate of irradiated murine neuroblastoma was increased at doses of 100 micrograms lipoic acid/d from 2% to about 10%. In agreement with the in vitro studies, in vivo experiments with whole body irradiation (5 and 8 Gy) in mice revealed that the number of surviving animals was doubled at a dose of 16 mg lipoic acid/kg. Improvement of cell viability and irradiation protection by the physiological compound lipoic acid runs parallel with an increase of intracellular GSH/GSSG ratio.
Lead induced oxidative damage and its response to combined administration of alpha-lipoic acid and succimers in rats. Pande M, Flora SJ. Toxicology. 2002 Aug 15; 177(2-3):187-96. 12135622 PubMed. Lead induced increase in renal GSSG, TBARS levels and catalase activity, were effectively reduced by LA, while, the two chelators when administered alone were effective only in reducing GSSG and catalase activity. The most prominent beneficial effects, however, were observed in animals treated concomitantly with LA and one of the chelators (DMSA or MiADMSA). Brain GSH and GSSG levels decreased moderately while superoxide dismutase (SOD) activity remained statistically unaltered on lead exposure. Brain catalase activity, on the other hand, increased significantly. Administration of LA was effective in reducing these alterations in the brain, however, the best effects were achieved in animals co-administered LA and one of the thiol chelators. The results point to a significant beneficial role of LA in the recovery of altered biochemical variables both during monotherapy and when given in combination with succimer. It however, showed no chelating properties in decreasing lead burden from blood, liver and kidneys except for a significantly more pronounced decrease in brain lead concentration in animals administered LA plus thiol chelators, compared to the effects of chelating agents alone. This is an interesting and notable observation, which requires further exploration. The results thus provide evidence of an encouraging role of LA when given in combination with a thiol chelator in the therapeutic intervention of lead poisoning, particularly in reducing the oxidative stress and brain lead concentration.
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Lipoic acid increases glutathione production and enhances the effect of mercury in human cell lines. Hultberg B, Andersson A, Isaksson A. Toxicology. 2002 Jun 14; 175(1-3):103-10. 12049840 PubMed. Thiols are known to influence the metabolism of glutathione. In a previous study (Toxicology 156 (2001) 93) dithiothreitol (DTT) did not show any effect on intra- or extracellular glutathione concentrations in HeLa cell cultures but increased the effects of mercury ions on glutathione concentrations, whereas monothiols such as N-acetylcysteine (NAC) or glutathione did not. In the present study, we have investigated the effects of thiols as well as the interaction between thiols and mercury ions in cultures of both HeLa and hepatoma cells. Furthermore, we have added alpha-lipoic acid (LA) to the previously used test panel of thiols, since it is metabolised intracellularly to a dithiol (dihydrolipoate). The present study shows that LA increased intra- and extracellular concentrations of glutathione in both HeLa and hepatoma cell cultures. In contrast to results for HeLa cells, the presence of DTT increased the intracellular glutathione concentration in hepatoma cells. No increase of glutathione concentrations was observed in hepatoma cell cultures in the presence of the monothiols (NAC, homocysteine or glutathione) tested, in agreement with previous findings in HeLa cell cultures. The presence of dithiols, either DTT or dihydrolipoate (the metabolite of LA), increased the effects of mercury ions on glutathione concentrations in hepatoma cells, whereas monothiols such as NAC or glutathione did not, in agreement with previous findings in HeLa cells. Thus, metabolic effects of mercury ions were observed in hepatoma cells as well as in HeLa cells at a lower concentration than the supposed toxicity threshold for mercury in blood.
Mercury toxicity and antioxidants: Part 1: role of glutathione and alpha-lipoic acid in the treatment of mercury toxicity. Patrick L. Altern Med Rev. 2002 Dec; 7(6):456-71. 12495372 PubMed. Mercury exposure is the second-most common cause of toxic metal poisoning. Public health concern over mercury exposure, due to contamination of fish with methylmercury and the elemental mercury content of dental amalgams, has long been a topic of political and medical debate. Although the toxicology of mercury is complex, there is evidence for antioxidant protection in the prevention of neurological and renal damage caused by mercury toxicity. Alpha-lipoic acid, a coenzyme of pyruvate and alpha-ketoglutarate dehydrogenase, has been used in Germany as an antioxidant and approved treatment for diabetic polyneuropathy for 40 years. Research has attempted to identify the role of antioxidants, glutathione and alpha-lipoic acid specifically, in both mitigation of heavy metal toxicity and direct chelation of heavy metals. This review of the literature will assess the role of glutathione and alpha-lipoic acid in the treatment of mercury toxicity.
Protective role of DL-alpha-lipoic acid against mercury-induced neural lipid peroxidation. Anuradha B, Varalakshmi P. Pharmacol Res. 1999 Jan; 39(1):67-80. 10051379 PubMed. Experimental neurotoxicity in rat models was induced by an intramuscular injection of mercuric chloride. dl-alpha-lipoic acid was administered as an antidote in three protocols of experimental design. Two protocols of short-term exposure of mercury was designed, one with prophylactic therapy and the other with curative therapy of lipoic acid. The third protocol was with prophylactic therapy of lipoic acid on long-term exposure of mercury. Enhanced lipid peroxidation, depleted non-enzymic and perturbed enzymic antioxidant status were observed in cerebral cortex, cerebellum and sciatic nerves of the toxic groups. The ameliorating effect of lipoic acid and its therapeutic efficacy during various modes of therapy, on the antioxidant status was established in the nervous tissues.
Biotoxicity of mercury as influenced by mercury(II) speciation. Farrell RE, Germida JJ, Huang PM. Appl Environ Microbiol. 1990 Oct; 56(10):3006-16. 2126698 PubMed. The toxicity of mercuric nitrate at pH 8.0 was unaffected by the addition of citrate, enhanced by the addition of chloride, and reduced by the addition of cysteine.
Cysteine metabolism and metal toxicity. Quig D. Altern Med Rev. 1998 Aug; 3(4):262-70. 9727078 PubMed. Chronic, low level exposure to toxic metals is an increasing global problem. The symptoms associated with the slow accumulation of toxic metals are multiple and rather nondescript, and overt expression of toxic effects may not appear until later in life. The sulfhydryl-reactive metals (mercury, cadmium, lead, arsenic) are particularly insidious and can affect a vast array of biochemical and nutritional processes. The primary mechanisms by which the sulfhydryl-reactive metals elicit their toxic effects are summarized. The pro-oxidative effects of the metals are compounded by the fact that the metals also inhibit antioxidative enzymes and deplete intracellular glutathione. The metals also have the potential to disrupt the metabolism and biological activities of many proteins due to their high affinity for free sulfhydryl groups. Cysteine has a pivotal role in inducible, endogenous detoxication mechanisms in the body, and metal exposure taxes cysteine status. The protective effects of glutathione and the metallothioneins are discussed in detail. Basic research pertaining to the transport of toxic metals into the brain is summarized, and a case is made for the use of hydrolyzed whey protein to support metal detoxification and neurological function. Metal exposure also affects essential element status, which can further decrease antioxidation and detoxification processes. Early detection and treatment of metal burden is important for successful detoxification, and optimization of nutritional status is paramount to the prevention and treatment of metal toxicity.
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Dimercaptosuccinic acid (DMSA), a non-toxic, water-soluble treatment for heavy metal toxicity. Miller AL. Altern Med Rev. 1998 Jun; 3(3):199-207. 9630737 PubMed. Heavy metals are, unfortunately, present in the air, water, and food supply. Cases of severe acute lead, mercury, arsenic, and cadmium poisoning are rare; however, when they do occur an effective, non-toxic treatment is essential. In addition, chronic, low-level exposure to lead in the soil and in residues of lead-based paint, to mercury in the atmosphere, in dental amalgams and in seafood, and to cadmium and arsenic in the environment and in cigarette smoke is much more common than acute exposure. Meso-2,3-dimercaptosuccinic acid (DMSA) is a sulfhydryl-containing, water-soluble, non-toxic, orally-administered metal chelator which has been in use as an antidote to heavy metal toxicity since the 1950s. More recent clinical use and research substantiates this compounds efficacy and safety, and establishes it as the premier metal chelation compound, based on oral dosing, urinary excretion, and its safety characteristics compared to other chelating substances. Whey protein can also be beneficial as it contains branched-chain amino acids, which will occupy transport sites at the blood-brain barrier, effectively keeping bound metals from being re-deposited in the brain.
Accumulation and handling of inorganic mercury in the kidney after coadministration with glutathione. Zalups RK, Barfuss DW. J Toxicol Environ Health, 1995 Apr; 44(4):385-99. Significantly more of the injected dose of inorganic mercury was present in the blood of the rats injected with inorganic mercury alone than in the blood of the rats injected simultaneously with both inorganic mercury and GSH at all times evaluated after injection. The blood and plasma findings indicate that much of the mercury injected with GSH was in some complex that allowed the mercury to be cleared from the blood more readily and prevented the mercury from entering readily into red blood cells. These data indicate that coadministration of a nontoxic dose of inorganic mercury with a twofold higher amount (in moles) of GSH increases significantly the clearance of mercury from the blood and increases the renal cortical accumulation of inorganic mercury during the initial 1 h after injection. Moreover, the data in this study are consistent with the hypothesis that extracellular GSH is an important ligand to which mercuric ions bind, and that complexes of inorganic mercury and GSH in the blood and/or ultrafiltrate probably play a role in the renal uptake of some of the mercury in blood after exposure to mercuric compounds.
Activity of glutathione peroxidase and superoxide dismutase in workers occupationally exposed to mercury. Bulat P, Dujic I, Potkonjak B, Vidakovic A. Int Arch Occup Environ Health. 1998 Sep; 71 Suppl: S37-9. 9827878 PubMed. On the basis of previous results, it can be concluded that occupational exposure to elemental mercury leads to increased lipid peroxidation in erythrocytes. Also, it can be postulated that this exposure leads to decreased activity of GPX and SOD in erythrocytes.
Biliary secretion of glutathione and of glutathione-metal complexes. Ballatori N, Clarkson TW. Fundam Appl Toxicol. 1985 Oct; 5(5):816-31. 4065458 PubMed. As bile is the main route of elimination of many metals, a large number of studies have been directed toward the characterization of the hepatobiliary transport of both endogenous and exogenous metals. Although some progress has been made, we still know little of the basic mechanisms involved in the hepatocellular uptake of metals, in their intracellular translocation and metabolism, or in their transport into bile. Our recent studies have focused on the last step in the hepatobiliary transport of mercury, namely, the secretion of the metal from liver cells into bile. The rate of secretion of methyl and inorganic mercury into bile was low in suckling rats and rapidly increased to adult rates soon after weaning. These changes closely followed similar developmental changes in the biliary secretion of reduced glutathione (GSH). When GSH secretion into bile was completely inhibited, without changing hepatic levels of GSH or mercury, mercury secretion was also completely blocked. Mercury secretion paralleled individual and sex-related differences in GSH secretion. At the same time, the secretion of mercury was independent of bile flow, of the thiol and mercury concentration gradients between bile and liver cells, and of those between bile and plasma. Our results, therefore, indicate a close coupling between the secretion of mercury and that of GSH. These in vivo findings, along with in vitro studies by others in vesicles isolated from the canalicular membrane of the liver cell, indicate a carrier-mediated transport system for GSH, but the nature of the linkage of this transport system with mercury secretion is not yet fully established. Our data and those in the literature are consistent with the involvement of at least two steps in the movement of mercury from liver cells to bile--the formation of a mercury-glutathione complex in the liver cell, followed by the secretion of this complex through a process closely linked to GSH secretion. The identification of GSH as an endogenous complexing agent in the transport of metals between tissues and body fluids now permits the design of therapeutic strategies aimed at exploiting this transport vehicle to effect the removal of metals via physiological routes of excretion. The present discussion considers the role of GSH in the hepatobiliary transport of metals. In doing so, a brief review is given of current understanding of hepatic GSH metabolism and transport.
Bioavailability of dietary glutathione: effect on plasma concentration. Hagen TM, Wierzbicka GT, Sillau AH, Bowman BB, Jones DP. Am J Physiol. 1990 Oct;259(4 Pt 1):G524-9. 2221062 PubMed. Plasma glutathione (GSH) concentration in rats increased from approximately 15 to 30 microM after administration of GSH either as a liquid bolus (30 mumol) or mixed (2.5-50 mg/g) in AIN-76 semisynthetic diet. GSH concentration was maximal at 90-120 min after GSH administration and remained high for over 3 h. Administration of the amino acid precursors of GSH had little or no effect on plasma GSH values, indicating that GSH catabolism and resynthesis do not account for the increased GSH concentration seen. Inhibition of GSH synthesis and degradation by L-buthionine-[S,R]-sulfoximine and acivicin showed that the increased plasma GSH came mostly from absorption of intact GSH instead of from its metabolism. Plasma protein-bound GSH also increased after GSH administration, with a time course similar to that observed for free plasma GSH. Thus dietary GSH can be absorbed intact and results in a substantial increase in blood plasma GSH. This indicates that oral supplementation may be useful to enhance tissue availability of GSH.
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Captopril and glutathione inhibit the superoxide dismutase activity of Hg (II). Jay D. Arch Inst Cardiol Mex. 1998 Nov-Dec; 68(6):457-61. 10365221 PubMed. The purpose of this study was to determine if captopril, an angiotensin-converting enzyme inhibitor, and glutathione could interact with mercuric ions and so modify the catalytic dismutation of superoxide carried out by this metal. With an assay that generates superoxide anion radicals without the intervention of metal ions increasing concentrations of both reagents progressively inhibited the breakdown of superoxide brought about by mercury. Maximum inhibition was attained with a molar ratio of captopril (glutathione): Hg (II) = 1. These results may help to explain the protective and/or antioxidative effect of thiol compounds during mercury intoxication.
Dependence of biliary secretion of inorganic mercury on the biliary transport of glutathione. Ballatori N, Clarkson TW. Biochem Pharmacol. 1984 Apr 1; 33(7):1093-8. 6712719 PubMed. Conversely, the increase in the rate of GSH secretion into bile after cysteine or GSH administration was accompanied by an increase in the rate of mercury secretion into bile. The changes in the biliary secretion of mercury and of GSH after treatment with cysteine or GSH were not closely parallel, probably because of the tissue redistribution of mercury effected by these sulfhydryl-containing compounds. Mercury secretion into bile was independent of the changes in bile flow produced by dehydrocholate (DHC) or hypertonic sucrose, but it was closely related to the rate of GSH secretion. Further, sex differences and individual variability in the biliary secretion of inorganic mercury were correlated with differing abilities to secrete GSH into bile. These results suggest that the biliary secretion of inorganic mercury is in large part dependent on the biliary transport of GSH.
Depletion of glutathione in the kidney and the renal disposition of administered inorganic mercury. Zalups RK, Lash LH. Drug Metab Dispos. 1997 Apr; 25(4):516-23. 9107552 PubMed. Interestingly, pretreatment with BSO or DEM actually caused significant increases in the hepatic content of mercury 1 hr after the injection of mercuric chloride. We postulate that this effect was due to a diminished ability of hepatocytes to export mercuric conjugates of GSH out into either the bile or blood. The results of this study indicate that depletion of renal GSH by conjugation reactions between GSH and DEM leads to an acute reduction in the renal accumulation of inorganic mercury. However, the results also indicate that depletion of renal levels of GSH by inhibition of GSH synthesis does not affect acutely the ability of the kidneys to accumulate inorganic mercury. Thus, it seems that factors in addition to intracellular GSH status play an important role in the renal accumulation/retention of inorganic mercury.
Distribution of mercury 203 in pregnant rats and their fetuses following systemic infusions with thiol-containing amino acids and glutathione during late gestation. Aschner M, Clarkson TW. Teratology. 1988 Aug; 38(2):145-55. 3175948 PubMed. To investigate the effect of amino acids and the tripeptide glutathione (GSH) on tissue uptake of methylmercury (MeHg) in the developing rat fetus in utero, pregnant rats were continuously infused into the external jugular vein with 0.1 mM L-cysteine, 0.1 mM L-leucine, 0.1 mM GSH or saline commencing on day 17 of gestation. This was followed at 24, 48, and 72 hours by external jugular infusion of 50 microM [203Hg]-MeHgCl administered in 1 ml over 1 hour. Pups were surgically removed from the uterus on gestational day 21. Whole body, brain, kidney, liver, and placental 203Hg radioactivity was measured by means of gamma-spectrometry. Brain 203Hg concentration in pups exposed in utero to L-cysteine was significantly higher compared with pups exposed to saline (P less than 0.05). Brain 203Hg concentration in pups exposed in utero to L-leucine and GSH was significantly depressed compared with pups exposed to saline (P less than 0.05). Kidney 203Hg concentration was not significantly changed in all treatment groups compared with controls. Liver 203Hg concentration was significantly depressed in L-leucine- and GSH-treated pups compared with controls (P less than 0.05). Placental 203Hg concentration was not affected by any treatment compared with controls. These effects occurred despite no difference in total 203Hg body burden among pups, irrespective of the treatment. In addition, infusion with L-cysteine resulted in a significant increase in 203Hg brain concentration in dams compared with controls, and 203Hg brain concentration in L-leucine- and GSH-treated dams was significantly depressed compared with controls. Thus 203Hg distribution in both adult and developing animals is altered by chronic amino acid or GSH infusions and suggests that MeHg uptake may be mediated through the formation of a cysteine-MeHg complex which is transported across the blood-brain barrier by the neutral amino acid carrier transport system.
Effects of uninephrectomy and mercuric chloride on renal glutathione homeostasis. Zalups RK, Lash LH. J Pharmacol Exp Ther. 1990 Sep; 254(3):962-70. 2395124 PubMed. We hypothesize that both during compensatory renal growth and after administration of low, nontoxic to mildly toxic doses of Hg, GSH synthesis is induced. At higher, more toxic doses of Hg, GSH depletion becomes more prominent.
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Fate of dietary glutathione: disposition in the gastrointestinal tract. Hagen TM, Wierzbicka GT, Bowman BB, Aw TY, Jones DP. Am J Physiol. 1990 Oct;259(4 Pt 1):G530-5. Department of Biochemistry, Emory University School of Medicine, Atlanta, Georgia 30322. 2221063 PubMed. Studies were performed in rats that had been fasted 24 h, fed a glutathione (GSH)-free semisynthetic diet (AIN-76), and fed the same diet supplemented with GSH. The results from the fasted rats and those fed GSH-free diet showed that the duodenum and jejunum contained 0.2-0.5 mumol of GSH/gram wet wt of luminal contents. The GSH contents of biliary juice was sufficient to maintain this amount of GSH in the intestinal lumen. Other analyses showed that cell sloughing, bacterial GSH content, and GSH secretion by epithelial cells of the jejunum were not sufficient to account for this content. GSH concentrations following consumption of a GSH-supplemented diet (5-50 mg/g AIN-76) showed a rapid increase in all regions of the small intestine and indicated that removal occurred primarily in the jejunum. However, the combined activities of brush-border gamma-glutamyltransferase and GSH uptake systems were not sufficient to remove all of the ingested GSH. Results from in situ vascular perfusions of small intestine showed that the upper jejunum is a principal site of GSH absorption. Measurements of the GSH-to-glutathione disulfide (GSSG) ratio in the lumen after ingestion of GSSG (5 mg/g diet) indicated that the upper small intestine also has a mechanism for reducing GSSG to GSH. The results therefore indicate that GSH is present in the lumen of the small intestine of rat under most if not all conditions. Although the physiological importance of luminal GSH remains unclear, it could potentially be used to detoxify reactive electrophiles in the diet or be absorbed for intracellular detoxication reactions.
Glutathione, Ascorbate, and Cellular Protection. Alton Meister Cancer Research (suppl) 54. 1969s-1975s. April 1, 1991. Department of Biochemistry, Cornell University Medical College, New York, New York 10021 http://cancerres.aacrjournals.org/content/54/7_Supplement/1969s.full.pdf+html
Glutathione is probably the most important cellular antioxidant. Interestingly, Fahey and Sundquist findings indicate that glutathione evolved as a molecule that protects cells against oxygen toxicity. Cells that are deprived of glutathione typically suffer severe oxidative damage associated with mitochondria! degeneration.
Experimental findings summarized here that are relevant to this question include: (a) the observation that glutathione deficiency in animals that are unable to synthesize ascorbate (newborn rats, guinea pigs) is lethal and that death can be prevented by giving high doses of ascorbate; and (b) the onset of scurvy in guinea pigs that are fed a diet deficient in ascorbate is substantially delayed by giving glutathione monoethyl ester, a glutathione delivery agent. Glutathione also keeps a-tocopherol in its reduced form, either by a direct reaction or by a
pathway involving ascorbate is promising chemotherapeutic approach.
Glutathione effects on toxicity and uptake of mercuric chloride and sodium arsenite in rabbit renal cortical slices. Burton CA, Hatlelid K, Divine K, Carter DE, Fernando Q, Brendel K, Gandolfi. AJ.Environ Health Perspect. 1995 Feb; 103 Suppl 1:81-4. 7621807 PubMed. The mechanism of renal uptake of nephrotoxic heavy metals such as HgCl2 and NaAsO2 is not clear. The metals are known to react with endogenous sulfhydryls such as glutathione (GSH), so metal-GSH conjugates may be delivered to the kidney. Exogenous GSH decreased HgCl2 cytotoxicity and was correlated to a decrease in Hg accumulation in the slice. Exogenous GSH had limited if any protective effects against cytotoxicity by NaAsO2 and a decrease in As accumulation was not observed. Complex metal-GSH interactions appear to exist and impact on the uptake and toxicity of these metals.
Glutathione and Liver Detoxification: A classic explanation of the function of the liver in detoxification, including mercury and other heavy metals, with a very good explanation of the role glutathione plays in this process. It is important to learn just how important glutathione is in overall health and how its depletion by mercury can lead to a serious deficiency, lowering the bodies resistance to other diseases, toxins and free radicals. A must read and one you want to make a copy of. http://www.tuberose.com/Liver_Detoxification.html
Glutathione, Reduced (GSH) Monograph: One of the best articles, and fully referenced, on the role and function of glutathione in the body, including as a natural mecury chelator. This is a must read for anyone wanting to understand this critically important antioxidant. You'll want to print this one. http://www.woodmed.com/Glutathione%202002.htm
Glutathione mercaptides as transport forms of metals. Ballatori N. Adv Pharmacol. 1994; 27:271-98. 8068556 PubMed. Among the many cellular functions of GSH, the roles of this tripeptide in metal transport, storage, and metabolism have recently received considerable attention. Although these roles had often been overlooked, they are critical for normal cellular metabolism and for protection from xenobiotics. Indeed, a number of the protective and regulatory functions of GSH are related to its ability to chelate reactive metals. GSH functions in the mobilization and delivery of metals between ligands, in the transport of metals across cell membranes, as a source of cysteine for metal binding, and as a reductant or cofactor in redox reactions involving metals.
Impaired biliary excretion and whole body elimination of methylmercury in rats with congenital defect in biliary glutathione excretion. Ballatori N, Gatmaitan Z, Truong AT. Hepatology. 1995 Nov; 22(5):1469-73. 7590665 PubMed. Biliary excretion of methylmercury, a major route of elimination of this toxic compound, was less than 2% of control in Eisai hyperbilirubinemic (EHBR) rats, a mutant Sprague-Dawley strain with a defect in biliary excretion of a variety of organic anions, including glutathione S-conjugates and reduced glutathione (GSH). Biliary GSH excretion in EHBR rats was also < 2% of controls, confirming previous findings. Impaired biliary methylmercury and GSH excretion was not explained by decreased hepatic content of these compounds. Indeed, hepatic methylmercury and GSH concentrations in EHBR rats were actually double those of controls. To assess the significance of the impaired biliary excretion in the whole body elimination of the toxicant, 203Hg excretion was measured over a 17-day period after intraperitoneal administration of either 0.5 or 5 mumol/kg of 203Hg-methylmercury chloride. The results for the two doses were similar. Methylmercury was eliminated by a first order process; however, the biological half-line was significantly longer in the EHBR rats, 46 to 54 days versus 18 to 22 days. Fecal excretion was the main route of elimination in both control and mutant animals. At necropsy (17 days), 16% to 25% of the 203Hg dose was recovered in the liver of the EHBR rats, whereas livers of control animals contained less than 2%of the administered dose. These findings demonstrate the biliary excretion of methylmercury is markedly impaired in EHBR rats and is associated with a low biliary GSH excretion, providing support for the hypothesis that methylmercury is normally transported across the canalicular membrane by a GSH-dependent mechanism, and presumably as a GSH mercaptide (CH3Hg-SG).
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Inorganic mercury secretion into bile as a low molecular weight complex. Ballatori N, Clarkson TW. Biochem Pharmacol. 1984 Apr 1; 33(7):1087-92. 6424682 PubMed. Previous studies on the biliary secretion of inorganic mercury have concluded that inorganic mercury in bile is bound almost exclusively to substances of high molecular weight (HMW). In contrast, our results showed that inorganic mercury in bile is bound predominantly to a substance of low molecular weight (LMW), which is most likely glutathione (GSH). The previously reported binding of inorganic mercury to bile proteins is now explained as a postsecretory in vitro artifact resulting from the rapid oxidation of endogenous GSH which occurs during the collection and storage of bile samples. Gel filtration on Sephadex G-75 of freshly collected bile from rats treated with 203HgCl2 or of control bile supplemented in vitro with 203HgCl2 showed that most of the mercury was in the LMW fraction. On Sephadex G-25, the biliary mercury peak co-eluted with the mercury-GSH standard. However, when bile was allowed to stand at room temperature, there was a time-dependent shift of the mercury towards the HMW fraction. The rate of this shift was proportional to the rate of oxidation of GSH in bile. When GSH oxidation was inhibited by collecting bile in EDTA at 4 degrees, the mercury remained associated with the LMW fraction. At a given GSH concentration in bile, the fraction of mercury bound to the HMW fraction was independent of mercury concentration, in the range of 0.05 to 5.0 microM HgCl2. These results suggest that the inorganic mercury was secreted into bile complexed with a LMW substance. This LMW substance has been tentatively identified as GSH.
Mercury toxicity and antioxidants: Part 1: role of glutathione and alpha-lipoic acid in the treatment of mercury toxicity. Patrick, L.Altern Med Rev. 2002 Dec;7(6):456-71. 12495372 PubMed Mercury exposure is the second-most common cause of toxic metal poisoning. Public health concern over mercury exposure, due to contamination of fish with methylmercury and the elemental mercury content of dental amalgams, has long been a topic of political and medical debate. Although the toxicology of mercury is complex, there is evidence for antioxidant protection in the prevention of neurological and renal damage caused by mercury toxicity. Alpha-lipoic acid, a coenzyme of pyruvate and alpha-ketoglutarate dehydrogenase, has been used in Germany as an antioxidant and approved treatment for diabetic polyneuropathy for 40 years. Research has attempted to identify the role of antioxidants, glutathione and alpha-lipoic acid specifically, in both mitigation of heavy metal toxicity and direct chelation of heavy metals. This review of the literature will assess the role of glutathione and alpha-lipoic acid in the treatment of mercury toxicity.
Metallothionein and glutathione as determinants of cellular retention and extrusion of cadmium and mercury. Foulkes EC. Life Sci. 1993; 52(20):1617-20. 8483390 PubMed. This work explored cellular trapping and extrusion of Cd and Hg in epithelial cells, with special emphasis on the jejunal mucosa. Important determinants of these processes are the concentration, diffusibility and relative metal affinities of a variety of cellular metal-binding compounds including metallothionein (MT). As predicted from the known properties of MT, this protein can compete with other sulfhydryl compounds for Cd but not for Hg; this is illustrated by the observation that glutathione (GSH) stimulates extrusion of only Hg. Similar factors can help explain why, in spite of its tighter binding by MT, Hg has a shorter biological half-life in renal cortex than does Cd. Metal extrusion from cells presumably involves movement of diffusible complexes such as HgGSH.
Methylmercury efflux from brain capillary endothelial cells is modulated by intracellular glutathione but not ATP. Kerper LE, Mokrzan EM, Clarkson TW, Ballatori N. Toxicol Appl Pharmacol. 1996 Dec;141(2):526-31. 8975777 PubMed. To reach its target tissue, methylmercury must traverse brain capillary endothelial cells, the site of the blood-brain barrier. Methylmercury uptake from blood plasma into these cells is mediated in part by an amino acid carrier that transports the methylmercury-L-cysteine complex; however, the mechanism by which it is released from the endothelial cells into brain interstitial space is unknown. These results indicate that complexation with GSH and subsequent transport of the complex by an ATP-independent mechanism may be involved in the transport of methylmercury out of brain capillary endothelial cells.
Methylmercury inhibits cysteine uptake in cultured primary astrocytes, but not in neurons. Shanker G, Allen JW, Mutkus LA, Aschner M. Brain Res. 2001 Sep 28;914(1-2):159-65. 11578608 PubMed. The maintenance of adequate intracellular glutathione (GSH) concentrations is dependent on the availability and transport of the rate-limiting substrate, cysteine. A suggested mechanism of methylmercury (MeHg) neurotoxicity in brain involves the formation of oxygen radicals, and a decrease in intracellular levels of GSH. These results suggest that the inhibition of cysteine uptake by MeHg in astrocytes occurs through specific inhibition of both the X(AG(-)) as well as the ASC transport system.
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Neurodegenerative disorders in humans: the role of glutathione in oxidative stress-mediated neuronal death. Bains JS, Shaw CA. Brain Res Brain Res Rev. 1997 Dec; 25(3):335-58. 9495562 PubMed. Oxidative stress has been implicated in both normal aging and in various neurodegenerative disorders and may be a common mechanism underlying various forms of cell death including necrosis, apoptosis, and excitotoxicity. In this review, we develop the hypothesis that oxidative stress-mediated neuronal loss may be initiated by a decline in the antioxidant molecule glutathione (GSH). GSH plays multiple roles in the nervous system including free radical scavenger, redox modulator of ionotropic receptor activity, and possible neurotransmitter. GSH depletion can enhance oxidative stress and may also increase the levels of excitotoxic molecules; both types of action can initiate cell death in distinct neuronal populations. Evidence for a role of oxidative stress and diminished GSH status is presented for Lou Gehrig's disease (ALS), Parkinson's disease, and Alzheimer's disease. Potential links to the Guamanian variant of these diseases (ALS-PD complex) are discussed. In context to the above, we provide a GSH-depletion model of neurodegenerative disorders, suggest experimental verifications of this model, and propose potential therapeutic approaches for preventing or halting these diseases.
Role of extracellular glutathione and gamma-glutamyltranspeptidase in the disposition and kidney toxicity of inorganic mercury in rats. de Ceaurriz J, Payan JP, Morel G, Brondeau MT. J Appl Toxicol. 1994 May-Jun; 14(3):201-6. 7916024 PubMed. In gamma-GT-inhibited rats treated with HgCl2 the renal and plasma reduced glutathione (GSH) content increased by 68% and 330% respectively, as compared to controls. The gamma-GT inhibition affected the distribution profile of mercury within urinary proteins, shifting the binding of mercury from the high-molecular-weight fraction (3% against 80%) to the low-molecular-weight fraction (72% against 10%). A significant but less impressive shift of mercury from the high- to the low-molecular-weight fraction also arose in the plasma. These results taken together support the pivotal role of extracellular GSH and membrane-bound gamma-GT in the renal incorporation, toxicity and excretion of inorganic mercury in rats.
Role of extracellular thiols in accumulation and distribution of inorganic mercury in rat renal proximal and distal tubular cells. Lash LH, Putt DA, Zalups RK. J Pharmacol Exp Ther. 1998 Jun; 285(3):1039-50. 9618406 PubMed. Coexposure with Hg and GSH also decreased accumulation of Hg relative to exposure to Hg alone, but the decrease was less than coexposure with either BSA or DMPS, suggesting that either an Hg-GSH complex may be a transport form or that some of the Hg-GSH complexes were degraded to Hg-cysteine by the action of brush-border membrane enzymes. These results demonstrate that extracellular thiols markedly alter the renal accumulation of Hg and suggest that some Hg-thiol conjugates may be important physiological transport forms of Hg in the kidney.
Role of glutathione and hepatic glutathione S-transferase in the biliary excretion of methyl mercury, cadmium and zinc: a study with enzyme inducers and glutathione depletors. Gregus Z, Varga F. Acta Pharmacol Toxicol (Copenh). 1985 May; 56(5):398-403. 4036632 PubMed. These results do not provide evidence for the role of hepatic GST but strongly support the importance of biliary GSH excretion in the hepatobiliary transport of methyl mercury, cadmium and zinc. It is assumed that phenobarbital and PCN enhance the biliary excretion of these metals by increasing the transport of GSH, the carrier molecule, from liver to bile.
Tissue glutathione, nutrition, and oxidative stress. Bray TM, Taylor CG. Can J Physiol Pharmacol. 1993 Sep; 71(9):746-51. 8313240 PubMed. Glutathione, a cysteine-containing tripeptide, is the most abundant nonprotein thiol in mammalian cells. Glutathione plays an important role in the detoxification of xenobiotic compounds and in the antioxidation of reactive oxygen species and free radicals. Because of its multiple functions in various tissues and its involvement in many diseases and malnutrition, a clear understanding of the interrelationships among tissue glutathione, nutrition, and oxidative stress is clinically relevant. The focus of this review is to discuss the regulation of tissue glutathione concentration by diet and nutritional status, and to apply this information to those diseases and malnutrition in which decreased tissue glutathione and increased oxidative stress are implicated. A potential strategy to rapidly restore glutathione for both antioxidant and immune defense systems before therapeutic treatment in malnourished patients is discussed.
The effects of glutathione glycoside in methyl mercury poisoning. Choi BH, Yee S, Robles M. Toxicol Appl Pharmacol. 1996 Dec; 141(2):357-64. 8975759 PubMed. The use of glutathione glycoside (GSH-glyc), a compound newly synthesized in our laboratory, was highly effective in raising cellular GSH levels both in vitro and in vivo. Based on mass spectrometry and 1H NMR data, the structure of GSH-glyc was determined to be that of an S-glycoside. Rapid GSH uptake was observed by confocal microscopy in both A549 cells and mouse astrocytes following incubation with GSH-glyc. Intraperitoneal (i.p.) and per oral administration of GSH-glyc in C57BL/6J mice raised GSH concentrations in brain and liver to significantly higher levels than normal. Methyl mercury (MeHg) poisoning of mice with multiple doses of methylmercuric chloride (MMC) induced severe toxic effects associated with marked depletion of brain and liver GSH progressing to death in all animals, whereas the animals primed with GSH-glyc and given MMC and GSH-glyc concurrently were devoid of toxic signs. We suggest, on the basis of D-[3H]glucose and [2- 3H]deoxyglucose uptake studies, that the transport of GSH-glyc across the blood-brain barrier may occur through one of the glucose transport pathways. Although the precise mechanism by which GSH-glyc protects against MeHg poisoning is not clear, it is probable that any one of a number of factors, including conjugation of MeHg, scavenging of free radicals, restoration of reactive thiol groups, and enhancement of MeHg efflux, may have been instrumental. GSH-glyc is a nontoxic compound that can be used to transport GSH into cells, including those of brain and liver, and may prove to be useful for prophylaxis and therapy of tissue injury induced by various neurotoxic compounds, particularly when the capacity to synthesize or regenerate GSH has been compromised.
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The formation of constants of mercury (II)--glutathione complexes. Oram PD, Fang X, Fernando Q, Letkeman P, Letkeman D. Chem Res Toxicol. 1996 Jun; 9(4):709-12. 8831814 PubMed. The formation constants of the 1:1 and 1:2 complexes of Hg (II) with glutathione and their protonated species have been determined by using a competitive potentiometric titration with the competing ligand diethylenetriaminepentaacetic acid (DTPA). The formation constants of the 1:1 complex and its protonated species have not been reported previously. The formation constant of the 1:2 complex of Hg (II) and glutathione is substantially smaller than the accepted values that has been reported in the literature. These results have important implications in the models that have been employed to explain the mobilization and distribution of Hg (II) in biological systems.
Thiol and redox reactive agents exert different effects on glutathione metabolism in HeLa cell cultures. Hultberg B, Andersson A, Isaksson A. Clin Chim Acta. 1999 May; 283(1-2):21-32. 10404728 PubMed. Glutathione protects cells against oxidative damage, free radical damage and other types of toxicity. The aim of the present study was to investigate the impact on glutathione metabolism exerted by different thiol or redox reactive agents. Intracellular concentrations of glutathione in HeLa cell cultures were lowered after addition of agents mainly exerting oxidative stress (homocysteine and hydrogen peroxide), whereas thiol reactive oxidative agents (mercury ions, copper ions and hydroquinone) in concentrations not affecting cell growth seemed to stimulate the production of glutathione. Possibly, the thiol reactive agents decrease the concentration of glutathione, thereby stimulating further synthesis of glutathione, since glutathione synthesis is subject to feedback regulation by glutathione on gamma-glutamylcysteine synthase.
Metallothionein induction in fetal rat brain and neonatal primary astrocyte cultures by in utero exposure to elemental mercury vapor (Hg0). Aschner M, Lorscheider FL, Cowan KS, Conklin DR, Vimy MJ, Lash LH. Brain Res. 1997 Dec 5; 778(1):222-32. 9462895 PubMed. Consistent with the increase in MT mRNA, an increase in astrocytic levels of MT proteins was noted by Western blot analysis and MT-immunoreactivity. These studies suggest that in utero exposure to Hg0 induces brain MT gene expression, and that MT mRNAs and their respective proteins are useful quantitative biochemical markers of intrauterine exposure to Hg0, a potentially cytotoxic challenge to astrocytes in the developing brain. It is concluded that induction of MT by fetal/neonatal astrocytes represents an attempt by these glial cells to protect against Hg cytotoxicity in maintaining cerebral homeostasis.
Metallothionein in human gingival amalgam tattoos. Lau JC, Jackson-Boeters L, Daley TD, Wysocki GP, Cherian MG. Arch Oral Biol. 2001 Nov; 46(11):1015-20. 11543708 PubMed. Blood vessels exhibiting relatively few amalgam particles stained positively for MT. Cells with the morphological features of histiocytes located directly adjacent to larger pieces of amalgam showed intense MT staining. These results indicate that amalgam tattoos contain no Hg or free Ag except in large globular pieces of amalgam, which still contain Hg and which induce MT expression in adjacent histiocytes. This suggests that Hg leaching from impacted dental amalgam particles induces MT, while residual Ag(2)S and Sn particles do not. MT may therefore act to reduce Hg exposure in patients with amalgam tattoos.
Methylmercury alters glutamate transport in astrocytes. Aschner M, Yao CP, Allen JW, Tan KH. Neurochem Int. 2000 Aug-Sep; 37(2-3):199-206. 10812205 PubMed. This manuscript details the role of astrocytes in mediating MeHg-induced excitotoxicity, and elaborates on the protective role afforded by metallothioneins (MTs) in attenuating MeHg cytotoxicity.
Recent studies on metallothionein: protection against toxicity of heavy metals and oxygen free radicals. Sato M, Kondoh M. Tohoku M. J Exp Med. 2002 Jan; 196(1):9-22. 12498322 PubMed. Metallothionein (MT) is a ubiquitous, cysteine-rich, metal-binding protein. MT synthesis is induced by various stimuli such as cadmium, mercury, zinc, oxidative stress, glucocorticoid, and anticancer agents. Recently, transgenic mice with loss-of-function mutations in the MT-I/-II genes were established. It has been assumed that MT plays a role in the detoxification of heavy metals. In recent studies using MT-null mice, the ability of MT to protect against cadmium-induced renal, liver and bone injuries has been confirmed. Moreover, MT is also capable of scavenging oxygen free radicals. MT is involved in the protection of tissues against various forms of oxidative injury, including radiation, lipid peroxidation, oxidative stress caused by anticancer drugs, and conditions of hyperoxia. However, MT still lacks an established biological function. Unexpectedly, the MT-null mice were apparently in good health, and the critical biological roles of MT have been questioned. MT seems to be a protective protein produced in response to a variety of stresses.
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Temporal changes in metallothionein gene transcription in rat kidney and liver: relationship to content of mercury and metallothionein protein. Zalups RK, Koropatnick J. J Pharmacol Exp Ther. 2000 Oct;295(1):74-82. 10991963 PubMed. Metallothioneins are encoded by a family of genes that are induced by inorganic mercury. Despite the well-characterized acute response of metallothionein (MT) genes in the kidneys and liver after a single exposure to inorganic mercury, relatively little is known about the activity of these genes and the content of MT protein during prolonged periods after exposure. Rats treated with inorganic mercury accumulate mercury rapidly in kidneys and liver during the first 24 h after exposure, but only in the kidneys does the content of mercury remain elevated throughout the initial 2 weeks. We report herein that transcription of MT genes in response to treatment with inorganic mercury differs dramatically between the kidneys and liver. MT gene transcription and levels of MT protein remained elevated in the kidneys throughout 14 days after treatment. In contrast, the initially high rates of MT gene transcription and enhanced content of MT protein in the liver fell to control levels by 14 days. In the liver, the rates of MT gene transcription and levels of MT protein were strongly correlated with each other and with the content of mercury. In the kidneys, however, these correlations were very weak or absent. Our data indicate that hepatic levels of MT protein are determined primarily by MT gene transcription, but that post-transcriptional events are important in determining the renal content of MT protein during the initial weeks after exposure. This has important implications in understanding differences in mechanisms controlling MT expression in the kidneys and liver.
The effect of dietary zinc status on biliary metal excretion of rats. Jaw S, Jeffery EH. J Nutr. 1988 Nov; 118(11):1385-90. 3193255 PubMed. The effect of dietary zinc status on biliary excretion of zinc, cadmium and mercury administered as a bolus of metal chloride (1 mg metal/kg body weight i.v.) was studied. Female rats were fed a purified diet containing either 9 micrograms/g (low), 45 micrograms/g (adequate) or 1150 micrograms/g (high) zinc for 8 d. Hepatic metallothionein (MT) was similar in low- and adequate-zinc groups, but was 18-fold higher in the high-zinc group than in the other two groups. Liver zinc content varied in relation to dietary zinc level. Biliary excretion of all metals studied was significantly lower in the high-zinc group than in the low-zinc group. The cumulative excretion of zinc, cadmium and mercury over 2.5 h in rats fed these two diets was 6.2 +/- 1.4 vs. 33.5 +/- 7.7, 0.006 +/- 0.02 vs. 22.8 +/- 8.4 and 1.6 +/- 0.6 vs. 14.9 +/- 5.3 micrograms/kg body weight, respectively. A relationship was found between the disposition of metal in liver and the extent of biliary metal excretion. Biliary metal excretion was highly correlated with liver cytosolic non-MT-bound metal; r = 0.999, 0.998 and 0.993 for endogenous + exogenous zinc, cadmium and mercury, respectively.
The protective effect of metallothionein on the toxicity of various metals in rat primary hepatocyte culture. Liu J, Kershaw WC, Klaassen CD. Toxicol Appl Pharmacol. 1991 Jan; 107(1):27-34. 1987657 PubMed. In summary, Zn-induced MT in rat primary hepatocyte cultures protects against Ag-, Co-, Cu-, Hg-, Ni-, Pb-, and Zn-induced cytotoxicity. This protection appears to be due to the binding of metals to MT with a concomitant reduction of metal content in critical organelles and proteins.
Effect of different renal glutathione levels on renal mercury disposition and excretion in the rat. Girardi G, Elias MM. Toxicology. 1993 Jul 11;81(1):57-67. 8367881 PubMed. The results indicate a higher HgCl2 renal clearance in N-acetylcysteine-treated rats compared to controls and less renal mercury accumulation. The data agree with diminished renal toxicity. On the other hand, renal mercury accumulation was higher and mercury renal clearance lower in diethylmaleate-treated animals, associated with higher renal toxicity. The results suggest that non-protein sulfhydryl levels (principally glutathione) might determine renal accumulation of mercury as well as its elimination rate and hence might enhance or mitigate the nephrotoxicity induced by the metal.
Effectiveness of N-acetylcysteine in protecting against mercuric chloride-induced nephrotoxicity. Girardi G, Elias MM. Toxicology. 1991 Apr 8; 67(2):155-64. 1674384 PubMed. Mercuric chloride (HgCl2)-induced nephrotoxicity, as measured by functional and biochemical parameters was evaluated in rats at different kidney non-protein sulfhydryls (NPS) levels. Diethylmaleate (DEM) induced a 75% of NPS diminution 1 h after the administration. Renal function (clearance) and biochemical measurements (gamma-glutamyltranspeptidase activity in urine, and lipoperoxides in kidney tissue) were impaired when the animals were HgCl2-treated. DEM treatment promoted a higher accumulation of HgCl2 in both kidney and liver while NAC-treatment reduced significantly the metal content in these organs. These data are in favour of a positive relationship among mercury content and organ injury.
Identification of a mechanism by which the methylmercury antidotes N-acetylcysteine and dimercaptopropanesulfonate enhance urinary metal excretion: transport by the renal organic anion transporter-1. Koh AS, Simmons-Willis TA, Pritchard JB, Grassl SM, Ballatori N. Mol Pharmacol. 2002 Oct; 62(4):921-6. 12237339 PubMed. N-Acetylcysteine (NAC) and dimercaptopropanesulfonate (DMPS) are sulfhydryl-containing compounds that produce a dramatic acceleration of urinary methylmercury (MeHg) excretion in poisoned animals, but the molecular mechanism for this effect is unknown. NAC and DMPS are themselves excreted in urine in high concentrations. The present study tested the hypothesis that the complexes formed between MeHg and these anionic chelating agents are transported from blood into proximal tubule cells by the basolateral membrane organic anion transporters (Oat) 1 and Oat3. These results indicate that the MeHg antidotes NAC and DMPS and their mercaptide complexes are transported by Oat1 but are comparatively poor substrates for Oat3. This is the first molecular identification of a transport mechanism by which these antidotes may enhance urinary excretion of toxic metals.
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Lung and blood superoxide dismutase activity in mercury vapor exposed rats: effect of N-acetylcysteine treatment. Livardjani F, Ledig M, Kopp P, Dahlet M, Leroy M, Jaeger A. Toxicology. 1991 Mar 11;66(3):289-95. 2011853 PubMed. Rats were exposed to mercury vapors (30 mg/m3) for either 1 or 2 h. Histological lesions like alveolar oedema, hyaline membranes and sometimes fibrosis were observed. The lesions were more significant after 2 h of exposure, with about 50% of the animals dying within 2 weeks. The mercury level and the superoxide dismutase activity in the blood and the lungs demonstrated differences according to the time of exposure. In the animals exposed for 2 h to mercury vapors, N-acetylcysteine treatment increased survival time and the percentage of living animals. The lung superoxide dismutase was lower than in the non-treated animals indicating an antioxidant effect. Mercury levels were decreased in blood and lung, suggesting some chelating effect of N-acetylcysteine. The exact mechanism of its action must be further elucidated.
N-acetylcysteine. No authors listed. Altern Med Rev. 2000 Oct; 5(5):467-71. 11056417 PubMed. N-acetylcysteine (NAC) is the acetylated precursor of both the amino acid L-cysteine and reduced glutathione (GSH). Historically it has been used as a mucolytic agent in chronic respiratory illnesses as well as an antidote for hepatotoxicity due to acetaminophen overdose. More recently, animal and human studies of NAC have shown it to be a powerful antioxidant and a potential therapeutic agent in the treatment of cancer, heart disease, HIV infection, heavy metal toxicity, and other diseases characterized by free radical oxidant damage. NAC has also been shown to be of some value in treating Sjogren's syndrome, smoking cessation, influenza, hepatitis C, and myoclonus epilepsy.
N-acetylcysteine as an antidote in methylmercury poisoning. Ballatori N, Lieberman MW, Wang W. Environ Health Perspect. 1998 May; 106(5):267-71. 9520359 PubMed. Methylmercury is a ubiquitous environmental pollutant and potent neurotoxin. Treatment of methylmercury poisoning relies almost exclusively on the use of chelating agents to accelerate excretion of the metal. The present study demonstrates that oral administration of N-acetylcysteine (NAC), a widely available and largely nontoxic amino acid derivative, produces a profound acceleration of urinary methylmercury excretion in mice. Mice that received NAC in the drinking water (10 mg/ml) starting at 48 hr after methylmercury administration excreted from 47 to 54% of the 203Hg in urine over the subsequent 48 hr, as compared to 4-10% excretion in control animals. When NAC-containing water was given from the time of methylmercury administration, it was even more effective at enhancing urinary methylmercury excretion and at lowering tissue mercury levels. In contrast, excretion of inorganic mercury was not affected by oral NAC administration. The ability of NAC to enhance methylmercury excretion when given orally, its relatively low toxicity, and is wide availability in the clinical setting indicate that it may be an ideal therapeutic agent for use in methylmercury poisoning.
Treatment of acute methylmercury ingestion by hemodialysis with N-acetylcysteine (Mucomyst) infusion and 2,3-dimercaptopropane sulfonate. Lund ME, Banner W Jr, Clarkson TW, Berlin M. J Toxicol Clin Toxicol. 1984 Jul; 22(1):31-49. 6492229 PubMed. A case of acute methylmercury ingestion was treated sequentially with oral D-penicillamine, hemodialysis during N-acetylcysteine (NAC) infusion, and 2,3-dimercaptopropane sulfonate (DMPS) an experimental oral agent. Urinary organic mercury elimination rate increased almost 40-fold during and 84-fold after hemodialysis with NAC infusion, compared with elimination during initial D-penicillamine therapy.
Correlation of mercury and selenium in the human kidney. Drasch G, Wanghofer E, Roider G, Strobach S. J Trace Elem Med Biol. 1996 Dec;10(4) :251-4. 9021677 PubMed. The total mercury (Hg) and selenium (Se) concentrations were determined in kidney cortex samples of 195 deceased, non-occupationally burdened individuals. Mercury was determined by means of Cold-vapour Atomic Absorption Spectrometry (CV-AAS) and selenium by Graphite-Furnace Atomic Absorption Spectrometry (GF-AAS). The molar Se/Hg ratio is high (up to (a) 300) in cases with relatively low mercury concentrations [Hg]. The ratio decreases with increasing [Hg]. At [Hg] of 700-1000 ng/g it reaches unity, where it remains constant even at larger [Hg]. Since in vitro mercury and selenium form relatively stable adducts, our results suggest the formation of a 1:1 Hg-Se compound that may explain mercury detoxification by selenium. This effect also results in the trapping of available selenium by mercury, too. Decreasing the reserve of free (i.e. not Hg-bound) selenium. The effect of this decrease of free selenium is under further investigation.
Dental amalgam affects urinary selenium excretion. Hol PJ, Vamnes JS, Gjerdet NR, Eide R, Isrenn R. Biol Trace Elem Res. 2002 Feb; 85(2):137-47. 11899021 PubMed. Selenium may have a protective effect against mercury toxicity. Individuals with amalgam excreted less selenium (36.4 microg, median value) over 24 hours than those without amalgam (47.5 microg) (p = 0.016). The findings indicate that individuals exposed to low levels of elemental mercury from dental amalgam excrete less selenium to urine than unexposed individuals.
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Dental amalgam and selenium in blood. Hol PJ, Vamnes JS, Gjerdet NR, Eide R, Isrenn R. Environ Res. 2001 Dec;87(3):141-6. 11771928 PubMed. The median concentration of Se in blood (119.2 microg/L) was statistically significantly lower in subjects who claimed symptoms of mercury amalgam illness than in healthy subjects with amalgam (130.3 microg/L). The difference was more evident in individuals with more than 35 amalgam surfaces (P=0.003). Additional control groups without amalgam fillings comprised 19 healthy controls without amalgam experience and 20 subjects who have had amalgam fillings removed due to suspected symptoms associated with amalgam. The Se concentrations in these groups were not different from those with amalgam. It is indicated that persons with ill health self-related to dental amalgam might have a Se metabolism different from that of healthy people.
Detoxification of mercury by selenium by binding of equimolar Hg-Se complex to a specific plasma protein. Yoneda S, Suzuki KT. Toxicol Appl Pharmacol. 1997 Apr; 143(2):274-80. 9144444 PubMed. Toxicity of mercury (Hg) can be reduced by coadministration with selenium (Se), and this has been explained by the formation of a complex between a specific plasma protein and the two elements, which are bound to the protein at an equimolar ratio.
Effects of maternal dietary supplementation with selenite on the postnatal development of rat offspring exposed to methyl mercury in utero. Fredriksson A, Gardlund AT, Bergman K, Oskarsson A, Ohlin B, Danielsson B, Archer T. Pharmacol Toxicol. 1993 Jun; 72(6):377-82. 8395689 PubMed. The results of the study showed that supplementing the diet with Se partly antagonized some adverse effects of the MeHg such as hypoactivity especially in the high MeHg dose group. There were no changes in physical development or body weight except a tendency to decreased body weight in offspring of mothers exposed to 6 mg Hg/kg. The GSH-Px activity was significantly increased in animals fed on Se supplemented diet. The dietary Se supplementation resulted in considerably increased concentrations of mercury in the blood of the offspring despite milder signs of CNS toxicity and no increase in brain concentrations of mercury.
Effect of supplementation with organic selenium on mercury status as measured by mercury in pubic hair. Seppanen K, Kantola M, Laatikainen R, Nyyssonen K, Valkonen VP, Kaarlopp V, Salonen JT. J Trace Elem Med Biol. 2000 Jun; 14(2):84-7. 10941718 PubMed. The purpose of this study was to evaluate the effect of four months of yeast-based selenium supplementation on selenium and mercury status in subjects with low serum selenium. The study was carried out in Rakvere, Estonia. Pubic hair mercury, serum selenium and blood selenium concentrations in 23 subjects (serum selenium < 90 micrograms/l) were investigated before and after selenium supplementation. Thirteen subjects were randomized into the selenium supplementation group and ten into the placebo group. The selenium supplementation group received daily 100 micrograms of selenomethionine. Selenium supplementation reduced pubic hair mercury level by 34% (p = 0.005) and elevated serum selenium by 73% and blood selenium by 59% in the supplemented group (p < 0.001 for both). The study indicates that mercury accumulation in pubic hair can be reduced by dietary supplementation with small daily amounts of organic selenium in a short range of time.
Effects of selenium and mercury on the enzymatic activities and lipid peroxidation in brain, liver, and blood of rats. El-Demerdash FM. J Environ Sci Health B. 2001 Jul; 36(4):489-99. 11495025 PubMed. Selenium in combination with Hg partially or totally alleviated the toxic effects of Hg on different studied enzymes. It is concluded that Se could be able to antagonize the toxic effects of mercury.
Equimolar Hg-Se complex binds to selenoprotein. P. Yoneda S, Suzuki KT. Biochem Biophys Res Commun. 1997 Feb 3; 231(1):7-11. 9070209 PubMed. These results indicate that equimolar Hg and Se bind to Sel P to form the inverted question mark(Hg-Se)n inverted question markm-Sel P complex, where n is the number of Hg-Se complexes and m the number of binding sites in Sel P.
Influence of selenium on mercuric chloride cellular uptake and toxicity indicating protection: studies on cultured K-562 cells. Frisk P, Yaqob A, Nilsson K, Carlsson J, Lindh U. Biol Trace Elem Res. 2001 Sep; 81(3):229-44. 11575680 PubMed. 11575680 PubMed. Selenium and mercuric chloride (MC) interactions regarding cellular uptake and selenium protection on MC toxicity have been studied. Human K-562 cells were pretreated or simultaneously treated with either selenite (5 or 50 microM) or selenomethionine (10 or 50 microM) together with MC (35 or 50 microM). Both treatments with selenite showed an increase of mercury uptake with increased selenium dose. In the pretreated or simultaneously treated selenite and 35 microM MC combinations, no inhibition of growth was seen, whereas all 50-microM MC combinations were toxic to the cells. A selenite-dependent protection was obtained for both exposure protocols when considering the cellular uptake of mercury. The cells died when the accumulation on d 4 reached more than about 0.8 x 10(-15) mol/cell of mercury, whereas they survived up to twofold more mercury uptake when exposed to selenite. Selenomethionine gave, with a few exceptions, similar effects as selenite on MC uptake and toxicity.
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Landscapes of longevity: the calcium-selenium-mercury connection in cancer and heart disease. Foster HD. Med Hypotheses. 1997 Apr; 48(4):355-60. 9160292 PubMed. Cancer and heart disease display spatial patterns that suggest the possible involvement of calcium and selenium deficiencies and mercury excess in their aetiologies. As a consequence, longevity tends to be most common in regions where the environment is calcium- and selenium-enriched but contains only low levels of mercury. Examples are cited from West Africa, China, England and the USA.
Mercury-binding capacity of organic and inorganic selenium in rat blood and liver. Seppanen K, Laatikainen R, Salonen JT, Kantola M, Lotjonen S, Harri M, Nurminen L, Kaikkonen J, Nyyssonen K. Biol Trace Elem Res. 1998 Dec; 65(3):197-210. 9892493 PubMed. Seleno-DL-methionine had a tendency to increase both methyl mercury and total mercury in blood, although it also seemed to reduce the proportion of methyl mercury of total mercury. Selenium dioxide lowered mercury levels by 24-29% both in the blood and in the liver of rats that were fed with northern pike. 3
Modification of mercury toxicity by selenium: Practical importance? Watanabe C. Tohoku J Exp Med. 2002 Feb;196(2):71-7. 12498318 PubMed. An interaction between MeHg and seleno-proteins or a possible interaction between the inorganic mercury, resulting from the demethylation of MeHg, and the selenium may be important.
Selenium concentrations in brain after exposure to methylmercury: relations between the inorganic mercury fraction and selenium. Bjorkman L, Mottet K, Nylander M, Vahter M, Lind B, Friberg L. Arch Toxicol. 1995; 69(4):228-34. 7755482 PubMed. The results indicated an association between concentrations of inorganic mercury and selenium in both occipital pole and thalamus in the MeHg-exposed animals. A linear regression model using concentrations of inorganic mercury (nmol/g wet wt) as independent variable, and selenium concentrations (nmol/g wet wt) as the dependent variable showed significant correlations between the variables in both occipital pole and thalamus (r = 0.85 and r = 0.91, P < 0.0001). The intercept of the regression line was slightly lower (about 2 nmol Se/g wet wt) than the selenium concentrations found in control monkeys (about 3 nmol Se/g wet wt). There was a tendency to a "hockey stick"-shaped relationship between concentrations of selenium and inorganic mercury in the thalamus of monkeys with ongoing exposure to MeHg. An important role for selenium in the retention of mercury in brain is indicated.
Selenium protection against toxicity from cadmium and mercury studied at the cellular level. Lindh U, Danersund A, Lindvall A. Cell Mol Biol (Noisy-le-grand). 1996 Feb; 42(1):39-48. 8833665 PubMed. Interaction between selenium and the heavy metals cadmium and mercury was studied in an experimental rat model (Sprague-Dawley). The rats were administered either one single trace element or combinations of selenium and cadmium as well as selenium and mercury. Salts of these trace elements were administered intraperitoneally daily during thirty days. Thereafter the animals were sacrificed and kidneys and livers excised rapidly. Thin sections were produced by a cryotome and subsequently freeze-dried. Nuclear microscopy of the sections showed that in the combination groups there was a co-localization of selenium and the heavy metals. None of the expected pathological signs of cadmium and mercury toxicity were observed. The conclusion was that selenium exerted a protective effect against the toxicity of cadmium and mercury through mechanisms still to be unveiled.
Serum selenium and glutathione-peroxidase activities and their interaction with toxic metals in dialysis and renal transplantation patients. Turan B, Delilbasi E, Dalay N, Sert S, Afrasyap L, Sayal A. Biol Trace Elem Res. 1992 Apr-Jun; 33:95-102. 1379465 PubMed. These findings imply that dietary selenium supplement may be suggested in renal failure for the detoxification of elements, such as cadmium and mercury. The essential trace element selenium takes part not only in the direct protection of endothelial cells against the accumulation of aggressive oxygen species, but also in the prevention of the toxic effects of cadmium or in the modulation of the active calcium transport.
Structural basis of the antagonism between inorganic mercury and selenium in mammals. Gailer J, George GN, Pickering IJ, Madden S, Prince RC, Yu EY, Denton MB, Younis HS, Aposhian HV. Chem Res Toxicol. 2000 Nov; 13(11):1135-42. 11087435 PubMed. Mercuric chloride toxicity in mammals can be overcome by co-administration of sodium selenite. The molecular detoxification product of sodium selenite and mercuric chloride in rabbits exhibits similarities to the synthetic Hg-Se-S species.
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A prospective study of prenatal mercury exposure from maternal dental amalgams and autism severity. Geier DA, Kern JK, Geier MR. Acta Neurobiol Exp (Wars). 2009;69(2):189-97. Dental amalgams containing 50% mercury (Hg) have been used in dentistry for the last 150 years, and Hg exposure during key developmental periods was associated with autism spectrum disorders (ASDs). This study examined increased Hg exposure from maternal dental amalgams during pregnancy among 100 qualifying participants born between 1990-1999 and diagnosed with DSM-IV autism (severe) or ASD (mild) Subjects with more than 6 amalgams were 3.2-fold significantly more likely to be diagnosed with autism (severe) in comparison to ASD (mild) than subjects with 5 or fewer amalgams. Dental amalgam policies should consider Hg exposure in women before and during the child-bearing age and the possibility of subsequent fetal exposure and adverse outcomes. 19593333 PubMed.
Age-dependent lower or higher levels of hair mercury in autistic children than in healthy controls. Maria Dorota Majewska, et al. Acta Neurobiol Exp 2010, 70: 196–208. 20628443 PubMed. Autistic children had a significantly greater prevalence of adverse reactions after vaccinations and abnormal development than controls. Between 45 and 80% of autistic children experienced developmental regress. Autistic children significantly differed from healthy peers in the concentrations of mercury in hair: younger autistics had lower levels, while older – higher levels than their respective controls. The results suggest that autistic children differ from healthy children in metabolism of mercury, which seems to change with age.
Autism, an extreme challenge to integrative medicine. Part 2: medical management. Kidd PM. Altern Med Rev. 2002 Dec; 7(6):472-99. 12495373 PubMed. Detoxification of mercury and other heavy metals by DMSA/DMPS chelation can have marked benefit. Documented sulfoxidation-sulfation inadequacies call for sulfur-sulfhydryl repletion and other liver p450 support. Many nutrient supplements are beneficial and well tolerated, including dimethylglycine (DMG) and a combination of pyridoxine (vitamin B6) and magnesium, both of which benefit roughly half of ASD cases. Vitamins A, B3, C, and folic acid; the minerals calcium and zinc; cod liver oil; and digestive enzymes, all offer benefit.
Autism: a novel form of mercury poisoning. Bernard S, Enayati A, Redwood L, Roger H, Binstock T. Med Hypotheses. 2001 Apr; 56(4):462-71. 11339848 PubMed. Autism is a syndrome characterized by impairments in social relatedness and communication, repetitive behaviors, abnormal movements, and sensory dysfunction. Recent epidemiological studies suggest that autism may affect 1 in 150 US children. Exposure to mercury can cause immune, sensory, neurological, motor, and behavioral dysfunctions similar to traits defining or associated with autism, and the similarities extend to neuroanatomy, neurotransmitters, and biochemistry. Thimerosal, a preservative added to many vaccines, has become a major source of mercury in children who, within their first two years, may have received a quantity of mercury that exceeds safety guidelines. A review of medical literature and US government data suggests that: (i) many cases of idiopathic autism are induced by early mercury exposure from thimerosal; (ii) this type of autism represents an unrecognized mercurial syndrome; and (iii) genetic and non-genetic factors establish a predisposition whereby thimerosal's adverse effects occur only in some children.
Autism: treatment-chelation of mercury. Amy S. Holmes, M.D. We currently have over 500 autistic patients under treatment with DMSA ranging in age from 1 to 24 years old. In general, we do not expect to see any behavioral, language, or social improvements until at least some of the CNS mercury has been removed. As of 1/15/01, we had 85 patients who had finished DMSA alone and had completed at least 4 months of DMSA + lipoic acid. The results of treatment in these patients are presented below:
n = 85
Once lipoic acid is added, we usually track mercury excretion via tests of fecal mercury. We have noticed a large dependence of excretion on age of patient with the younger patients excreting much more mercury than the older patients. We think this difference in rapidity of excretion may explain the differences in response between the various age groups. We have 6 patients, all 1 to 2 years of age who are finished with treatment by measurements of urinary and fecal mercury excretion. These 6 patients are "normal" by parent reports and repeat psychological testing. We have no children over the age of 2 who are finished with treatment. The rapidity of excretion seems to decrease markedly with each additional year of age. There are several children, mostly in the younger age groups, who have made remarkable progress to the point of being able to be mainstreamed in school, but who are still have some "oddities" of behavior none of these children have completed treatment yet. These are very early results, but appear very promising. As more data is gathered, outcomes will be better able to be predicted, including length of treatment as well as ultimate prognosis. http://www.healing-arts.org/children/holmes.htm
Autism Treatments. Metal-Metabolism and Autism. Amy S. Holmes, M.D. Dr. William Walsh and Dr. Anjum Usman have discovered that defective functioning of metallothionein protein (MT) is a distinctive feature of autism. This abnormality results in impaired brain development and extreme sensitivity to toxic metals and other environmental substances. This disorder is often unnoticed in infancy and early childhood until aggravated by a serious environmental insult. In a study of 503 autism-spectrum patients, the authors found abnormal levels of copper and zinc in blood (p<0.0001) indicating defective functioning of metallothionein (MT) proteins. Also, calculation of unbound copper provides a reliable indication of the degree of metallothionein function (or dysfunction). In humans, MT proteins regulate blood levels of these trace minerals, detoxify mercury and other heavy metals, and assist in neuronal development. The expected consequences of defective MT during gestation or early infancy are consistent with several classic symptoms of autism. It appears that defective functioning of MT proteins may represent the underlying cause of autism. http://www.healing-arts.org/children/metal-metabolism.htm
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Autism Treatments. Heavy Metal Detoxification and Metallothionein Promotion. Amy S. Holmes, M.D. Recent developments have been made to promote metallothionein (MT) in the G.I. tract, brain, and elsewhere. This protocol is based on 1,200 published articles describing MT synthesis, activation, and redox mechanisms. A total of 22 nutrients that enhance MT production were identified and tested in informal clinical trials involving staff and volunteer autism families. We found that aggressive zinc loading must precede full-scale MT Promotion therapy for best results. Each molecule of MT requires 7 atoms of zinc (Zn) for proper functioning. Premature synthesis of MT at intestinal mucosa can temporarily prevent Zn transport into the bloodstream, resulting in severe irritability. Our best clinical outcomes were achieved using a two-phase protocol: Preloading with Zn and augmenting nutrients, followed by: Cautious, gradual introduction of MT promotion nutrients. Treatment for Patients Found to Have Metallothionein Dysfunction
A good trial of the gluten-free, casein-free diet (at least 6 months) is highly recommended.
a. Gut Clean-up - restore good levels of friendly bacteria and reduce overgrowths of unfriendly organisms such as Clostridia and yeast
b. Supporting Nutrients - exact nutrients determined by testing
c. Reduction of elevated plasma ammonia (if necessary)
d. Aggressive zinc pre-loading
e. DMSA alone until very little mercury, lead or tin is excreted in urine (if necessary)
Step 2 - MT Promotion Protocol
Phase 1: Zinc Loading: Aggressive supplementation with Zn and augmenting nutrients for 4 to 8 weeks is recommended. Sensitive patients may require gradual build-up of Zn dosage. Plasma zinc levels should be greater than 100 mcg/dL prior to Phase 2 to minimize irritability side effects. Zinc dosages vary with body weight. A helpful rule of thumb for small patients is to provide a daily mg dosage of Zn equal to weight (lbs) plus 15-20 mg. For example, a 40 lb child would receive 55-60 mg/day during Phase 1. In addition, we recommend the following augmenting nutrients be given with the Zn: Pyridoxal-5-Phosphate, Manganese Gluconate, and Vitamins C and E. Also, Taurine may be used for patients with seizure tendencies. We have developed a compounded supplement for Phase 1, which we call the "Metabolic Primer".
Phase 2: After Phase 1 is completed, GSH, Se, and the 14 amino-acid constituents of MT are introduced gradually, as tolerated. These nutrients are available in a compounded blend called the MTP supplement. Continuation of casein/gluten-free diets, probiotics, the Metabolic Primer, and other ongoing therapies is recommended. http://www.healing-arts.org/children/mtpromotion.htm
Detoxification for Heavy Metals as a Treatment for Autism Lewis Mehl-Madrona, M.D., Ph.D. The concept behind detoxification is that heavy metals have accumulated in the child and that removal of these heavy metals (and other toxins) will improve symptoms. Some parents have reported that the effects of detoxification are as dramatic as those found with secretin. Nevertheless, since we do not yet know how biologically active secretin is (it could be working because of the Pygmalion Effect or working in subsets of children for reasons completely unrelated to current theory), we do not know with certainty whether detoxification is working due to biological principles or do to parents' expectations.
One source of heavy metals is thought to be the timerosol in vaccines which is associated with mercury. The first step is often testing to determine if heavy metals are present. Typically, a 24 hour urine is obtained for heavy metals and then a dose of DMSA is given and the 24 hour urine is repeated. If heavy metals are present, they should increase when a chelating agent is given. Doctor's Data, Great Smokies Smokies Labs and Great Plains Laboratories do these tests. During chelation therapy, lead is thought to come out first, then mercury, then tin. Typical treatments include the administration of DMSA, 10 mg/kf three times per day for three days and off 11 days. DMPS can be added for additional boosting of effect. Adding lipoic acid is thought to help remove mercury from the Central Nervous System. Detoxification is a long process and may take months. Liver enzymes and a CBC should be obtained - at first monthly, and then at regular intervals of 1-3 months to be sure that no toxicity from the DMSA is developing. http://www.healing-arts.org/children/detoxification.htm
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Mercury and autism: accelerating evidence? Mutter J, Naumann J, Schneider R, Walach H, Haley B. Neuro Endocrinol Lett. 2005 Oct;26(5):439-46. 16264412 PubMed. The causes of autism and neurodevelopmental disorders are unknown. Genetic and environmental risk factors seem to be involved. Because of an observed increase in autism in the last decades, which parallels cumulative mercury exposure, it was proposed that autism may be in part caused by mercury. We review the evidence for this proposal. Several epidemiological studies failed to find a correlation between mercury exposure through thimerosal, a preservative used in vaccines, and the risk of autism. Recently, it was found that autistic children had a higher mercury exposure during pregnancy due to maternal dental amalgam and thimerosal-containing immunoglobulin shots. It was hypothesized that children with autism have a decreased detoxification capacity due to genetic polymorphism. In vitro, mercury and thimerosal in levels found several days after vaccination inhibit methionine synthetase (MS) by 50%. Normal function of MS is crucial in biochemical steps necessary for brain development, attention and production of glutathione, an important antioxidative and detoxifying agent. Repetitive doses of thimerosal leads to neurobehavioral deteriorations in autoimmune susceptible mice, increased oxidative stress and decreased intracellular levels of glutathione in vitro. Subsequently, autistic children have significantly decreased level of reduced glutathione. Promising treatments of autism involve detoxification of mercury, and supplementation of deficient metabolites.
Mercury levels in maternal and cord blood and attained weight through the 24months of life. Kim BM, Lee BE, Hong YC, Park H, Ha M, Kim YJ, Kim Y, Chang N, Kim BN, Oh SY, Yoo M, Ha EH. Sci Total Environ. 2011 Dec 1;410(411):26-33. Epub 2011 Oct 15. 22000783 PubMed. Birth weight is a strong determinant of attained weight at early ages. Until now, many studies have reported that low birth weight corresponds with high mercury levels. However, the relationship between mercury exposure and attained weight of infant has not been well studied. Therefore, the aim of the present study was to assess the degree of prenatal exposure to mercury by measuring the total mercury levels in maternal and cord blood, and examine the relationship between the mercury level during pregnancy and the attained weight of infant during the first 24months of life. The prospective cohort study of Mothers and Children's Environmental Health (MOCEH) was built up in 2006, and 921 mother-infant pairs were recruited. Information on the socio-demographic characteristics, health behavior and environmental exposure were collected from an interview with trained nurses. After delivery, infants and mothers were followed up at 6, 12 and 24months and the weights of the infants were measured. The mercury concentrations in the late maternal blood (β=-0.19. p=0.05) and cord blood (β=-0.36. p=0.01) were negatively associated with the infants' attained weight over the first 24months of age. The infants' attained weight in the small for their gestational age (SGA) group was lower than the normal birth weight group at the highest quartile of the mercury level. Therefore, efforts should be made to reduce the mercury level in the maternal blood at late pregnancy and cord blood. Further research on the possible harmful effects of prenatal mercury exposure on postnatal growth is recommended.
Reduced levels of mercury in first baby haircuts of autistic children. Holmes AS, Blaxill MF, Haley BE. Int J Toxicol. 2003 Jul-Aug; 22(4):277-85. 12933322 PubMed. The mothers in the autistic group had significantly higher levels of mercury exposure through Rho D immunoglobulin injections and amalgam fillings than control mothers. Within the autistic group, hair mercury levels varied significantly across mildly, moderately, and severely autistic children, with mean group levels of 0.79, 0.46, and 0.21 ppm, respectively. Hair mercury levels among controls were significantly correlated with the number of the mothers' amalgam fillings and their fish consumption as well as exposure to mercury through childhood vaccines, correlations that were absent in the autistic group. Hair excretion patterns among autistic infants were significantly reduced relative to control. These data cast doubt on the efficacy of traditional hair analysis as a measure of total mercury exposure in a subset of the population. In light of the biological plausibility of mercury's role in neurodevelopmental disorders, the present study provides further insight into one possible mechanism by which early mercury exposures could increase the risk of autism. (Indicates more mercury went in then went out in autistic children) http://www.healing-arts.org/children/metal-metabolism.htm
The role of mercury in the pathogenesis of autism. Bernard S, Enayati A, Roger H, Binstock T, Redwood L. Mol Psychiatry. 2002; 7 Suppl 2:S42-3. 12142947 PubMed. A review of medical literature has shown that exposure to mercury, whether organic or inorganic, can give rise to the symptoms and traits defining or commonly found in ASD individuals. Mercury can cause impairments in social interaction, communication difficulties, and repetitive and stereotyped patterns of behavior, which comprise the three DSM-IV autism diagnostic criteria. Additionally, mercury can induce features prominent in ASD such as sensory abnormalities, emotional/psychological changes, movement disorder, impairments in abstract or complex thinking, severe sleep disturbances, and self injurious behavior. Males are more affected than females in both conditions. Physiological abnormalities more common in ASD populations and known to be caused by mercury exposure include gastrointestinal problems, autonomic nervous system disturbance, unusual EEG activity, immune system alterations, irregularities in neurotransmitter systems, and non-specific brain lesions.
Thimerosal and autism? A plausible hypothesis that should not be dismissed. Blaxill MF, Redwood L, Bernard S. Med Hypotheses. 2004;62(5):788-94. 15082108 PubMed. The autism-mercury hypothesis first described by Bernard et al. has generated much interest and controversy. The Institute of Medicine (IOM) reviewed the connection between mercury-containing vaccines and neurodevelopmental disorders, including autism. They concluded that the hypothesis was biologically plausible but that there was insufficient evidence to accept or reject a causal connection and recommended a comprehensive research program. Without citing new experimental evidence, a number of observers have offered opinions on the subject, some of which reject the IOM's conclusions. In a recent review, Nelson and Bauman argue that a link between the preservative thimerosal, the source of the mercury in childhood vaccines, is improbable. In their defense of thimerosal, these authors take a narrow view of the original hypothesis, provide no new evidence, and rely on selective citations and flawed reasoning. We provide evidence here to refute the Nelson and Bauman critique and to defend the autism-mercury hypothesis.
Blood and Body Fluids
The contribution of dental amalgam to mercury in blood. Snapp KR, Boyer DB, Peterson LC, Svare CW. J Dent Res. 1989 May; 68(5):780-5. 2715470 PubMed. The mean baseline concentration of total mercury in whole blood of the ten subjects was 2.18 (SD = 0.90) ng Hg/mL before the amalgams were removed. After removal of the amalgams, nine of the ten subjects exhibited a statistically significant decrease in blood mercury at the 95% level of confidence.
Metal exposure from amalgam alters the distribution of trace elements in blood cells and plasma. Lindh U, Carlmark B, Gronquist SO, Lindvall A. Clin Chem Lab Med. 2001 Feb; 39(2):134-42. 11341747 PubMed. Twenty-seven consecutive patients with health problems associated with dental amalgam were recruited. In spite of thorough medical examinations, there were no diagnoses available. The patient group was dominated by women. A healthy age- and sex-matched control group with dental amalgams without symptoms was also recruited. Metal level monitoring in plasma and nuclear microscopy of isolated individual blood cells were carried out. Significant increases of copper, iron, zinc and strontium were found in patient plasma. There was no significant difference in plasma selenium between the groups. Mercury was significantly increased in patient plasma, although there was overlap between the groups. In erythrocytes a significant increase in calcium and a significant decrease in magnesium, copper, manganese and zinc were found. Calcium, magnesium, manganese and copper increased in patient neutrophil granulocytes. A significant decrease was found for zinc. A conspicuous finding was the presence of measurable mercury in a few of the cells from the patient but not in the control group.
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ADP-ribosylation of brain neuronal proteins is altered by in vitro and in vivo exposure to inorganic mercury. Palkiewicz P, Zwiers H, Lorscheider FL. J Neurochem. 1994 May; 62(5):2049-52. 8158153 PubMed. ADP-ribosylation is an essential process in the metabolism of brain neuronal proteins, including the regulation of assembly and disassembly of biological polymers. Here, we examine the effect of HgCl2 exposure on the ADP-ribosylation of tubulin and actin, both cytoskeletal proteins also found in neurons, and B-50/43-kDa growth-associated protein (B-50/GAP-43), a neuronal tissue-specific phosphoprotein. In rats we demonstrate, with both in vitro and in vivo experiments, that HgCl2 markedly inhibits the ADP-ribosylation of tubulin and actin. This is direct quantitative evidence that HgCl2, a toxic xenobiotic, alters specific neurochemical reactions involved in maintaining brain neuron structure.
Acute and chronic neuropsychological consequences of mercury vapor poisoning in two early adolescents. Yeates KO, Mortensen ME. Clin Exp Neuropsychol. 1994 Apr; 16(2):209-22. 8021308 PubMed. Mercury is an extremely toxic heavy metal that can devastate the central nervous system. The neuropsychological consequences of mercury vapor intoxication have been studied primarily in adults. We present two adolescent half-siblings, ages 13 and 15, who were unintentionally exposed to concentrated mercury vapor for 3 months. Both children participated in neuropsychological evaluations shortly after being diagnosed with mercury toxicity, and again 1 year later. Results from the initial assessments documented functional deficits consistent with diffuse encephalopathy. Upon follow-up, neuropsychological functioning had improved, but deficits remained in visuoperceptual and constructional skills, nonverbal memory, and conceptual abstraction. The deficits persisted despite removal from exposure, return of urinary and blood mercury to acceptable levels, and resolution of neuropsychiatric symptoms. The deficits were similar to, but more severe than, those found in adults suffering from mercury vapor intoxication. The results suggest that the developing brain may be especially vulnerable to mercury vapor toxicity.
Apolipoprotein E genotyping as a potential biomarker for mercury neurotoxicity. Godfrey ME, Wojcik DP, Krone CA. J Alzheimers Dis. 2003 Jun; 5(3):189-95. 12897404 PubMed. Apolipoprotein-E (apo-E) genotyping has been investigated as an indicator of susceptibility to heavy metal (i.e., lead) neurotoxicity. Moreover, the apo-E epsilon (epsilon)4 allele is a major risk factor for neurodegenerative conditions, including Alzheimer's disease (AD). A theoretical biochemical basis for this risk factor is discussed herein, supported by data from 400 patients with presumptive mercury-related neuro-psychiatric symptoms and in whom apo-E determinations were made. A statistically relevant shift toward the at-risk apo-E epsilon4 groups was found in the patients p<0.001). The patients possessed a mean of 13.7 dental amalgam fillings and 31.5 amalgam surfaces. This far exceeds the number capable of producing the maximum identified tolerable daily intake of mercury from amalgam. The clinical diagnosis and proof of chronic low-level mercury toxicity has been difficult due to the non-specific nature of the symptoms and signs. Dental amalgam is the greatest source of mercury in the general population and brain, blood and urine mercury levels increase correspondingly with the number of amalgams and amalgam surfaces in the mouth. Confirmation of an elevated body burden of mercury can be made by measuring urinary mercury, after provocation with 2,3,-dimercapto-propane sulfonate (DMPS) and this was measured in 150 patients. Apo-E genotyping warrants investigation as a clinically useful biomarker for those at increased risk of neuropathology, including AD, when subjected to long-term mercury exposures. Additionally, when clinical findings suggest adverse effects of chronic mercury exposure, a DMPS urine mercury challenge appears to be a simple, inexpensive procedure that provides objective confirmatory evidence. An opportunity could now exist for primary health practitioners to help identify those at greater risk and possibly forestall subsequent neurological deterioration.
Application of a latent variable model for a multicenter study on early effects due to mercury exposure. Lucchini R, Calza S, Camerino D, Carta P, Decarli A, Parrinello G, Soleo L, Zefferino R, Alessio L. Neurotoxicology. 2003 Aug; 24(4-5):605-16. 12900073 PubMed. In conclusion, this study supports the finding of alterations of neuroendocrine secretion and motor coordination at very low occupational exposure levels of inorganic mercury, below the current ACGIH Biological Exposure Index. These changes occur at lower levels than other subtle effects on the renal function and the immunitary system.
A neurological and neurophysiological study of chloralkali workers previously exposed to mercury vapour. Andersen A, Ellingsen DG, Morland T, Kjuus H. Acta Neurol Scand. 1993 Dec; 88(6):427-33. 8116345 PubMed. Neurological and neurophysiological examinations were conducted in 77 former chloralkali workers previously exposed to mercury vapour and 53 referents. The exposure had ceased on average 12.3 years prior to the study. There was a higher prevalence of reduced distal sensation (13.0% vs 1.9%), postural tremor (18.2% vs 7.5%) and impaired coordination (10.4% vs 1.9%) among the exposed subjects as compared to the referents. Abnormal Romberg's test (6.5% vs 0%) and line walking (7.8% vs 0%) were also more prevalent. The first negative peak in visual evoked response (N75) was bilaterally prolonged, and the median motor (55.9 m/s vs 58.0 m/s) and sensory nerve conduction velocity (55.6 m/s vs 59.0 m/s) were slightly reduced among the highly exposed subjects. The results indicate that slight neurological abnormalities, which in most cases could not be classified as disease, may persist many years after exposure cessation.
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Chronic Elemental Mercury Intoxication: Neuropsychological Follow Up Case Study. Hua MS, Huang CC, Yang YJ. Brain Inj. 1996 May; 10(5):377-84. 8735667 PubMed. Our findings thus suggest a reversibility of impaired neuropsychological function in persons with elemental mercury poisoning if a prompt removal from the toxic environment is accomplished, together with proper medical treatment.
Chronic encephalopathies induced by mercury or lead: aspects of underlying cellular and molecular mechanisms. Rönnbäck L; Hansson E. Br J Ind Med, 1992 Apr, 49:4, 233-40 Br J Ind Med. 1992 Apr; 49(4):233-40. 1571293 PubMed. Impairments of astrocyte function are probably important, especially due to their capacity to regulate the ionic and amino acid concentration in the extracellular micromilieu, brain energy metabolism, and cell volume.
Comparison of the developmental effects of two mercury compounds on glial cells and neurons in aggregate cultures of rat telencephalon. Monnet-Tschudi F, Zurich MG, Honegger P. Brain Res. 1996 Nov 25; 741(1-2):52-9. 9001704 PubMed. In immature cultures, a general cytotoxicity was observed at 10(-6) M for both mercury compounds. In these cultures, HgCl2 appeared somewhat more toxic than MeHgCl. However, no appreciable demethylation of MeHgCl could be detected, indicating similar toxic potencies for both mercury compounds. In highly differentiated cultures, by contrast, MeHgCl exhibited a higher toxic potency than HgCl2. In addition, at 10(-6) M, MeHgCl showed pronounced neuron-specific toxicity. Below the cytotoxic concentrations, distinct glia-specific reactions could be observed with both mercury compounds.
Correlation of dental amalgam with mercury in brain tissue. Eggleston DW, Nylander M. J Prosthet Dent. 1987 Dec; 58(6):704-7. 3480359 PubMed. Data from this project demonstrate a positive correlation between the number of occlusal surfaces of dental amalgam and mercury levels in the brain (p less than .0025 in white matter). This is indirect evidence suggesting that mercury from dental amalgam fillings may contribute to the body burden of mercury in the brain. The toxic levels of mercury in human tissues have not been sufficiently investigated and the amount of mercury in human brain tissue from dental amalgam may or may not be clinically significant. Nevertheless, dental amalgam exposure should be considered in monitoring sources of mercury accumulation in human brain tissue.
Defensive characteristics in individuals with amalgam illness as measured by the percept-genetic method Defense Mechanism Test. Henningsson M, Sundbom E. Acta Odontol Scand. 1996 Jun; 54(3):176-81. 8811140 PubMed. Twenty patients complaining of symptoms deriving from their amalgam fillings and a non-patient group were assessed by means of the perceptual projective Defense Mechanism Test (DMT). The test protocols were scored for 130 DMT variables and analyzed by means of the multivariate statistical method Partial Least Squares discriminant analysis. The objective was to try to distinguish the group with amalgam illness from the non-patient group by means of the DMT. The results showed that it was possible to distinguish the two groups significantly from each other. The most characteristic traits of the patient group were a general lateness in perception and few emotional responses compared with the non-patient group and, especially, an inability to perceive the aggressive component in the stimulus picture. The DMT seems to be a powerful method in the effort to understand the mechanisms underlying the problems of amalgam illness.
Effects of cadmium and mercury on Na(+)-K+, ATPase and uptake of 3H-dopamine in rat brain synaptosomes. Rajanna B, Hobson M, Harris L, Ware L, Chetty CS. Arch Int Physiol Biochim. 1990 Oct; 98(5):291-6. 1708997 PubMed. Effects in vivo of cadmium (Cd), mercury (Hg) and methylmercury (CH3Hg) on Na(+)-K+ ATPase and uptake of 3H-dopamine (DA) in rat brain synaptosomes were studied. These heavy metals significantly inhibited the Na(+)-K+ ATPase activity in a dose-dependent manner. Similarly, inhibition of DA uptake by synaptosomes was also observed in rats treated with these metals. Intraperitoneal route of metal administration was found to be more effective than per os treatment. Mercuric compounds compared to Cd elicited a higher inhibition of Na(+)-K+ ATPase and DA uptake in rat brain synaptosomes.
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Effects of continuous low-dose exposure to organic and inorganic mercury during development on epileptogenicity in rats. Szasz A, Barna B, Gajda Z, Galbacs G, Kirsch-Volders M, Szente M. Neurotoxicology. 2002 Jul; 23(2):197-206. 12224761 PubMed. The effects of chronic, low-dose fetal and lactational organic (MeHgCl) and inorganic (HgCl2) mercury intoxication on epileptogenicity were investigated and compared in rats. The main observations after both mercury treatments were a facilitated seizure expression and propagation evoked by 4-aminopyridine (4-AP). The seizure susceptibility of the offspring seemed to be in a parallel relation to the mercury concentration in the cortical tissue, which was significantly higher in treated animals as compared to the controls. While MeHgCl enhanced the number of ictal periods, HgCl2 facilitated the duration of seizure discharges in younger animals. HgCl2 intoxication seemed to be more permanent than MeHgCl. Changes in the summated ictal activity--which is an indication of epileptogenicity--were observed in the opposite directions in the two treated groups with increasing age. The amplitudes of seizure discharges were smaller in both mercury-treated groups than in the controls, which could be a consequence of a depressed proliferation of neurons or enhanced cell death in the neocortex. In summary, we observed that adult rats exposed to organic or inorganic mercury chemicals during their embryonic life, are more prone to epilepsy than control rats given only 4-AP.
Effects of methylmercury and inorganic mercury on the growth of nerve fibers in cultured chick dorsal root ganglia. Miura K, Himeno S, Koide N, Imura N. Tohoku. J Exp Med. 2000 Nov; 192(3):195-210. 11249149 PubMed. Electron microscopic examination revealed that methylmercury decreased microtubule mass extensively in nerve fibers, while inorganic mercury markedly altered surface membrane structure.
Entry of low doses of mercury vapor into the nervous system. Pamphlett R, Coote P. Neurotoxicology. 1998 Feb; 19(1):39-47. 9498219 PubMed. Inorganic mercury remains within neurons indefinitely and has been implicated in some human neurodegenerative diseases. In conclusion, low doses of mercury vapor, well within WHO guidelines for safe human occupational exposure, enter and remain within motor neurons of mice.
Evidence that mercury from silver dental fillings may be an etiological factor in smoking. Siblerud RL, Kienholz E, Motl. J. Toxicol Lett 1993 Sep; 69(3):305. 8516784 PubMed. The smoking habits of 119 subjects without silver/mercury dental fillings were compared to 115 subjects with amalgams. The amalgam group had 2.5-times more smokers per group than the non-amalgam group, which was highly significant. Because mercury decreases dopamine, serotonin, norepinephrine, and acetylcholine in the brain, and nicotine has just the opposite effect on these neurotransmitters, this may help explain why persons with dental amalgams smoke more than persons without amalgams.
Improvement of Nerve and Immunological Damages after Amalgam Removal. Daunderer M. Amer. J. Probiotic Dentistry and Medicine, Jan 1991. http://www.toxicteeth.net/RemovalResults.cfm
Interaction of mercury compounds with muscarinic receptor subtypes in the rat brain. Castoldi AF, Candura SM, Costa P, Manzo L, Costa LG. Neurotoxicology. 1996 Fall-Winter; 17(3-4):735-41. 9086496 PubMed. In all cases HgCl2 showed steep and monophasic inhibition curves, whereas those of CH3HgOH were biphasic (M1) or shallow (M2). CH3HgOH-induced inhibition of both [3H]telenzepine and [3H]AF-DX 384 binding was of the competitive type, while HgCl2 caused a pronounced reduction of the Bmax value associated with a small change in affinity. CH3HgOH also decreased the affinity of the agonist carbachol for M1 and M2 receptors, while inorganic mercury had minimal effects on the carbachol dose-response curves. These results indicate that inorganic and organic mercury differ in their interaction with muscarinic receptor subtypes and that M1 receptors may represent a preferential target for their effects.
Interactions of methylmercury with rat primary astrocyte cultures: inhibition of rubidium and glutamate uptake and induction of swelling. Aschner M, Eberle NB, Miller K, Kimelberg HK. Brain Res. 1990 Oct 22; 530(2):245-50. 2265356 PubMed. These observations support the hypothesis that the astrocyte plasma membrane is an important target for MeHg's toxic effect and specifically that small concentrations of this organometal inhibit the ability of astrocytes to maintain a transmembrane K+ gradient. Exposure to MeHg (0-5 x 10(-4) M) caused a marked increase in the cell volume that was proportional to concentrations of MeHg.
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In vitro effect of organic and inorganic mercury on the serotonergic system. Oudar P, Caillard L, Fillion G. Pharmacol Toxicol. 1989 Oct; 65(4):245-8. 2587506 PubMed. These results show that mercury ions interact with the serotonergic system by different mechanisms depending on their concentrations and their ionic forms.
Low concentrations of inorganic mercury inhibit in vitro autonomic transmission in the presence of albumin. Moberg LE, Appelgren B, Sjostrand NO. Acta Odontol Scand. 1991 Dec; 49(6):351-9. 1776402 PubMed. The influence of albumin, 4.5 and 45 g/l, on the effects of Hg2+, 10(-9)-10(-3) M, on the neuromuscular transmission of the isolated guinea-pig ileum and vas deferens was investigated. Hg2+, 10(-9)-10(-6) M, transiently increased the basal tone of the ileum in Tyrode solution without albumin. Albumin, 4.5 g/l, reversed this stimulant effect but enhanced the contractile response to direct muscle stimulation. This contractile response also increased in the vas deferens. Albumin, 45 g/l, obliterated the stimulant effects of Hg2+ on the smooth muscle of the ileum but not of the vas deferens. The effects caused by higher concentrations of Hg2+, 10(-5)-10(-4) M, were only partly inhibited when albumin was present. When neurogenic contractions were elicited in the presence of albumin (45 g/l), Hg2+, 10(-9)-10(-4) M, reduced the contractions in both organs. Consequently, Hg2+ in concentrations presently considered acceptable in blood plasma (10(-9)-10(-8) M) suppressed both cholinergic and adrenergic neuromuscular transmission even in the presence of albumin.
Mercury and proteins in cerebrospinal fluid in subjects exposed to mercury vapor. Sallsten G, Barregard L, Wikkelso C, Schutz A. Environ Res. 1994 May; 65(2):195-206. 8187736 PubMed. Mercury (Hg) and protein levels in cerebrospinal fluid (CSF), and mercury in plasma (P), erythrocytes (Ery), and urine (U), were determined in 10 workers exposed to mercury vapor for 2-28 (median 13) years and in 16 occupationally unexposed referents. CSF-Hg was analyzed using radiochemical neutron activation analysis and P-Hg, Ery-Hg, and U-Hg were analyzed using cold-vapor atomic absorption spectrometry. P-Hg and U-Hg were significantly higher, but Ery-Hg was similar in the exposed workers (37 nmole/liter, 16 nmole/mmole creatinine, and 56 nmole/liter, respectively) compared with the referents (7.1 nmole/liter, 1.9 nmole/mmole creatinine, and 52 nmole/liter, respectively). CSF-Hg was correlated to P-Hg, and in workers with current high exposure (P-Hg > 50 nmole/liter), the CSF-Hg was significantly higher than in the reference group (1.08 versus 0.35 nmole/liter; P = 0.002). In two individuals, studied after ceased occupational exposure, a decrease of CSF-Hg was seen. There were no indications of changes in the CSF protein pattern in the exposed workers.
Mercury distribution in the mouse brain after mercury vapour exposure. Warfvinge K. Int J Exp Pathol. 1995 Feb; 76(1):29-35. 7734337 PubMed. Female SJL/N mice were exposed to mercury vapour 5 days/week for 10 weeks, at a mercury concentration of approximately 0.5 mg/m3, 19 h/day; 1 mg/m3, 3 h/day; 0.3 mg/m3, 6 h/day or 1 mg/m3, 1.5 h/day. The total mercury concentrations in the brain were 6.4, 6.3, 1.6 and 0.64 micrograms/g tissue, respectively. The mercury distribution in the brains was examined. Mercury was found in almost the whole brain in the two groups with the highest exposure. In the third group, mercury was primarily found in the neocortical layer V, the white matter, thalamus, and the brain-stem. In the fourth group, the white matter and the brain-stem were the targets for mercury accumulation. Similarities and differences between rats and mice in the distribution pattern are discussed.
Mercury distribution in the neonatal and adult cerebellum after mercury vapor exposure of pregnant squirrel monkeys. Warfvinge K. Environ Res. 2000 Jun; 83(2):93-101. 10856181 PubMed. The results demonstrate that the distribution of mercury in the cerebellum after mercury vapor exposure is similar to the distribution pattern obtained after methyl mercury exposure and that mercury is trapped in the cerebellum over a long period of time.
Mercury (Hg 2+) enhances the depressant effect of kainate on Ca-inactivated potassium current in telencephalic cells derived from chick embryos. Dyatlov VA, Platoshin AV, Lawrence DA, Carpenter DO. Toxicol Appl Pharmacol. 1996 Jun; 138(2):285-97. 8658530 PubMed. Moreover 1 microM Hg2+ delayed and reduced the recovery to basal [Ca2+]i after washout of KA. Exposure to 5-30 microM H2+ caused an irreversible decline of membrane resistance, an increased cell size, and reduced cell granularity and complexity. Intracellular recording of spontaneous neuronal activity and immunocytochemical identification showed that the KA/Hg2+-sensitive Ca-inactivated K+ current exists in early differentiating telencephalic neurons. Because depression of the K+ current by KA and Hg2+ decreases the interspike interval and irreversibly perturbs the frequency code of information in the nervous system, the expression of this current during early neuroembryogenesis may be one of the reasons for the developmental toxicity of inorganic mercury.
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Mercury poisoning from dental amalgam - a hazard to the human brain. Stortebecker P. Bio-Probe, Inc. ISBN: 0-941011001-1 http://www.toxicteeth.net/RemovalResults.cfm
Mercury neurotoxicity: mechanisms of blood-brain barrier transport. Aschner M, Aschner JL. Neurosci Biobehav Rev. 1990 Summer;14(2):169-76. 2190116 PubMed. Mercury exists in a wide variety of physical and chemical states, each of which has unique characteristics of target organ toxicity. The classic symptoms associated with exposure to elemental mercury vapor (Hg0) and methylmercury (CH3Hg+; MeHg) involve the central nervous system (CNS), while the kidney is the target organ for the mono- and divalent salts of mercury (Hg+ and Hg++, respectively). Physical properties and redox potentials determine the qualitative and quantitative differences in toxicity among inorganic mercury compounds, while the ability of MeHg to cross the blood-brain barrier accounts for its accumulation in the CNS and a clinical picture that is dominated by neurological disturbances. This review gives an up-to-date account of mercury's physical and chemical properties and its interaction with biologically active sites pertinent to transport across the blood-brain barrier, a major regulator of the CNS millieu.
Mercury vapor inhalation inhibits binding of GTP to tubulin in rat brain: Similarity to a molecular lesion in Alzheimer diseased brain. Pendergrass JC, Haley BE, Vimy MJ, Winfield SA, Lorscheider FL. Neurotoxicology. 1997; 18(2):315-24. 9291481 PubMed. Since the rate of tubulin polymerization is dependent upon binding of GTP to tubulin dimers, we conclude that chronic inhalation of low-level Hg0 can inhibit polymerization of brain tubulin essential for formation of microtubules.
Metals and free radicals in neurodegeneration. Olanow CW, Arendash GW. Curr Opin Neurol. 1994 Dec; 7(6):548-58. 7866588 PubMed. Substantial evidence has accumulated implicating metals and free radicals in the pathogenesis of the major neurodegenerative disorders (Parkinson's disease, Alzheimer's disease, and amyotrophic lateral sclerosis). Metal-induced oxidant stress can damage critical biological molecules and initiate a cascade of events including mitochondrial dysfunction, excitotoxicity, and a rise in cytosolic free calcium, leading to cell death. In Parkinson's disease and Alzheimer's disease there is evidence of oxidative stress in affected brain regions, as indicated by increased metal accumulation (which promotes free radical formation), decreased antioxidant levels (which protect against free radical formation), and oxidative damage. Recently, studies of the familial form of amyotrophic lateral sclerosis have detected mutations in the gene that encodes superoxide dismutase, which is one of the body's primary oxidant defense mechanisms. Mice that are transfected with the human mutant superoxide dismutase gene develop an amyotrophic lateral sclerosis syndrome. These studies demonstrate that oxidant stress can initiate the development of a chronic progressive neurodegenerative disorder.
Modulation of protein kinase C by heavy metals. Rajanna B, Chetty CS, Rajanna S, Hall E, Fail S, Yallapragada PR. Toxicol Lett. 1995 Nov 15; 81(2-3):197-203. 8553375 PubMed. Protein kinase C (PKC) regulates a variety of intracellular and extracellular signals across the neuronal membrane. PKC requires calcium and phospholipid, particularly phosphatidylserine (PS) for its activation. The data indicates that mercury (Hg), lead (Pb) and methyl mercury (CH3Hg) in vitro inhibited the PKC activity at micromolar concentrations in a concentration-dependent manner with IC50 values of 1.5, 2.12 and 0.22 microM, respectively. The IC50 values indicate that CH3Hg was more potent in inhibiting the enzyme activity than Hg or Pb. The basal PKC activity was also inhibited by Pb or Hg. However, the PS-stimulated PKC activity was more sensitive to Pb or Hg than the basal enzyme. The phorbol ester binding to PKC was also found to be inhibited by micromolar concentrations of these metals in vitro. Hg and CH3Hg were more potent inhibitors of phorbol ester binding than Pb. Dithiothreitol (DTT), a dithiol, but not glutathione (GSH) a monothiol, protected the activities of both PS-stimulated and basal PKC from metal-inhibition in a concentration-dependent manner. The present study suggests that the dithiols but not monothiols effectively protect metal-inhibited activity of PKC in rat brain.
Motor neuron uptake of low dose inorganic mercury. Pamphlett R, Waley P. J Neurol Sci. 1996 Jan; 135(1):63-7. 8926498 PubMed. Low doses of inorganic mercury are therefore selectively taken up and retained by motor neurons, making this neurotoxin a good candidate for a cause of sporadic motor neuron disease.
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Neurobehavioral effects from exposure to dental amalgam Hg(o): new distinctions between recent exposure and Hg body burden. Echeverria D, Aposhian HV, Woods JS, Heyer NJ, Aposhian MM, Bittner AC Jr, Mahurin RK, Cianciola M. FASEB J. 1998 Aug;12(11):971-80. 9707169 PubMed. New distinctions between subtle preclinical effects on symptoms, mood, motor function, and cognition were found associated with Hg body burden as compared with those associated with recent exposure. The pattern of results, comparable to findings previously reported among subjects with urinary Hg >50 microg/l, presents convincing new evidence of adverse behavioral effects associated with low Hg(o) exposures within the range of that received by the general population.
Neurological and electrophysiological examinations on three groups of workers with different levels of exposure to mercury vapors. Urban P, Lukas E, Nerudova J, Cabelkova Z, Cikrt M. Eur J Neurol. 1999 Sep; 6(5):571-7. 10457390 PubMed. An isolated decrease of sural nerve conduction velocity was observed in 18% of total workers. In 70% of the cases, this was associated with an abnormality in VEP. The combination of a decrease in sural nerve conduction velocity and an abnormality of VEP seems to be a characteristic pattern of electrophysiological changes in persons exposed to mercury vapors.
Neurotoxic effect of exposure to low doses of mercury. Lucchini R, Cortesi I, Facco P, Benedetti L, Camerino D, Carta P, Urbano ML, Zaccheo A, Alessio L. Med Lav. 2002 May-Jun; 93(3):202-14. 12197270 PubMed. To assess early effects on the Central Nervous System due to occupational exposure to low levels of inorganic mercury (Hg) in a multicenter nationwide cross-sectional study, including workers from chloro-alkali plants, chemical industry, thermometer and fluorescent lamp manufacturing. The contribution of non-occupational exposure to inorganic Hg from dental amalgams and to organic Hg from fish consumption was also considered. Conclusion, this study supports the finding of early alterations of motor function and neuroendocrine secretion at very low exposure levels of inorganic Hg, below the current ACGIH BEI and below the most recent exposure levels reported in the literature.
Neurotoxicity of dental amalgam is mediated by zinc. Lobner D, Asrari M. J Dent Res. 2003 Mar; 82(3):243-6. 12598557 PubMed. These results indicate that amalgam is toxic to nerve cells in culture by releasing zinc. While zinc is known to be neurotoxic, ingestion of zinc is not a major concern because zinc levels in the body are tightly regulated.
Psychometric evidence that mercury from silver dental fillings may be an etiological factor in depression, excessive anger, and anxiety. Siblerud RL, Motl J, Kienholz E. Psychol Rep. 1994 Feb;74(1):67-80. 8153237 PubMed. The women with amalgams also had significantly higher levels of mercury in the oral cavity before and after chewing gum. The study suggests that amalgam mercury may be an etiological factor in depression, excessive anger, and anxiety because mercury can produce such symptoms perhaps by affecting the neurotransmitters in the brain.
Relation between exposure related indices and neurological and neurophysiological effects in workers previously exposed to mercury vapour. Ellingsen DG, Morland T, Andersen A, Kjuus H. Br J Ind Med. 1993 Aug; 50(8):736-44. 8398861 PubMed. A cross sectional study of aspects of their neurology was carried out on 77 chloralkali workers previously exposed to mercury (Hg) vapour and compared with 53 age matched referents. The chloralkali workers had been exposed for an average of 7.9 years at a concentration of 59 micrograms Hg/m3 in the working atmosphere. The individual mean urinary concentration of Hg for each year of exposure was 531 nmol Hg/1. On average the exposure had ceased 12.3 years before the examinations. Both the median sensory nerve conduction velocity and the amplitude of the sural nerve were associated with measures of cumulative exposure to Hg. An association was also found between years since first exposure to Hg and aspects of the visual evoked response. Previously exposed subjects with postural tremor or impaired coordination also had alterations in visual evoked response. These results may indicate an effect of previous exposure to mercury vapour on the nervous system, possibly in the visual pathway, cerebellum, and the peripheral sensory nerves.
Repeated neurobehavioral investigations in workers exposed to mercury in a chloralkali plant. Gunther W, Sietman B, Seeber A. Neurotoxicology. 1996 Fall-Winter; 17(3-4):605-14. 9086481 PubMed. Subgroups of 30 controls, 37 low exposed and 14 high exposed workers were examined in a follow-up study with repeated measurements. Significant exposure effects were shown for finger dexterity and aiming.
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Residual neurobehavioural effects associated with chronic exposure to mercury vapour. Kishi R, Doi R, Fukuchi Y, Satoh H, Satoh T, Ono A, Moriwaka F, Tashiro K, Takahata N, Sasatani H, et al. Occup Environ Med. 1994 Jan; 51(1):35-41. 8124461 PubMed. These results suggest that there are slight but persistent effects on neurobehavioural function, especially on motor coordination, among mercury miners even more than 10 years after the end of exposure.
Retrograde axonal transport of mercury. Arvidson B. Exp Neurol. 1987 Oct; 98(1):198-203. 2443381 PubMed. The results are regarded as strong evidence of retrograde axonal transport of mercury in the hypoglossal nerve.
Retrograde degeneration of neurite membrane structural integrity of nerve growth cones following in vitro exposure to mercury. Leong CC, Syed NI, Lorscheider FL. Neuroreport. 2001 Mar 26; 12(4):733-7. 11277574 PubMed. We found that in the presence of Hg ions, neuronal somata failed to sprout, whereas other metalic ions did not effect growth patterns of cultured PeA cells. We conclude that this visual evidence and previous biochemical data strongly implicate Hg as a potential etiological factor in neurodegeneration.
Silent latency periods in methylmercury poisoning and in neurodegenerative disease. Weiss B, Clarkson TW, Simon W. Environ Health Perspect. 2002 Oct; 110 Suppl 5:851-4. 12426145 PubMed. This article discusses three examples of delay (latency) in the appearance of signs and symptoms of poisoning after exposure to methylmercury. First, a case is presented of a 150-day delay period before the clinical manifestations of brain damage after a single brief (<1 day) exposure to dimethylmercury. The second example is taken from the Iraq outbreak of methylmercury poisoning in which the victims consumed contaminated bread for several weeks without any ill effects. Indeed, signs of poisoning did not appear until weeks or months after exposure stopped. The last example is drawn from observations on nonhuman primates and from the sequelae of the Minamata, Japan, outbreak in which low chronic doses of methylmercury may not have produced observable behavioral effects for periods of time measured in years. The mechanisms of these latency periods are discussed for both acute and chronic exposures. Parallels are drawn with other diseases that affect the central nervous system, such as Parkinson disease and post-polio syndrome, that also reflect the delayed appearance of central nervous system damage.
Shrinkage of Motor Axons Following Systemic Exposure to Inorganic Mercury. Pamphlett R, Png, FY. J Neuropathol Exp Neurol. 1998 Apr; 57(4):360-6. 9600230 PubMed. Inorganic mercury within motor neurons therefore appears to behave as a slowly-acting neurotoxin that shrinks motor axons.
Subclinical effects of exposure to inorganic mercury revealed by somatosensory-evoked potentials. Lamm O, Pratt H. Eur Neurol. 1985; 24(4):237-43. 4006993 PubMed. This study examined the validity of evoked somatosensory potentials as a measure of subclinical neurological damage to workers chronically exposed to nonorganic mercury. In this study potentials were recorded along the somatosensory pathway from the periphery to the primary cortex in response to electrical and mechanical stimuli. The findings of this study indicate that such workers exhibit subclinical damage which manifested in a delay in nerve ending conduction times at the periphery, and an acceleration of the conduction from brain stem to cortex. These findings support the suggestion that evoked potentials may be a sensitive and reliable measure in the detection of subclinical neuropathic phenomena. They may consequently be utilized as an efficient early warning system in the prevention of clinical symptoms.
Subclinical neurotoxicity of mercury vapor revealed by a multimodality evoked potential study of chloralkali workers. Chang YC, Yeh CY, Wang JD. Am J Ind Med. 1995 Feb; 27(2):271-9. 7755016 PubMed. In brainstem auditory and somatosensory EP studies, prolonged neural conduction times in the central nervous system (CNS) were found in workers exposed to mercury vapor. In the pattern visual EP study, mercury workers had higher interpeak amplitudes. Findings of this study suggested that chronic exposure to mercury vapor would affect the CNS functions. A multimodality EP study is a useful adjunct in evaluation of chronic mercury neurotoxicity, especially in an epidemiological study.
Subjective symptoms and neurobehavioral performances of ex-mercury miners at an average of 18 years after the cessation of chronic exposure to mercury vapor. Mercury Workers Study Group. Kishi R, Doi R, Fukuchi Y, Satoh H, Satoh T, Ono A, Moriwaka F, Tashiro K, Takahata N. Environ Res. 1993 Aug; 62(2):289-302. 8344236 PubMed. Although the extent of the workers' symptoms caused by mercury poisoning, termed erethismus merculialis, markedly decreased after the cessation of exposure, the prevalence of neurological symptoms (such as hand tremors, headaches, and slurred speech) and symptoms of senility (such as low-back pain, loss of sexual desire) in the ex-miners was significantly higher than those in the controls. Matched-pair analysis showed that performances of motor coordination, Simple reaction time, and Short-term memory in the ex-miners were significantly deteriorated compared to those of controls. There are slight but persistent effects on neurobehavioral function, especially on motor coordination function, among mercury miners more than 10 years after the cessation of exposure.
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The effect of mercury chloride and methyl mercury on brain microsomal Na+-K+-ATPase after partial delipidisation with Lubrol. Magour S, Maser H, Greim H. Pharmacol Toxicol. 1987 Mar; 60(3):184-6. 3035529 PubMed. The microsomal Na+-K+-ATPase of rat brain was inhibited by mercury chloride and methyl mercury.
The neuropsychiatric sequelae of mercury poisoning. The Mad Hatter's disease revisited. O'Carroll RE, Masterton G, Dougall N, Ebmeier KP, Goodwin GM. Br J Psychiatry. 1995 Jul; 167(1):95-8. 7551618 PubMed. BACKGROUND. The detailed effects of mercury poisoning on cognitive function, brain anatomy and regional brain function are largely unknown. We report the case of a 38-year-old man who was exposed to toxic levels of inorganic mercury. METHOD. Four years after exposure, the patient was assessed using magnetic resonance imaging (MRI), single-photon emission computerised tomography (SPECT) and detailed neuropsychological evaluation. RESULTS. The patient developed a myriad of physical and psychiatric complaints, including stomatitis, muscle spasm, tremor, skin rash and the psychiatric syndrome known as 'erythism' (Mad Hatter's disease). Neuropsychological evaluation revealed marked and significant deficits of attention concentration, particularly when under time pressure. The MRI scan was unremarkable; however, SPECT revealed hypermetabolism of the posterior cingulate CONCLUSIONS. Mercury poisoning appeared to result in a dysregulation of posterior cingulate cortex, which was associated with attention/concentration deficits and marked anxiety/agitation.
Toxicity of ionic mercury and elemental mercury vapor on brain neuronal protein metabolism. Lorscheider FL,Vimy MJ, Pendergrass JC, Haley BE. 12th International Neurotoxicology conference, Hot Springs, AR, October 31, 1994. Neurotoxicology 15, 955. Recent studies have demonstrated that Hg is selectively concentrated in human brain regions involved with memory function, and may be implicated in the aetiology of Alzheimer's disease (AD). Abnormal microtubule formation in AD brains has been associated with a defect in the tubulin polymerization cycle (Khatoon et al. Ann Neurol., 26:210-215, 1989) which may increase the density of neurofibrillary tangles. A similar tubulin defect can be induced in the brain of HgCI2-treated rats, suggesting a connection between exposure to inorganic Hg and AD (literature reviewed in Goering et a]. ibid). We have also demonstrated that HgCl2 markedly inhibits in vivo ADP-ribosylation of rat tubulin and therefore alters a specific neurochemical reaction involved in maintain-ing brain neuron structure (Palkiewicz et al. Neurochem., 62:049-2052: 1994). In our present investigations 3 groups of rats were exposed to Hg vapour 4 h/day for 0, 2 or 14 consecutive days. Vapour concentration during exposure periods was maintained at 300 mcg Hg/m air, a level detectable in mouths of some human subjects with large numbers of amalgam fillings. Cold vapour atomic fluorescence spectrometry (Winfield et al. Clin Chem., 40:206-210, 1994) revealed average brain Hg concentrations after 0, 2 and 14 days exposure to be 10, 108 and 396 ng/g tissue (wet wt.) respectively. Photoaffinity labeling of the beta-subunit of the tubulin dimer with a 32P@8N3GTP in brain homogenates was partially diminished after 2 days, and very markedly diminished after 14 days of Hg vapour exposure. Since the rate of tubulin polymeriza-tion is dependent upon binding of tubulin dimers to GTP, we conclude that low-level Hg vapour exposure inhibits the polymerisation of tubulin essential for formation of microtubules.
Uptake of inorganic mercury by the human brain. Pamphlett R, Waley P. Acta Neuropathol (Berl). 1996 Nov; 92(5):525-7. 8922066 PubMed. The finding that elemental mercury enters human cortical motor neurons in preference to other cerebral neurons raises the possibility that this neurotoxin may play a part in the pathogenesis of some human motor neuron diseases.
Effect of home bleaching products on mercury release from an admixed amalgam. Robertello FJ, Dishman MV, Sarrett DC, Epperly AC. Am J Dent. 1999 Oct; 12(5):227-30. 10649913 PubMed. ANOVA indicated there was no significant difference between the bleaches and controls at 8 and 40 hours, however at 80 hours, Opalescence caused significantly more mercury release.
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Mercury release from dental amalgam after treatment with 10% carbamide peroxide in vitro. Totstein I, Dogan H, Avron Y, Shemesh H, Steinberg D. Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 2000 Feb; 89 (2):216-9. 10673659 PubMed. Treatment with 10% carbamide peroxide bleaching agents caused an increase in mercury release from amalgam restorations, possibly increasing exposure of patients to its adverse effects. Amalgam brands differed in the amounts of mercury release after bleaching with carbamide peroxide.
Therapeutic effects of oral NADH on the symptoms of patients with chronic fatigue syndrome. Forsyth LM, Preuss HG, MacDowell AL, Chiazze L Jr, Birkmayer GD, Bellanti JA. Ann Allergy Asthma Immunol. 1999 Feb;82(2):185-91. 10071523 PubMed. BACKGROUND: Chronic fatigue syndrome (CFS) is a disorder of unknown etiology, consisting of prolonged, debilitating fatigue, and a multitude of symptoms including neurocognitive dysfunction, flu-like symptoms, myalgia, weakness, arthralgia, low-grade fever, sore throat, headache, sleep disturbances, and swelling and tenderness of lymph nodes. No effective treatment for CFS is known. OBJECTIVE: The purpose of the study was to evaluate the efficacy of the reduced form of nicotinamide adenine dinucleotide (NADH) i.e., ENADA the stabilized oral absorbable form, in a randomized, double-blind, placebo-controlled crossover study in patients with CFS. Nicotinamide adenine dinucleotide is known to trigger energy production through ATP generation which may form the basis of its potential effects. RESULTS: No severe adverse effects were observed related to the study drug. Within this cohort of 26 patients, 8 of 26 (31%) responded favorably to NADH in contrast to 2 of 26 (8%) to placebo. Based upon these encouraging results we have decided to conduct an open-label study in a larger cohort of patients. CONCLUSION: Collectively, the results of this pilot study indicate that NADH may be a valuable adjunctive therapy in the management of the chronic fatigue syndrome and suggest that further clinical trials be performed to establish its efficacy in this clinically perplexing disorder.
Exposure to toxic elements via breast milk. Oskarsson A, Palminger Hallen I, Sundberg. J. Analyst. 1995 Mar; 120(3):765-70. 7741226 PubMed. Inorganic mercury exposure from amalgam was reflected in blood and milk mercury levels. Recent exposure to methylmercury from consumption of fish was reflected in mercury levels in the blood but not in milk.
Mercury from maternal "silver" tooth fillings in sheep and human breast milk. A source of neonatal exposure. Vimy MJ, Hooper DE, King WW, Lorscheider FL. Biol Trace Elem Res. 1997 Feb; 56(2):143-52. 9164660 PubMed. These findings suggest that placement and removal of "silver" tooth fillings in pregnant and lactating humans will subject the fetus and neonate to unnecessary risk of Hg exposure.
Methyl mercury exposure via placenta and milk impairs natural killer (NK) cell function in newborn rats. Ilback NG, Sundberg J, Oskarsson A. Toxicol Lett. 1991 Oct; 58(2):149-58. 1949074 PubMed. These results indicate that placental and lactational transfer of MeHg does adversely affect the developing immune system of the rat.
Total and inorganic mercury in breast milk and blood in relation to fish consumption and amalgam fillings in lactating women. Oskarsson A, Schultz A, Skerfving S, Hallen IP, Ohlin B, Lagerkvist BJ. Arch Environ Health 1996; 51:234-241. Arch Environ Health. 1996 May-Jun; 51(3):234-41. 8687245 PubMed. The results indicated that there was an efficient transfer of inorganic mercury from blood to milk and that, in this population, mercury from amalgam fillings was the main source of mercury in milk. We concluded that efforts should be made to decrease mercury burden in fertile women.
Cancer mortality in Minamata disease patients exposed to methylmercury through fish diet. Kinjo Y, Akiba S, Yamaguchi N, Mizuno S, Watanabe S, Wakamiya J, Futatsuka M, Kato H. J Epidemiol. 1996 Sep; 6(3):134-8. 8952217 PubMed. In addition, a statistically significant eight-fold excess risk, based on 5 observed deaths, was noted for mortality from leukemia (RR, 8.35; 95 % confidence interval 1.61-43.3). It is, however, unlikely for these observed risks to be derived from methylmercury exposure only. Further studies are needed to understand the mechanisms involved in the observed risks among MD patients.
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Carcinogenicity of mercury and mercury compounds. Boffetta P, Merler E, Vainio H. Scand J Work Environ Health. 1993 Feb; 19(1):1-7. 8465166 PubMed. Mercury and mercury compounds are widely used in modern society, but only sparse data are available on their carcinogenicity. Methylmercury chloride causes kidney tumors in male mice. Mercury chloride has shown some carcinogenic activity in male rats, but the evidence for female rats and male mice is equivocal. Other mercury compounds and metallic mercury have not been tested adequately in experimental animals. Epidemiologic data are available for chloralkali workers, dentists and dental nurses, and nuclear weapons workers, three groups occupationally exposed to low levels of mercury and its compounds, but those highly exposed in the past, such as miners, or populations which have suffered massive environmental exposure have not been adequately studied. However, the sparse epidemiologic data point toward the possibility of a risk of lung, kidney, and central nervous system tumors. Better data are needed on the carcinogenicity of mercury and mercury compounds in humans and experimental animals.
Levels of cadmium, lead, and mercury in human brain tumors. Al-Saleh I, Shinwari N. Biol Trace Elem Res. 2001 Mar; 79(3):197-203. 11354345 PubMed. This article reports on the levels of cadmium, lead, and mercury in 21 benign brain tumors and 23 malignant brain tumors. All measurements were performed by atomic absorption spectrometry following digestion by nitric acid. Average concentrations of cadmium, lead, and mercury in brain tumors were 2.02 (ND-72.78), 0.625 (ND-83.13), and 0.118 (ND-1.96) microg/g wet weight, respectively. Our values were higher than data reported by others.
Molecular mechanisms of metal toxicity and carcinogenesis. Wang S, Shi X. Mol Cell Biochem. 2001 Jun; 222(1-2):3-9. 11678608 PubMed. Many metals and metal-containing compounds have been identified to be potent mutagens and carcinogens. Recently, a new sub-discipline of molecular toxicology and carcinogenesis has been developed. The combination of newly developed molecular techniques and free radical approach makes it possible to insightfully examine metal-induced carcinogenesis in precise molecular terms so that intricate biological interrelationships can be elucidated. In consideration of the increased amount of new findings deciphered by utilizing these new methods, the 1st Conference on Molecular Mechanisms of Metal Toxicity and Carcinogenesis was held. In this conference, more than 50 scientists from nine countries presented their novel discoveries concerning metal-induced carcinogenesis, delineated molecular mechanism of metal carcinogenesis, and proposed novel therapeutic intervention and prevention strategies. This article reviews some of the state-of-the-art information presented at the meeting regarding the molecular mechanisms of metal cytotoxicity and carcinogenesis.
Possible roles of nitric oxide and redox cell signaling in metal-induced toxicity and carcinogenesis: a review. Buzard GS, Kasprzak KS. J Environ Pathol Toxicol Oncol. 2000; 19(3):179-99. 10983886 PubMed. Toxic doses of transition metals are capable of disturbing the natural oxidation/reduction balance in cells through various mechanisms stemming from their own complex redox reactions with endogenous oxidants and effects on cellular antioxidant systems. The resulting oxidative stress may damage redox-sensitive signaling molecules, such as NO, S-nitrosothiols, AP-1, NF-kappaB, IkappaB, p53, p21ras, and others, and thus derange the cell signaling and gene expression systems. This, in turn, may produce a variety of toxic effects, including carcinogenesis. Experimental support for the relevance of oxidative damage to the mechanisms of metal toxicity and carcinogenicity is particularly strong for two essential (but toxic when overdosed) metals--iron and copper-- and three well-established human metal carcinogens--nickel, chromium, and cadmium. However, along with more specific effects of toxic metals associated with their selective binding to particular cell constituents and affecting calcium signaling, oxidative damage seems to become important as well in explaining mechanisms of pathogenicity of other metals, such as lead, mercury, and arsenic.
Trace elements and thyroid cancer. Zaichick VYe, Tsyb AF, Vtyurin BM. Analyst. 1995 Mar; 120(3):817-21. 7741233 PubMed. In paranodular tissue, the Ag, Co, Hg, I and Rb contents were much higher for malignant and benign nodules than they were for the standard. There was also a slight deficiency of Se in the nodules compared with the standard. This result supports the hypothesis that the direct toxic heavy metal influence on thyrocytes plays a major role in thyroid cancer etiology, provided that an adequate level of the defence mechanisms is absent. Iodine concentrations are 15 times lower, on average, in malignant compared with benign nodules.
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DMSA & DMPS
2,3-Dimercaptosuccinic acid treatment of heavy metal poisoning in humans. Fournier L, Thomas G, Garnier R, Buisine A, Houze P, Pradier F, Dally S. Med Toxicol Adverse Drug Exp. 1988 Nov-Dec; 3(6):499-504. 2851085 PubMed. 14 patients with heavy metal poisoning received 2,3-dimercaptosuccinic acid (DMSA). 12 subjects were given 30 mg/kg/day for 5 days; 1 subject was started on a lower dose because of a history of atopy; another subject was treated for 15 days because of very high initial blood lead concentrations. In the 9 subjects who had lead poisoning, DMSA decreased blood lead concentrations by 35 to 81%, and induced a 4.5- to 16.9-fold increase in mean daily urinary excretion of the metal. In the acutely arsenic-poisoned case, the plasma arsenic concentration on day 7 was half the pretreatment value, while no clear decrease was observed in a chronically exposed subject. In 3 mercury cases, DMSA increased daily mercury urinary excretion 1.5-, 2.8- and 8.4-fold, respectively, while blood mercury concentrations remained below detection limits. No serious side effects were observed and 3 weeks after administration of the drug the clinical condition of all subjects was either stable or improved. These results indicate the efficacy of DMSA for lead poisoning in humans and provide a rationale for further investigating its usefulness in mercury and arsenic poisoning cases.
A cluster of pediatric metallic mercury exposure cases treated with meso-2,3-dimercaptosuccinic acid (DMSA). Forman J, Moline J, Cernichiari E, Sayegh S, Torres JC, Landrigan MM, Hudson J, Adel HN, Landrigan PJ. Environ Health Perspect. 2000 Jun; 108(6):575-7. 10856034 PubMed. Nine children and their mother were exposed to vapors of metallic mercury. The source of the exposure appears to have been a 6-oz vial of mercury taken from a neighbor's home. The neighbor reportedly operated a business preparing mercury-filled amulets for practitioners of the Afro-Caribbean religion Santeria. At diagnosis, urinary mercury levels in the children ranged from 61 to 1,213 microg/g creatinine, with a geometric mean of 214.3 microg/m creatinine. All of the children were asymptomatic. To prevent development of neurotoxicity, we treated the children with oral meso-2,3-dimercaptosuccinic acid (DMSA). During chelation, the geometric mean urine level rose initially by 268% to 573.2 microg mercury/g creatinine (p<0.0005). At the 6-week follow-up examination after treatment, the geometric mean urine mercury level had fallen to 102.1 microg/g creatinine, which was 17.8% of the geometric mean level observed during treatment (p<0.0005) and 47.6% of the original baseline level (p<0.001). Thus, oral chelation with DMSA produced a significant mercury diuresis in these children. We observed no adverse side effects of treatment. DMSA appears to be an effective and safe chelating agent for treatment of pediatric overexposure to metallic mercury.
Acute effects of the heavy metal antidotes DMPS and DMSA on circulation, respiration, and blood homoeostasis in dogs. Klimmek R, Krettek C, Werner HW. Arch Toxicol. 1993; 67(6):428-34. 8215913 PubMed. The heavy metal antidotes sodium-2,3-dimercaptopropane-1-sulfonate (DMPS) and meso-2,3-dimercaptosuccinic acid (DMSA) were investigated in anaesthetized dogs for their effects on a variety of physiological variables and parameters. In addition, the influence of both dithiols on oxygen consumption and ferrihaemoglobin production was studied in blood and red blood cells in vitro. DMPS (15 and 75 mg/kg i.v.) did not affect respiration, central venous pressure, left ventricular pressure or cardiac output and showed only marginal, statistically non-significant effects on aortic and effective perfusion pressure. In contrast to the slight, non-significant changes due to DMPS (15 mg/kg i.v.), an equimolar dose of DMSA (12 mg/kg i.v.) led to a slight transient decrease in femoral blood pressure with strong reflex tachycardia and increase in blood flow. The higher DMPS dose (75 mg/kg i.v.), however, caused marked decreases in femoral blood pressure and blood flow, strong changes in blood gases and pH, and lactacidosis. Most of the physiological variables and parameters did not return to the initial level by 60 min. The R-spike of the electrocardiogram decreased, and the T-wave increased. Experiments on the denervated hind leg indicate that DMPS may be a direct vasodilator. The fall of blood pressure due to DMPS was markedly reduced when 30% ferrihaemoglobin had been formed by 4-dimethylaminophenol.HCl (DMAP). The highest DMPS dose (150 mg/kg i.v.) provoked circulatory failure and respiratory arrest. Artificial ventilation with room air restored spontaneous respiration, but one of three animals did not survive this dose for more than 90 min. DMPS and DMSA reacted with oxygen.
Comparison of the effectiveness of 2,3-dimercaptopropanol (BAL) and meso-2,3-dimercaptosuccinic acid (DMSA) as protective agents against mercuric chloride-induced nephrotoxicity in rats. de la Torre A, Belles M, Llobet JM, Mayayo E, Domingo JL. Biol Trace Elem Res. 1998 Jul; 63(1):1-10. 9764565 PubMed. In contrast to BAL, DMSA was effective in increasing the urinary excretion of Hg and in reducing the renal Hg content. These results show that DMSA would be more effective than BAL in preventing or in protecting against inorganic Hg-induced nephrotoxicity.
Confirmation of Mercury Retention and Toxicity Using 2,3-Dimercapto-1-Propane Sulfonic Acid Sodium Salt (DMPS). Godfrey M, Campbell N. J Advancce Med., 7(1):19-30. Spring 1994. Australasian Society for Oral Medicine and Toxicology (ASOMAT).
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Determination and metabolism of dithiol chelating agents. VI. Isolation and identification of the mixed disulfides of meso-2,3-dimercaptosuccinic acid with L-cysteine in human urine. Maiorino RM, Bruce DC, Aposhian HV. Toxicol Appl Pharmacol. 1989 Feb; 97(2):338-49. 2538007 PubMed. Virtually nothing is known about the biotransformation of the heavy metal chelating agent, meso-2,3-dimercaptosuccinic acid (DMSA). Two fasted, normal, young men were given 10.0 mg DMSA/kg po, and their urines were collected over a 14-hr period. Urine samples were analyzed, before and after electrolytic reductive treatment, for DMSA and its biotransformants using bromobimane derivatization, HPLC separation, and fluorescence detection. Metabolites were isolated by HPLC, ion-pairing extraction, ion-exchange extraction, and TLC. By 14 hr after DMSA administration, 87% of the total DMSA and 95% of the total L-cysteine found in urine consisted of altered forms of these compounds. The urinary excretion of altered DMSA, at 1, 2, 4, 6, 9, and 14 hr after administration of DMSA, when compared to the urinary excretion of altered L-cysteine had a correlation coefficient of 0.952 and p less than 0.003. Approximately 90% of the altered DMSA excreted in the 2- to 4-hr urine was found in disulfide linkage with L-cysteine. The remaining 10% was found as cyclic disulfides of DMSA. Of the mixed disulfides found in 4- to 6-hr urine, 97% consisted of two L-cysteine residues per one DMSA and the remaining 3% consisted of one L-cysteine per one DMSA. The 2:1 mixed disulfides (97%) were isolated as three distinct species by TLC, consisting of 77, 12, and 8% of the total mixed disulfides found. In addition to the novelty of these biotransformants of DMSA, the DMSA-cysteine mixed disulfides indicate a thiol-disulfide interchange between DMSA and L-cystine. The discovery of the formation of these water soluble DMSA-cysteine mixed disulfides should encourage the evaluation of DMSA in the treatment of cystinuria.
Dimercaptosuccinic acid (DMSA), a non-toxic, water-soluble treatment for heavy metal toxicity. Miller AL. Altern Med Rev. 1998 Jun; 3(3):199-207. 9630737 PubMed. Heavy metals are, unfortunately, present in the air, water, and food supply. Cases of severe acute lead, mercury, arsenic, and cadmium poisoning are rare; however, when they do occur an effective, non-toxic treatment is essential. In addition, chronic, low-level exposure to lead in the soil and in residues of lead-based paint, to mercury in the atmosphere, in dental amalgams and in seafood, and to cadmium and arsenic in the environment and in cigarette smoke is much more common than acute exposure. Meso-2,3-dimercaptosuccinic acid (DMSA) is a sulfhydryl-containing, water-soluble, non-toxic, orally-administered metal chelator which has been in use as an antidote to heavy metal toxicity since the 1950s. More recent clinical use and research substantiates this compound s efficacy and safety, and establishes it as the premier metal chelation compound, based on oral dosing, urinary excretion, and its safety characteristics compared to other chelating substances.
Disposition of [14C] dimercaptosuccinic acid in mice. Liang YY, Marlowe C, Waddell WJ. Fundam Appl Toxicol. 1986 Apr; 6(3):532-40. 3009254 PubMed. Dimercaptosuccinic acid labeled with 14C ([14C]DMSA) was administered to mice iv; the mice were frozen by immersion in dry ice/hexane at 6 and 20 min and 1, 3, 9, and 24 hr after injection. The frozen mice were sectioned and processed for whole-body autoradiography for soluble substances. The radioactivity was highly localized in extracellular fluids such as the subcutaneous, intrapleural, intraperitoneal, and periosteal spaces. There was a pronounced accumulation in the periosteal fluid above that in other fluids during the first hour after injection. Most of the radioactivity was eliminated by the kidney and liver. Pretreatment of a mouse with HgCl2 subcutaneously 1 hr before [14C]DMSA produced an increase in radioactivity in the liver and decrease in lung. A high concentration of radioactivity was seen at the subcutaneous site of injection of the HgCl2. The results are interpreted to indicate that most of the DMSA is in the extracellular space but that it can cross cellular membranes to some extent. The pronounced accumulation in periosteal fluid may be an interaction of DMSA with Ca2+ in this space. No tissue had a pronounced retention of the compound, but lung retained more than most other tissues.
DMPS side effects. Ray Saarela. A very extensive list of problems with DMPS. http://www.web-light.nl/AMALGAM/EN/dmps.html#test
DMSA administration to patients with alleged mercury poisoning from dental amalgams: a placebo-controlled study. Sandborgh Englund G, Dahlqvist R, Lindelof B, Soderman E, Jonzon B, Vesterberg O, Larsson KS. J Dent Res. 1994 Mar; 73(3):620-8. 8163732 PubMed. DMSA-treatment resulted in an average increase in urinary mercury excretion by 65% and a decrease in blood mercury levels of 0.04 microgram/L/day. At the check-up after 3 months, urinary mercury excretion had returned to the pre-treatment level.
Effect of four thiol-containing chelators on disposition of orally administered mercuric chloride. Nielsen JB, Andersen O. Hum Exp Toxicol. 1991 Nov; 10(6):423-30. 1687854 PubMed. The present study, using oral administration of HgCl2 labelled with 203Hg, demonstrates that DMPS is superior to the other chelators in preventing mortality. Moreover, both DMSA and DMPS are superior to BAL and NAPA in alleviating acute toxicity and in preventing the undesirable distribution of orally administered mercury, especially to the brain. Further, oral administration of these chelators were more efficient than parenteral administration in reducing whole-body retention and organ deposition of orally administered mercuric chloride, most likely due to the prevention of intestinal uptake of mercury.
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Effects of meso-2,3-dimercaptosuccinic acid (DMSA) on methyl mercury-induced teratogenesis in mice. Sanchez DJ, Gomez M, Llobet JM, Domingo JL. Ecotoxicol Environ Saf. 1993 Aug;26(1):33-9. 7691533 PubMed. Methyl mercury has been reported to be embryotoxic and teratogenic in numerous systems such as fish, birds, and mammals. Meso-2,3-Dimercaptosuccinic acid (DMSA) has been useful for prevention and treatment of mercury poisoning. In this study, the protective activity of DMSA on methyl mercury-induced embryo/fetotoxicity was evaluated in mice. A series of four DMSA injections was administered subcutaneously to pregnant Swiss mice immediately after oral administration of 25 mg/kg methyl mercury chloride (MMC) given on Day 10 of gestation, and at 24, 48, and 72 hr thereafter. DMSA effectiveness was tested at 0, 80, 160, and 320 mg/kg/day. Oral administration of MMC resulted in a high rate of resorptions and dead fetuses as well as a reduced fetal body weight. Moreover, cleft palate (46.9%) and various developmental variations were found in the positive control group. Treatment with DMSA at 160 and 320 mg/kg/day significantly decreased the embryolethality of MMC, whereas at 320 mg DMSA/kg/day the incidence of skeletal anomalies and cleft palate (2.8%) was also significantly reduced. According to these results, DMSA offers encouragement with regard to its therapeutic potential for pregnant women exposed to methyl mercury.
Elemental mercury vapour toxicity, treatment, and prognosis after acute, intensive exposure in chloralkali plant workers. Part I: History, neuropsychological findings and chelator effects. Bluhm RE, Bobbitt RG, Welch LW, Wood AJ, Bonfiglio JF, Sarzen C, Heath AJ, Branch RA. Hum Exp Toxicol. 1992 May; 11(3):201-10. 1352115 PubMed. Mercury poisoning occurred after the acute, prolonged exposure of 53 construction workers to elemental mercury. Of those exposed, 26 were evaluated by clinical examination and tests of neuropsychological function. Patients received treatment with chelation therapy in the first weeks after exposure. Eleven of the patients with the highest mercury levels were followed in detail over an extended period. Rapidly resolving metal fume fever was the earliest manifestation of symptoms. CNS symptoms and abnormal performance on neuropsychological tests persisted over the prolonged period of follow-up. There were significant correlations between neuropsychological tests and indices of mercury exposure. Serial mercury in the blood and urine verified the long half-life and large volume of distribution of mercury. Chelation therapy with both drugs resulted in the mobilization of a small fraction of the total estimated body mercury. However, DMSA was able to increase the excretion of mercury to a greater extent than NAP. These observations demonstrate that acute exposure to elemental mercury and its vapour induces acute, inorganic mercury toxicity and causes long-term, probably irreversible, neurological sequelae.
Evaluation of methyl mercury chelating agents using red blood cells and isolated hepatocytes. Aaseth J, Alexander J, Deverill J. Chem Biol Interact. 1981 Sep; 36(3):287-97. 7285235 PubMed. The relative efficacy of thiol-containing mercurial scavengers was assayed by using cellular suspensions of erythrocytes or isolated hepatocytes. The blood cells incubated in a buffer (pH 7.4) containing 1 mM glucose (10% hematocrit) were exposed to 5 microM methyl mercuric chloride. In the absence of extracellular thiols the red blood cells took up more than 90% of methyl mercury from the surrounding medium during 5--10 min. This uptake was almost completely inhibited by dimercaptosuccinic acid (DMSA) (1 mM) and the same chelant could rapidly remove 80% of the mercury from 'pre-loaded' erythrocytes. Hepatocytes prepared according to the method of Seglen  in a suspension of 10(6) cells/ml in a buffer containing 5 mM glucose and 5 mg/ml of bovine serum albumin were also exposed to methyl mercuric chloride (4 microM). Almost 50% of the mercurial was taken up by the cells slowly during the incubation period of 240 min. DMSA (1 mM) almost completely blocked the methyl mercury binding by the hepatocytes. 2-Mercaptopropionylglycin (Thiola) or mercaptosuccinic acid (MSA) was almost as effective mercurial scavengers as DMSA in hepatocytes and in red blood cells. Diethyldithiocarbamate (DDC) and dimercaptopropanol (BAL) were considerably less effective than DMSA to inhibit the mercurial binding to hepatocytes. Experiments in vivo have shown that DMSA is a better mercurial chelator than Thiola or MSA, whereas DDC and BAL may both be considered to be inapplicable in methyl mercury poisonings. Our cellular assay provides preliminary information of the efficiency of chelating thiols and may serve as a useful first approximation when planning further experiments.
Factors influencing the efficiency of chelation therapy. Kostial K, Kargacin B, Arezina R, Landeka M, Simonovic I. Hyg Epidemiol Microbiol Immunol. 1991; 35(4):337-50. 1804865 PubMed. After ingestion of metals oral chelation therapy was more effective in younger than older animals. In suckling rats the treatment effectively reduced metal retention and this was mostly due to decrease in gut retention. This treatment in sucklings was also very effective in condition of late administration. In older rats early oral DMPS treatment after 203Hg ingestion is contraindicated since it increases significantly mercury retention while DMSA and ZnDTPA treatments reduced mercury retention.
Influence of 2,3-dimercaptopropane-1-sulfonate and dimercaptosuccinic acid on the mobilization of mercury from tissues of rats pretreated with mercuric chloride, phenylmercury acetate or mercury vapors. Buchet JP, Lauwerys RR. Toxicology. 1989 Mar; 54(3):323-33. 2539660 PubMed. The efficiency of the sodium salt of 2,3-dimercaptopropanesulfonic acid (DMPS) and meso-dimercaptosuccinic acid (DMSA) to mobilize mercury from tissues has been assessed in rats pretreated with different doses of HgCl2, phenylmercury acetate or exposed to different concentrations of mercury vapors. These pretreatments increase the mercury concentration in the kidney and to a lower extent in the liver. Only exposure to metallic mercury vapor leads to mercury accumulation in the brain. Both chelators mobilize mercury stored in the kidney and the amount of metal excreted in urine following a single administration of DMSA is a good indicator of the renal burden of mercury. The rate of removal is greater after DMPS administration than after DMSA but repeated administration of either agents eventually leads to the same total amount of mercury mobilized from the kidney. The loss of mercury from the liver can be slightly accelerated by repeated administration of the chelators. However, the chelators are inefficient in removing mercury from the brain.
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Influence of 2,3-dimercaptopropane-1-sulfonate (DMPS) and meso-2,3-dimercaptosuccinic acid (DMSA) on the renal disposition of mercury in normal and uninephrectomized rats exposed to inorganic mercury. Zalups RK. J Pharmacol Exp Ther. 1993 Nov; 267(2):791-800. 8246154 PubMed. When a 100-mg/kg dose of either DMPS or DMSA was injected (i.p.) 24 and 30 hr after treatment with HgCl2, the renal concentration and burden of inorganic mercury decreased markedly in both normal and NPX rats during the 24 hr after the first dose of the respective chelating agent was administered. The findings in the present study suggest that DMPS and DMSA are very effective agents in reducing the renal (and whole body) burden of inorganic mercury in normal and NPX rats.
Intravenous mercury injection and ingestion: clinical manifestations and management. McFee RB, Caraccio TR. J Toxicol Clin Toxicol. 2001; 39(7):733-8. 11778672 PubMed. A 40-year-old male injected 3 mL of elemental mercury intravenously and ingested 3 mL as a suicide attempt. Within 24 hours, he became dyspneic, febrile, tachycardic, and voiced mild gastrointestinal complaints. Chest X-ray revealed scattered pulmonary infiltrates and embolized mercury bilaterally. A ventilation/perfusion scan demonstrated ventilation/ perfusion deficits. Additionally, his renal function declined, as manifest by minor elevations in blood urea nitrogen and creatinine and decreased urine output. Pulmonary therapy, intravenous hydration, and chelation using 2,3-dimercaptoscuccinic acid (DMSA/Succimer) were started. Over the next 36 hours, the patient's pulmonary and renal functions improved. Temperature and heart rate subsequently normalized, and symptoms at discharge were mild exertional dyspnea. DISCUSSION: Liquid mercury injected intravenously embolizes to the pulmonary vasculature and perhaps vessels in other organs such as heart and kidney. In-situ oxidation to inorganic mercury, which is directly toxic to a variety of tissues, may help explain the multisystem involvement. CONCLUSION: Significant pulmonary dysfunction accompanied by radiographically demonstrated mercury emboli and temporary abnormalities in several organs improved shortly after initiation of chelation. The impact of chelation on long-term outcome of parenteral mercury exposure remains uncharacterized.
Human studies with the chelating agents, DMPS and DMSA. Aposhian HV, Maiorino RM, Rivera M, Bruce DC, Dart RC, Hurlbut KM, Levine DJ, Zheng W, Fernando Q, Carter D, et al. J Toxicol Clin Toxicol. 1992; 30(4):505-28. 1331491 PubMed. Meso-2,3-dimercaptosuccinic acid (DMSA) is bound to plasma albumin in humans and appears to be excreted in the urine as the DMSA-cysteine mixed disulfide. The pharmacokinetics of DMSA have been determined after its administration to humans po. For the blood, the tmax and t1/2 were 3.0 h + 0.45 SE and 3.2 h + 0.56 SE, respectively. The Cmax was 26.2 microM + 4.7 SE. To determine whether dental amalgams influence the human body burden of mercury, we gave volunteers the sodium salt of 2,3-dimercaptopropane-1-sulfonic acid (DMPS). The diameters of dental amalgams of the subjects were determined to obtain the amalgam score. Administration of 300 mg DMPS by mouth increased the mean urinary mercury excretion of subjects over a 9 h period. There was a positive correlation between the amount of mercury excreted and the amalgam score. DMPS might be useful for increasing the urinary excretion of mercury and thus increasing the significance and reliability of this measure of mercury exposure. DMSA analogs have been designed and synthesized in attempts to increase the uptake by cell membranes of the DMSA prototype chelating agents. The i.v. administration of the monomethyl ester of DMSA, the dimethyl ester of DMSA or the zinc chelate of dimethyl DMSA increases the biliary excretion of platinum and cadmium in rats.
Mercury from dental amalgam fillings: studies on oral chelating agents for assessing and reducing mercury burdens in humans. Hibberd AR, Howard MA, Hunnisett AG. J Nutr Environ Med 1998; 8:219-231. When these three agents were tested, along with potassium citrate (5 g), DMPS (orally given at a dose of 10 mg/kg intravenously it is dosed at 3 mg/kg), DMSA (30 mg/kg), and NAC (30 mg/kg), their effects on mercury excretion were comparable.
Meso-2,3-Dimercaptosuccinic Acid (DMSA)Alternative Medicine Review. Volume 5, Number 3, pg 264-67, 2000, Thorne Research, Inc. Research has demonstrated that DMSA, when compared to treatment with other chelating agents, resulted in the greatest urinary excretion of mercury, as well as being the most effective at removing mercury from the blood, liver, brain, spleen, lungs, large intestine, skeletal muscle, and bone.17 Another study indicated that mercury excretion was greatest in the first 8-24 hours after oral DMSA administration. Animal studies show that following intravenous administration of methylmercury, DMSA was the “most efficient chelator for brain mercury,” removing two-thirds of the brain mercury deposits. DMSA (Thorne) http://www.thorne.com/pdf/journal/5-3/dmsa_monograph.pdf
Methylmercury removal in the dog during infusion of 2,3-dimercaptosuccinic acid (DMSA). Kostyniak PJ. J Toxicol Environ Health. 1983 Apr-Jun; 11(4-6):947-57. 6312064 PubMed. 2,3-Dimercaptosuccinic acid (DMSA) has been utilized in chelation therapy and in extracorporal complexing hemodialysis therapy for experimental methylmercury intoxication. In the latter application, substantial excretion of methylmercury occurred by the urinary route. This prompted the current study of the effects of continuous intravenous DMSA infusion therapy on methylmercury kinetics in the dog. Animals previously dosed with 203Hg-labeled methylmercury at 2.5 mg Hg/kg received a priming dose of DMSA, followed by a continuous iv infusion at dose rates that resulted in DMSA concentrations in plasma similar to those observed during DMSA complexing hemodialysis therapy. The kinetics of 203Hg removal in DMSA-infused dogs was compared with both saline-infused controls and DMSA complexing hemodialysis treated dogs. DMSA infusion therapy resulted in a shift in 203Hg binding within systemic blood from the red-cell fraction into plasma. This was consistent with an observed association of DMSA with the plasma fraction. The shift in 203Hg from red cells into plasma was paralleled by an increase in urinary clearance of 203Hg during the DMSA infusion period. In four dogs treated in this fashion, an average of 6.5 micrograms of mercury was removed by the urinary route over the 5-h treatment period, compared to 0.007 micrograms in the saline-infused dogs. Although a similar magnitude of mercury output into urine was observed during DMSA complexing hemodialysis, an additional 5 micrograms was removed by the dialyzer, making that technique 1.5 times as effective as infusion therapy. Comparing 203Hg tissue concentration after DMSA infusion therapy with the saline-treated controls revealed a 6.5-fold decrease in liver, a 3-fold reduction in kidney, and a 27% reduction in cerebrum. No significant differences were observed in medulla or cerebellum. Histopathology revealed no consistent differences between DMSA-treated and saline-treated animals. The DMSA infusion therapy was effective in causing a rapid removal of 203Hg from animals previously dosed with 203Hg-labeled methylmercury. DMSA infusion therapy may provide a useful therapeutic alternative for methylmercury poisoning when rapid removal of the intoxicant is desired and hemodialysis equipment and expertise are not readily available.
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Mobilization of heavy metals by newer, therapeutically useful chelating agents. Aposhian HV, Maiorino RM, Gonzalez-Ramirez D, Zuniga-Charles M, Xu Z, Hurlbut KM, Junco-Munoz P, Dart RC, Aposhian MM. Toxicology. 1995 Mar 31; 97(1-3):23-38. 7716789 PubMed. Four chelating agents that have been used most commonly for the treatment of humans intoxicated with lead, mercury, arsenic or other heavy metals and metalloids are reviewed as to their advantages, disadvantages, metabolism and specificity. Of these, CaNa2EDTA and dimercaprol (British anti-lewisite, BAL) are becoming outmoded and can be expected to be replaced by meso-2,3-dimercaptosuccinic acid (DMSA, succimer) for treatment of lead intoxication and by the sodium salt of 2,3-dimercapto-1-propanesulfonic acid (DMPS, Dimaval) for treating lead, mercury or arsenic intoxication. Meso-2,3-DMSA and DMPS are biotransformed differently in humans. More than 90% of the DMSA excreted in the urine is found in the form of a mixed disulfide in which each of the sulfur atoms of DMSA is in disulfide linkage with an L-cysteine molecule. After DMPS administration, however, acyclic and cyclic disulfides of DMPS are found in the urine. The Dimaval-mercury challenge test holds great promise as a diagnostic test for mercury exposure, especially for low level mercurialism. Urinary mercury after Dimaval challenge may be a better biomarker of low level mercurialism than unchallenged urinary mercury excretion.
Mobilization of mercury and arsenic in humans by sodium 2, 3-dimercapto-1-propane sulfonate (DMPS). Aposhian HV. Environ Health Perspect. 1998 Aug; 106 Suppl 4:1017-25. 9703487 PubMed. The tests involve collecting an overnight urine, administering 300 mg DMPS at zero time, collecting the urine from 0 to 6 hr, and determining the urinary Hg before and after DMPS is given. The challenge test, when applied to normal college student volunteers with and without amalgam restorations in their mouths, indicated that two-thirds of the Hg excreted in the urine after DMPS administration originated in their dental amalgams. In addition, there was a positive linear correlation between the amalgam score (a measure of amalgam surface) and urinary Hg after the challenge test. When the DMPS-Hg challenge test was used to study dental personnel occupationally exposed to Hg, the urinary excretion of Hg was 88, 49, and 35 times greater after DMPS administration than before administration in 10 dental technicians, 5 dentists, and 13 nondental personnel, respectively.
Placebo response in environmental disease. Chelation therapy of patients with symptoms attributed to amalgam fillings. Grandjean P, Guldager B, Larsen IB, Jorgensen PJ, Holmstrup P. J Occup Environ Med. 1997 Aug; 39(8):707-14. 9273873 PubMed. Treatment of patients who attribute their environmental illness to mercury from amalgam fillings is largely experimental. On the Symptom Check List, overall distress, and somatization, obsessive-compulsive, depression, and anxiety symptom dimensions, were increased in 50 consecutive patients examined, and Eysenck Personality Questionnaire scores suggested less extroversion and increased degree of emotional liability. Succimer (meso-2, 3-dimercaptosuccinic acid) was given at a daily dose of 30 mg/kg for five days in a double-blind, randomized placebo-controlled trial. Urinary excretion of mercury and lead was considerably increased in the patients who received the chelator. Immediately after the treatment and 5 to 6 weeks later, most distress dimensions had improved considerably, but there was no difference between the succimer and placebo groups. These findings suggest that some patients with environmental illness may substantially benefit from placebo.
Prevention by chelating agents of metal-induced developmental toxicity. Domingo JL. Reprod Toxicol. 1995 Mar-Apr; 9(2):105-13. 7795320 PubMed. DMSA and DMPS were found to be effective in alleviating arsenate- and arsenite-induced teratogenesis, whereas BAL afforded only some protection against arsenic-induced embryo/fetal toxicity. Also, DMSA, DMPS, and Tiopronin were effective in ameliorating methyl mercury-induced developmental toxicity. Although the embryotoxic and teratogenic effects of vanadate were significantly reduced by Tiron, no significant amelioration of uranium-induced embryotoxicity was observed after treatment with this chelator.
Succimer, an oral lead chelator. Mann KV, Travers JD. Clin Pharm. 1991 Dec; 10(12):914-22. 1663439 PubMed. The pharmacology, pharmacokinetics, clinical efficacy, adverse effects, and dosage and administration of succimer when used for the treatment of lead poisoning are reviewed. Succimer is an orally active, heavy-metal chelating agent that forms stable, water-soluble complexes with lead; it also chelates other toxic heavy metals, such as arsenic and mercury. It is a designated orphan drug that is indicated for the treatment of lead poisoning, specifically in children with blood lead concentrations higher than 45 micrograms/dL. Succimer reverses the adverse metabolic effects of lead on heme synthesis while increasing urinary lead output without adversely affecting essential mineral excretion at the recommended dosage regimen. The rebound in lead concentrations that can occur after short courses of chelating therapies (caused by redistribution of lead from bone stores) may require frequent and multiple courses of chelation therapy. The most common adverse effects reported in clinical trials of succimer in children and adults were nausea, vomiting, diarrhea, appetite loss, and loose stools; these effects may be related to the drug's unpleasant mercaptan odor. There are no known drug interactions between succimer and other drugs, including iron supplements, although data are limited. The recommended initial dosage in children is 10 mg/kg or 350 mg/sq m every eight hours for five days. The dosage is then reduced to 10 mg/kg or 350 mg/sq m every 12 hours for an additional two weeks. Clinical studies indicate that succimer is relatively selective for lead and effectively lowers blood lead concentrations. Although clinical experience is limited, an oral lead chelator may offer advantages over currently available agents.
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The influence of chelating agents on the distribution and biotransformation of methylmercuric chloride in rats. Planas-Bohne F. J Pharmacol Exp Ther. 1981 May; 217(2):500-4. 6262488 PubMed. DMSA was most effective in removing the mercurial from all organs, except the kidneys, where 2,3-dimercaptopropane-1-sulfonate was better. N-acetylpenicillamine showed only marginal effectiveness. Separate determinations of [203Hg]MMC and 203Hg++ in liver and kidneys showed that DMSA removed more of the organic and 2,3-dimercaptopropane-1-sulfonate more of the inorganic Hg. DMSA injected i.p. or given p.o. removed almost equal amounts of MMC, indicating virtually 100% absorption of the chelating agent from the gastrointestinal tract.
The protective effects of thiol-containing compounds on mercuric chloride-induced acute inhibition of enzymes from mouse kidney. Suzuki S, Ozaki N. Toxicology. 1984 Jan; 29(3):207-20. 6320497 PubMed. The inhibitory effect of mercuric chloride on mouse kidney enzymes and the treatment of this inhibition with some thiol-containing compounds, e.g., dithiothreitol (DTT), dimercaptosuccinic acid (DMS) and D-penicillamine (Pen) was examined. To produce a significant inhibition of renal enzymes in vivo, it was necessary to administer 5 mg Hg/kg/day, s.c., once daily for 3 doses, and to sacrifice the animals 1 day after the last injection. With this Hg dose, microsomal Mg2+-Na+-K+-ATPase, mitochondrial Mg2+-HCO-3-ATPase and supernatant carbonic anhydrase activities decreased to about 30%, 70% and 60% of normal values, respectively. Combined administration of DTT (5-20 mg/kg, i.p.) and DMS (5-20 mg/kg, i.p.) with HgCl2 restored the enzyme activities to near normal or normal levels in parallel to the administered doses. The effect of Pen was slightly less than that of the above 2 compounds. This may be due to the number of thiol radicals, as Pen is a monothiol and the other 2 compounds are dithiol compounds. Since the toxicity of DMS is very low compared with DTT, DMS may be more suitable for the treatment of mercury poisoning.
The truth about DMPS. The purpose of this website is to share information regarding DMPS, and to collect information from those who have experienced adverse effects from this drug. In the process I hope not only to inform those individuals who are considering the use of this drug, but to stimulate the appropriate research to determine safe protocols for its use. It is my hope that researchers will want to investigate this collection of patient reports. http://www.dmpsbackfire.com/default.shtml
Treatment of mercuric chloride poisoning with dimercaptosuccinic acid and diuretics: preliminary studies. Aaseth J, Alexander J, Raknerud N. J Toxicol Clin Toxicol. 1982 Apr; 19(2):173-86. 6180172 PubMed. The distribution and excretion of mercury were studied in mice given a single injection of HgCl2 with or without chelation treatment. DMS (2,3-dimercaptosuccinic acid) given intravenously (0.5 mmol SH/kg) to mice 24 h after the mercury injection reduced the kidney Hg level significantly, while NAPA (N-acetyl-DL-penicillamine) and BAL (2,3-dimercaptopropanol) did not. The effectivity of DMS to remove Hg from kidneys was comparable to that of BAL-sulph (2,3-dimercaptopropane-1-sulfonate), irrespective of whether these chelating agents were given orally or intravenously. Immediate chelation treatment with DMS or mercaptodextran reduced the renal Hg level to about 50% of control levels, as measured 3 d after the treatment. Combination of DMS with immediate intraperitoneal treatment with spironolactone was even more effective in reducing the renal levels, and acted both by increasing the fecal and urinary excretion. The DMS treatment, as well as DMS + spironolactone in combination, could protect against kidney damage following injection of 30 mumol HgCl2/kg. Such treatment was essentially nontoxic.
Treatment of mercury and lead poisonings with dimercaptosuccinic acid and sodium dimercaptopropanesulfonate. Aaseth J, Jacobsen D, Andersen O, Wickstrom E. A review. Analyst. 1995 Mar; 120(3):853-4. 7741240 PubMed. DMSA was shown to cross the blood brain barrier and remove mercury. DMPS was less effective. DMPS has been shown to be 3 times more toxic than DMSA, based on LD-50. DMSA to be almost 3 times more effective than DMPS in removing brain mercury in animal studies.
Urinary excretion of mercury after occupational exposure to mercury vapour and influence of the chelating agent meso-2,3-dimercaptosuccinic acid (DMSA). Roels HA, Boeckx M, Ceulemans E, Lauwerys RR. Br J Ind Med. 1991 Apr; 48(4):247-53. 1851035 PubMed. The urinary mercury excretion was significantly higher during the 24 hours after DMSA administration in all groups compared with that in the 24 hours before. The bulk (50-70%) of the DMSA stimulated mercury excretion appeared within the first eight hours. In each group, the amount of mercury (microgram Hg/24h) excreted after DMSA was significantly correlated with that before administration of DMSA. The groups whose exposure had ceased, however, exhibited much higher correlation for coefficients (r=0.97 for group B and 0.86 for group C after three weeks of holiday) than those currently exposed to mercury vapour (r-0.66 for group C before and 9.58 after reduction of exposure). The data suggest that after a few days of cessation of occupational exposure to mercury vapour the HgU before and after administration of DMSA mainly reflects the amount of mercury stored in the kidney, which represents a mercury pool with a slow turnover.
Urinary excretion of meso-2,3-dimercaptosuccinic acid in human subjects. Aposhian HV, Maiorino RM, Dart RC, Perry DF. Clin Pharmacol Ther. 1989 May; 45(5):520-6. 2541962 PubMed. The urinary excretion of meso-2,3-dimercaptosuccinic acid (DMSA), which is an effective chelating agent for lead, was determined after the oral administration of 10 mg DMSA/kg to six normal young men. The DMSA that was absorbed was extensively biotransformed. After 14 hours only 2.53% of the administered DMSA was excreted in the urine as unaltered DMSA and 18.1% as altered forms. The unaltered DMSA was 12% of the total DMSA found in the urine. The altered form(s) of DMSA was 88% of the total urinary DMSA. The altered DMSA can be converted to unaltered DMSA by electrolytic reduction, which indicates that the altered forms of DMSA are disulfides. The excretion of altered DMSA reached a peak between 2 and 4 hours after DMSA administration. There were small but statistically significant increases in the excretion of zinc, copper, and lead after DMSA administration. DMSA did not influence the urinary excretion of 27 other metals and elements.
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Urinary excretion of trace elements in humans after sodium 2,3-dimercaptopropane-1-sulfonate challenge test. Torres-Alanis O, Garza-Ocanas L, Bernal MA, Pineyro-Lopez A. J Toxicol Clin Toxicol. 2000; 38(7):697-700. 11192456 PubMed. A significant increase in urinary excretion of mercury (3- to 107-fold) was observed after the DMPS dose. The DMPS treatment led to a 2- to 119-fold increase in copper excretion; 3- to 43.8-fold in selenium excretion; 1.6- to 44-fold in zinc excretion; and 1.75- to 42.7-fold in magnesium excretion. The excretion of manganese, chromium, cobalt, aluminium, and molybdenum remained unchanged. In this study, an intravenous DMPS challenge test produced a significant increase in mercury excretion and also led to an increased excretion of copper, selenium, zinc, and magnesium.
Urinary mercury after administration of 2, 3-dimercaptopropane-1-sulfonic acid: correlation with dental amalgam score. Aposhian HV, Bruce DC, Alter W, Dart RC, Hurlbut KM, Aposhian MM. FASEB J. 1992 Apr; 6(7):2472-6. 1563599 PubMed. Administration of 300 mg DMPS by mouth increased the mean urinary mercury excretion of the amalgam group from 0.70 to 17.2 micrograms and that of the nonamalgam group from 0.27 to 5.1 micrograms over a 9-h period. Two-thirds of the mercury excreted in the urine of those with dental amalgams appears to be derived originally from the mercury vapor released from their amalgams. Linear regression analysis indicated a highly significant positive correlation between the mercury excreted in the urine 2 h after DMPS administration and the dental amalgam scores. DMPS can be used to increase the urinary excretion of mercury and thus increase the significance and reliability of this measure of mercury exposure or burden, especially in cases of micromercurialism.
Utilization of renal slices to evaluate the efficacy of chelating agents for removing mercury from the kidney. Keith RL, Setiarahardjo I, Fernando Q, Aposhian HV, Gandolfi AJ. Toxicology. 1997 Jan 15; 116(1-3):67-75. 9020508 PubMed. Mercury is an environmental contaminant that preferentially accumulates in the kidney. It has been previously shown using proton-induced X-ray emission analysis that mercury (HgCl2) accumulated in precision-cut rabbit renal cortical slices. In this study, the efficacy of seven chelating agents for the removal of Hg from renal slices has been examined. Rabbits were injected with HgCl2 (10 mg/kg) and 3 h later kidneys were sliced, or renal slices were exposed in vitro to a mildly toxic concentration of HgCl2 (5 x 10(-5)M, 4 h). The slices were then treated in vitro with 10 mM concentrations of EDTA, lipoic acid (LA), penicillamine (PA), glutathione (GSH), 1,4-dithiothreitol (DTT), DMSA, or DMPS. DMPS proved to be the most effective in mobilizing Hg from in vivo or in vitro HgCl2-exposed renal tissue ( > 85% of control after 3 h incubation). Relative efficacies for the seven agents were DMPS > DMSA, PA > DTT, GSH > LA, EDTA. The use of renal slices appears to be a useful in vitro tool for assessing the efficacy of chelating agents on mobilizing accumulated Hg from renal tissue.
Assessment of the protective activity of monisoamyl meso-2,3-dimercaptosuccinate against methylmercury-induced maternal and embryo/fetal toxicity in mice. Belles M, Sanchez DJ, Gomez M, Domingo JL, Jones MM, Singh PK. Toxicology. 1996 Jan 8; 106(1-3):93-7. 8571406 PubMed. The protective activity of monoisoamyl meso-2,3-dimercaptosuccinate (Mi-ADMS), a new monoester of 2,3-dimercaptosuccinic acid (DMSA), on methylmercury-induced maternal and developmental toxicity was assessed in mice. A series of four Mi-ADMS injections was given s.c. at 0.25, 6, 24, and 48 h after oral administration of 25 mg/kg of methylmercury chloride (MMC) given on day 10 of gestation. Mi-ADMS effectiveness was tested at 0, 23.8, 47.6 and 95 mg/kg. Cesarean sections were performed on gestation day 18. All live fetuses were examined for external, internal, and skeletal abnormalities. Oral MMC administration resulted in an increase in the number of resorptions, and a decrease in fetal body weight, whereas the incidence of cleft palate, micrognathia, and skeletal variations was also increased in the fetuses of the MMC-treated groups. Although significant amelioration of MMC-induced embryolethality by Mi-ADMS was not noted at any dose, MMC-induced fetotoxicity was reduced by administration of this agent at 23.8, 47.6, and 95 mg/kg. However, the intrinsic toxicity of Mi-ADMS would be a restrictive factor for the possible therapeutic use of this chelator in pregnant women exposed to organic mercury.
Methylmercury-thiol uptake into cultured brain capillary endothelial cells on amino acid system. L. Mokrzan EM, Kerper LE, Ballatori N, Clarkson TW. J Pharmacol Exp Ther. 1995 Mar; 272(3):1277-84. 7891344 PubMed. Recent in vivo studies suggest that the neurotoxin methylmercury (MeHg) is transported into brain as an L-cysteine complex by amino acid transport system L. To test this hypothesis, the mechanism of MeHg uptake into cultured calf brain capillary endothelial cells, an in vitro model of the blood-brain barrier, was examined. Uptake of Me203Hg-L-cysteine followed Michaelis-Menten kinetics, with a Km of 234 +/- 58 microM (mean +/- S.E.) and a Vmax of 57 +/- 25 pmol.micrograms DNA-1.15 sec-1. Uptake of 10 microM MeHg-L-cysteine was stereoselective and Na+ independent and it was inhibited by the system L substrates L-leucine, 2-amino-2-norbornanecarboxylic acid and L-methionine (5 mM), consistent with transport of MeHg-L-cysteine by the L amino acid carrier. L-Glutamate and methylaminoisobutyric acid, which are transported by the acidic and A amino acid carriers, respectively, had no effect. Moreover, uptake of 3H-L-leucine (5 microM) was inhibited by 1 mM MeHg-L-cysteine is transported into brain capillary endothelial cells by the L carrier. Uptake of other MeHg-thiols was also measured. MeHg-D, L-homocysteine uptake was 82 +/- 11% of MeHg-L-cysteine uptake, whereas uptakes of MeHg complexes of L-penicillamine, dimercaptosuccinic acid, N-acetyl-L-cysteine and glutathione were 57 +/- 16%, 19 +/- 7%, 10 +/- 4% and 8 +/- 5% of MeHg-L-cysteine uptake, respectively. These results illustrate the potential to minimize transport of MeHg across brain capillary endothelium by the careful choice of thiol complexing agent.
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Molecular mechanisms of in vivo metal chelation: implications for clinical treatment of metal intoxications. Andersen O, Aaseth J. Environ Health Perspect. 2002 Oct; 110 Suppl 5:887-90. 12426153 PubMed. 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. Dimercaptosuccinic acid and dimercaptopropionic sulfonate have gained more general acceptance among clinicians, undoubtedly improving the management of many human metal intoxications, including lead, arsenic, and mercury compounds. Still, development of new safer chelators suited for long-term oral administration for chelation of metal deposits (mainly iron), is an important research challenge for the future.
Monoisoamyl meso-2,3-dimercaptosuccinate as a delayed treatment for mercury removal in rats. Kostial K, Kargacin B, Blanusa M, Piasek M, Jones MM, Singh PK. Environ Health Perspect. 1994 Sep; 102 Suppl 3:309-11. 7843123 PubMed. Monoisoamyl meso-2,3-dimercaptosuccinate (Mi-ADMS) was found to be superior to meso-2,3-dimercaptosuccinic acid (DMSA) in decreasing the body burden of 203Hg in rats under conditions of early treatment. In this experiment Mi-ADMS was used as late treatment for mercury removal. Albino rats aged 6 weeks and 7-day-old sucklings received a single intraperitoneal injection of 203Hg (as nitrate). Two weeks later they were treated with DMSA or Mi-ADMS (0.25 mmole/kg bw) on two consecutive days. The radioactivity in the carcass (whole body after removal of the gastrointestinal tract), liver, kidneys and brain was determined by solid crystal gamma scintillation counting six days after chelation therapy administration (3 weeks after 203Hg application). Both chelators reduced the body burden of mercury compared to controls. The effect of Mi-ADMS was superior to DMSA treatment in older rats for decreasing carcass and kidney retention, and in suckling rats for decreasing carcass, liver, and kidney retention. They were equally effective in decreasing brain retention in older rats and had no effect on brain retention in sucklings. The efficiency of Mi-ADMS in reducing the body burden of mercury was generally higher than the efficiency of the DMSA treatment. Therefore, Mi-ADMS deserves further attention as a late treatment for mercury removal.
Racemic-2,3-dimercaptosuccinic acid for inorganic mercury mobilization in rats. Kostial K, Restek-Samarzija N, Blanusa M, Piasek M, Prester L, Jones MM, Singh PK. J Appl Toxicol. 1997 Jan-Feb; 17(1):71-4. 9048230 PubMed. Both chelators reduced 203Hg retention in whole body and kidney and at higher doses also in the liver. Racemic-DMSA was more efficient at lower dose levels and equal to meso-DMSA at the highest dose level. Kidney retention decreased after rac-DMSA to 27, 10 and 10% of controls and after meso-DMSA to 68, 39 and 10% of control values at the 0.5, 1.0 and 2.0 mmol kg-1 dose level, respectively. Since meso-DMSA is already approved for human use, its stereoisomeric form, rac-DMSA, deserves further attention for treatment of mercury poisoning.
Toxic metals and antioxidants: Part II. The role of antioxidants in arsenic and cadmium toxicity. Patrick L. Altern Med Rev. 2003 Apr; 8(2):106-28. 12777158 PubMed. The metabolism and excretion of these heavy metals depend on the presence of antioxidants and thiols that aid arsenic methylation and both arsenic and cadmium metallothionein-binding. S-adenosylmethionine, lipoic acid, glutathione, selenium, zinc, N-acetylcysteine (NAC), methionine, cysteine, alpha-tocopherol, and ascorbic acid have specific roles in the mitigation of heavy metal toxicity. Several antioxidants including NAC, zinc, methionine, and cysteine, when used in conjunction with standard chelating agents, can improve the mobilization and excretion of arsenic and cadmium.
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