History of Dental Amalgams
For the past two centuries, mercury amalgam use in dentistry has increased in popularity as the preferred tooth filling material.(1,2,3) However, when mercury amalgam was initially introduced into North America in the 1830s, its use was vehemently opposed by the dental licensing authority, the American Society of Dental Surgeons and official policies were adopted to prohibit the use of this material. Their concern was focussed upon the safety of placing mercury into humans since many toxic effects of mercury were well known; including dementia and loss of motor coordination. In spite of this official prohibition, several dentists continued to use mercury amalgam and some were subsequently suspended for malpractice. The popularity of this inexpensive, durable and easy to work with material continued to rise amongst dentists and by 1856, there were so many dentists using mercury amalgam that the American Society of Dental Surgeons was disbanded by overwhelming opposition to their policy surrounding amalgam fillings. Following this, in 1859 the American Dental Association was founded on the premise that mercury amalgam was a safe and desirable tooth filling material. Because of the low cost of amalgam, dentistry was now available to the masses for the first time. By 1895, the mercury amalgam mixture of metals was modified and this formula continues to be used to this day, with a typical mixture containing 50% metallic mercury, 35% silver, 9% tin, 6% copper, and a trace of zinc. Mercury amalgam continues to be the material preferred by 92% of dentists for restoring posterior teeth.(4,5) and over one hundred tons of mercury is now used in dentistry in the U.S. each year.
Mercury release from dental amalgams
The basic premise for regarding the amalgam filling as safe was the assumption that the amalgamation process resulted in a stabilization of the normally volatile mercury. This premise has now been shown to be entirely false. Since the 1980s, it has been well established that mercury vapor is continuously released from amalgam fillings. The release of this vapor into the mouth increases immediately after chewing(6) or tooth brushing(7) and can result in a daily absorbed dose of mercury which exceeds the excretory capacity via the urine and stool. It has now been well established and published by several authorities, including the World Health Organization, that amalgam tooth fillings are, by far, the major source of mercury exposure for the general population.(8) This was recently reiterated by Health Canada in its 1995 position paper on dental amalgam.(9) According to the World Health Organization's expert committee, the daily human exposure to mercury vapor from amalgam fillings ranges from 3micrograms to 17micrograms as compared to a maximum of 2.6micrograms from all other sources. It is disturbing to note that mercury was recently removed from latex paint in North America due to the health risks associated with inhalation of mercury vapor from the paint. Exposure to mercury from paint was estimated to be 4.6micrograms per day for approximately two weeks following application of the paint.(10) If mercury in latex paint was clearly considered such a health risk, why are amalgam fillings such a source of scornful dialog amongst the dental and medical community when amalgams are a much greater source and a far more persistent source of inhaled mercury?
Pharmacokinetics of inhaled mercury
Mercury vapor released from dental amalgams is efficiently absorbed through the alveoli. Following absorption through the lungs, elemental mercury vapor (Hg0) is only found very transiently in the blood. Due to its high lipid solubility elemental mercury is rapidly transported through cell membranes (including cell membranes of the cells comprising the blood-brain barrier). Once inside metabolically active cells, elemental mercury (Hg0) is then oxidized by catalase to form ionic mercury (Hg2+). Ionic mercury (Hg2+) is not lipid soluble and it therefore results in a high degree of retention of absorbed mercury and a tissue half life ranging from days to decades depending on the particular organ.(11,8,12,13,14,15) This phenomenon clarifies why, studies have repeatedly demonstrated that after placement of amalgam fillings, blood and urinary mercury levels remain relatively low even though many organs develop concentrations of mercury many times greater than that of the blood.(16,17,18) Thus, blood or non-challenged urinary mercury levels bear little relationship to the total body burden of mercury gradually acquired from amalgam fillings.(19)
Biochemical effects of inhaled mercury
Once mercury enters the cell, it ultimately becomes bound covalently to the sulfhydryl groups found in glutathione, and to a lesser degree to cysteine, biotin, lipoic acid, coenzyme A as well as to other protein sulfhydryl groups. The major intracellular sulfhydryl compound in mammals is the tripeptide glutathione. Glutathione and the glutathione rich enzyme, glutathione peroxidase are probably the most important antioxidant defenses in most species including the human.(20) Mercury has been shown to cause a marked reduction in glutathione production and glutathione peroxidase activity and thus it may result in a marked rise in oxidative stress within the brain and other organs.(21,22,23) Apart from the loss of antioxidant protection from mercury induced inhibition of glutathione and glutathione peroxidase, mercury results in a marked increase in free radical generation through Fenton reactions and other mechanisms.(22)
In addition to its key role in antioxidant defenses, glutathione is also a critical component in the liver's detoxification mechanisms. Enzymes within the liver must form conjugates between glutathione and certain toxic metabolites, organic xenobiotics, and heavy metals to enable these toxins to be eliminated from the body. This process of glutathione conjugation makes toxic molecules more water soluble and enables their excretion via the bile or through the kidney. If liver glutathione production is markedly inhibited, as occurs when mercury accumulates within hepatocytes, mercury and numerous other toxic substances may more readily accumulate throughout the body because the excretion of such substances are significantly impaired.(24,25,26,22) Furthermore, because the majority of mercury is excreted through the stool and urine as a glutathione conjugate, individuals with long standing body burdens of mercury (and thus depleted glutathione production) may not demonstrate elevated levels of mercury in the urine, blood or stool when specimens are gathered in the absence of a challenge with an appropriate metal chelating agent. Thus, tissue biopsy of target organs or a provocation test measuring urinary mercury after the administration of a chelating agent, may be the only valid means to assess chronic mercury body burden.(27,28,29,30)
Uptake and distribution of inhaled mercury
Numerous studies have been performed demonstrating the body tissue uptake and distribution of mercury from dental amalgams. Studies using whole body imaging in primates with dental amalgams have clearly demonstrated that the amalgams result in high levels of mercury in the kidney, intestinal tract, brain, liver, and other organs. (31,16) Of great concern are human fetal and neonatal studies which demonstrate that mercury concentrations in kidney, liver, and brain correlate significantly with maternal amalgam surfaces.(32) Furthermore, a recently published study has firmly established the presence of mercury from dental amalgam in the milk of nursing mothers.(33)
Clinical effects of inhaled mercury
The impact of chronic, low level mercury exposure is now known to adversely impact numerous other cellular and organ system processes.(19) Ionic mercury is antigenic and may contribute significantly to autoimmune processes.(34,35) Mercury is also immunotoxic and it may result in immune suppression and allergy.(36,37,38,39) Recent research has also demonstrated that multiple strains of antibiotic resistant bacteria develop rapidly in the gut and oral cavity of both humans as well as non-human primates following the placement of amalgam fillings.(40)
Amalgam fillings have been shown to contribute to mercury accumulation in human and animal kidneys and this has been associated with a significant decrease in renal function.(41,42) Human fertility has also been shown to be significantly impacted by low level exposure to mercury vapor. A recent study examining 7000 dental assistants demonstrated that this group experiences a fertility rate approximately 40% less than that of women who have no occupational exposure to mercury.(43)
Of perhaps greatest concern is the potential role of low level, chronic mercury exposure upon central nervous system function. It is now well established, that amalgam derived mercury accumulates in monkey and human brain tissues.(41,31,13) Mercury has been shown to concentrate selectively in human brain regions involved with memory function and it may play a significant role in the etiology of Alzheimer's disease.(44,45) Other reports have shown subclinical motor and neuropsychological deficits amongst dentists and dental workers as compared to control subjects.(46,47) Mounting evidence has lead some to suggest that, in fact, mercury from amalgams may play a highly significant role in the etiology of numerous mental illnesses and neuropsychological disorders.(48, 49,50,51,52,53)
Pharmacology of DMPS (Dimaval; 2,3-dimercapto-1-propane
DMPS (sodium salt of 2,3-dimercapto-1-propane sulfonic acid) is not a new drug. It was developed in the former Soviet Union in 1958. In 1978, DMPS became available to the western world following its synthesis and production by the German pharmaceutical company, Heyl.54 DMPS is a chelating agent in the group of dithiols, along with dimercaprol (BAL, British anti-Lewisite) and succimer (DMSA, 2,3-dimercaptosuccinic acid).
DMPS has been used extensively in Europe and on a limited basis in North America as a treatment for mercury (55), arsenic (56) or lead intoxication (57). It is a registered drug in Germany and, in fact, due to its long record of safety, is now available without prescription.(28) When compared with D-penicillamine and N-acetyl-DL-penicillamine, DMPS was the most effective agent to clear mercury from the blood of victims of the Iraqi mercury disaster in the 1960's. (58)
In addition to its safety and utility as an agent for detoxification, DMPS has been used frequently as an agent to approximate mercury body burden.(56,59) As described above, resting urine or blood levels of mercury bear little relationship to body burden of mercury in cases of long standing, low level intoxication, such as that which may occur from dental amalgams.(27),
There is a great wealth of scientific literature on the use of DMPS as both a diagnostic tool and a treatment agent in cases of acute and chronic heavy metal intoxication. Much of the European literature surrounding DMPS has been summarized in the English language in a thorough scientific monograph which is in its sixth edition.60 This monograph forms the basis for the rational use of DMPS by clinicians throughout the world. This monograph also formed the basis for the FDA sanctioned, multicentered trial on the use of DMPS in the evaluation of mercury body burden and response to mercury detoxification therapy in polysymptomatic patients with dental amalgams. (As an aside, Dr. Cline was a participant in the official training program for researchers participating in this multicentered trial and he achieved a mark in the 90th percentile range on the examination required for participation).
In the DMPS monograph, there is extensive reference to the work being done by European clinicians in the treatment of the polysymptomatic patient suffering from demonstrable mercury body burden. DMPS is initially used to assess the body burden of mercury and other heavy metals through provocation testing. Several methodological variations of this test are described. Because of the high degree of patient compliance, and because this methodology is in keeping with the pharmacokinetics of DMPS, I have elected to use the provocation testing methodology advocated by the German toxicologist, M. Daunderer, M.D.(61, 60) In this methodology, DMPS is given as a slow IV push. The patient then provides the first voided specimen after one to one and one half hours. The urine is then sent overnight to a toxicology laboratory. Mercury and other heavy metals are reported as micrograms metal per gram of urinary creatinine. The creatinine compensates for variations in urinary dilution. This has proven to be a simple test to perform, with a high degree of patient compliance. The quantity of heavy metal returned has generally correlated well to the symptom severity of the patients I have seen. Furthermore, the changes in metal excretion with this provocation test have corresponded well to the changes in symptom severity of the patients which I have seen. The provocation test forms a rational approach to the use of DMPS. When high quantities of toxic metals are no longer found with provocation urine testing, the DMPS is of no further value and its use may discontinued.
As mentioned previously, the pharmacology of DMPS has been extensively described.(54,28) Both oral and parenteral preparations of this agent are available. Pharmacokinetic data on both preparations are available.(62,63) The parentaral from of this agent allows for better control over the dosage in highly sensitive patients (the treatment can be interrupted if the patient experiences adverse effects). The parenteral route also avoids transport of metals from the gut to the liver through the portal circulation and may be better tolerated by the highly sensitive patient.
The metabolism of DMPS has also been studied thoroughly. DMPS is excreted largely through the urine. Before its excretion, DMPS is biotransformed largely to acyclic and cyclic disulfides. This mode of biotransformation may suggest one advantage of DMPS over the other dithiol chelator, DMSA (succimer). As opposed to DMPS, DMSA is biotransformed almost completely to a cysteine conjugate. Because of this, DMSA may lead to further depletion of cysteine and glutathione stores, which are often already low in metal toxic patients.(64,62,65,23) DMPS undergoes both renal and biliary excretion.(66) DMPS is distributed in both an intracellular and extracellular manner.(66,67,68) However, Unlike most other chelating agents, such as BAL and EDTA, DMPS does not cross the blood brain barrier and does not redistriute mercury to the brain(28).
The toxicity of DMPS is well known and, in this regard, it provides very distinct advantages to the officially approved dithiol chelator, Dimercaprol (BAL). Although BAL continues to be stockpiled by the military in preparation for chemical warfare attack with the arsenical nerve gas, lewisite, it is 300 times more toxic than DMPS, has no corresponding challenge test and it clearly causes redistribution of metals to the brain.(69) Animal studies on the acute and chronic toxicity of DMPS have been carried out and the results illustrate the safety of this agent and its wide therapeutic window.(60) Numerous human studies have failed to uncover any significant adverse impacts of DMPS upon human renal function, liver function, cardiovascular system, blood, immune system, G.I. tract or any other organs or systems. Minor or avoidable side effects such as local irritation at the site of parenteral infusion or hypotension with overly rapid infusion of the agent have been reported.(60)
Rationale For Using DMPS:
The scientific rationale for using DMPS in determining the body burden of and the removal of mercury and other heavy metals has been outlined above. The clinical rationale for using DMPS in people suffering from idiopathic polysymptomatic disorders such as fibromyalgia and chronic fatigue syndrome is as follows. Current scientific understanding of these disorders suggests that the etiologies are multifactorial and may have significant environmental components including accumulation of heavy metals in key target organs. Most patients coming to my clinic with these chronic disorders have already attended several practitioners and have tried all sorts of therapies, usually to no avail. These patients are well educated regarding the various possible underlying etiologies and want to explore the possibility that heavy metals may be an underlying factor. I have observed that in most individuals in which mercury and other heavy metals are present, that a major improvement in their health usually occurs when they undergo detoxification using DMPS. This is in keeping with the observations made by numerous clinicians in Europe and in the USA by the principle investigators in the multicenter phase III, FDA approved clinical trial mentioned earlier. Finally, I want to emphasize that DMPS is not being utilized as the sole treatment in individuals suffering from these disorders, but rather it is being utilized as a method to relieve the patient of significant physiological stresses by decreasing the body burden of heavy metals. Although further research is clearly required in this area, my clinical experience over the last year in using DMPS has convinced me that this valuable agent has a key role to play in the management of highly disabling and previously intractable cases of chronic fatigue syndrome and fibromyalgia. There are many patients in my practice who are now healthy productive citizens instead of hopeless invalids, thanks to the use of DMPS administered in a safe manner.
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