George A. Apergis

April 15, 1998

Toxicology Paper

No other metal better illustrates the diversity of effects caused by different chemical species than does mercury. On the basis of chemical speciation, there are three forms of mercury: elemental, inorganic, and organic compounds.

The major source of mercury is the natural degassing of the earth's crust, including land areas, rivers, and the ocean, and this source is estimated to produce on the order of 2700 to 6000 tons per year. The total man made release into the atmosphere is about 2000 to 3000 tons, and it is difficult to assess what quantities of mercury come from human activities and what quantities from natural resources. Run-off into natural bodies of water may contain mercury from both anthropogenic and natural sources, so it is difficult to assess how much released into the atmosphere is from man made or natural sources.

Nevertheless, mining, smelting, and industrial discharge have been factors in the environmental contamination in the past. For instance, it is estimated that loss in water effluent from chloralkali plants, one of the largest users of mercury, has been reduced to 99% in recent years. Industrial activities not directly employing mercury or mercury products give rise to substantial quantities of this metal.

Fossil fuel may contain as much as 1 ppm of mercury, and it is estimated that about 5000 tons of mercury per year may be emitted from burning coal, natural gas, and from the refining of petroleum products. Calculations based on the mercury content of the Greenland ice cap show an increase from the year 1900 to the present and suggest that the increment is related both to an increase in background levels of mercury in rainwater and to man made release.

Regardless of source, both organic and inorganic forms of mercury may undergo environmental transformation. Metallic mercury may be oxidized to inorganic divalent mercury, particularly in the presence of organic material such as in the aquatic environment. Divalent inorganic mercury may, in turn be reduced to metallic mercury when conditions are appropriate for reducing reactions to occur.

A potential source of alkyaltion of divalent mercury is methylation to dimethyl mercury by anaerobic bacteria. Methyl mercury is of major toxicology significance. If it is taken up into the food chain by fish, it may eventually cycle through humans or it may diffuse into the atmosphere and return to the earth's crust or to bodies of water as methyl mercury in rainfall¹.

The Japanese Tragedy

The steadily mounting environmental contamination by mercury was ignored until a tragic series of events occurred in Japan. In the beginning many cats were seen to dance in the small fishing villages along Minamata Bay on Kyushu Island. They clearly were mad, because they screamed incessantly and often ended their dance and their lives by flinging themselves into the sea.

This activity was first observed in 1953, and by 1960 the nervous tremors that preceded the dance were familiar not only in cats, but also in birds, fish, pigs, and dogs. A greater terror was aroused as human beings were also stricken, often several members of one family. Fearing that they might have a shameful infectious disease, the poor fisherman kept their tragedy to themselves for 3 years.

In 1956 though people started going to hospitals.
As more patients were being admitted to the municipal hospital, they were temporarily placed in an isolation ward because doctors suspected that they might have the contagious Encephalitis japonica, although they had no fever and their symptoms seemed to develop more slowly. Since all the victims lived near Minamata Bay, the syndrome was soon named Minamata disease after that small inlet.

Consequently, a committee was quickly formed to find the cause; and four months later, on August 24, 1956, the medical school of Kumamoto University was commissioned to treat the patients and undertake a field study. Because the families of victims ate more fish, researchers examined those taken from Minamata Bay more closely. The fish also seemed to show some symptoms, and they rose to the surface of the bay in large numbers.

The Chisso Company was the major source of pollution and discharged its waste directly into Minamata Bay. Knowing their waste effluent induced the symptoms in cats, Chisso officials refused the researchers access to company property to conduct tests and thereby delaying confirmation of the cause of the disease. Since the symptoms suggested heavy metal poisoning, a series of chemical analysis were conducted between October and December, 1958; and they confirmed that the factory discharged manganese, copper, iron, mercury, and lead as well as other elements and several organic substances. The heavy metals quickly settled in the bay near the plant's outfall, so levels were much higher in the mud near the pier and along the coastline than further offshore. The list of suspect elements was gradually narrowed by animal experiments in which the symptoms were compared with those from Minamata disease².

Manganese was quickly tested because earlier poisoning epidemic has been caused by drinking well water contaminated with this element, but the symptoms were not the same. Then thallium was also ruled out as was selenium, although it caused a "blind stagger" something like the ataxic gait associated with Minamata disease. A synergistic effect among elements was also possible, because selenium has since been determined to decrease the effects of mercurialsm in animals whose food contained both elements. Therefore, it is possible that the interaction of these elements influenced the course of the disease. Although these experiments did not help solve the mystery, the negative evidence did provide comparative verification of the actual cause later.

Although up to 2010 ppm of mercury (wet weight) were collected from the mud near the factory's drainage outlet, this element was not initially given high priority, because the patients did not display the familiar symptoms of inorganic mercury poisoning such as loose teeth, sore gums, and tremors. Instead, experimental animals underwent pathological changes in their central nervous systems. Cats seemed to be especially susceptible, because they consumed relatively large quantities of fish in proportion to their body weight.

But the poisoning compound was not extracted from aquatic organisms until February, 1969, when crystals of a sulfur containing methylmercuric compound were isolated from shellfish. Then it was identified as methylmercuric methylsulfide and was also synthesized in the laboratory. Cats were fed the synthesized compound and were stricken with the same symptoms as those with natural Minamata disease. When the fish and shellfish were tested, they contained up to 50 ppm of mercury. Some of them remained healthy, although they concentrated form 5000 to 50,000 times more mercury than the 1 ppb in the water.

Tests on the human subjects also verified elevated mercury in the hair, blood, and urine. Hair samples ranged from 300 to 700 ppm compared with 1 to 3 ppm of mercury in normal subjects. Although mercury in hair was later recognized as a fairly reliable indication of poisoning, the levels had declined after people stopped eating contaminated fish at Minamata. When men with short hair were checked, they had as little as 4.3 ppm of mercury, whereas women's long hair contained more mercury in the sections farthest from the scalp. Autopsies also revealed excessive mercury in the brain, liver, and kidney.

The diagnosis of methylmercury poisoning was confirmed when pathological changes in the brain structures were compared with those in an individual who died in 1954, 14 years after being poisoned while manufacturing alkylmercury fungicides. As the cause of Minamata disease was traced, the symptoms were also more accurately described, but no cure has yet to be found. Unlike acute inorganic mercury poisoning, much of the damage is permanent³.

Amalgam "silver-fillings" and their toxic effects

The issue of mercury exposure from dental "silver" fillings has gained considerable notoriety in the general media during the last decade. Specific attention has focused on the potential for human health consequences and the general well-being of the global environment. The modern silver amalgam (amalgam means mixed with mercury), traditionally known as the silver filling, has been employed as the principal tooth restorative material for over 180 years and presently accounts for 75-80% of all tooth restorations⁴.

These "silver" fillings contain approximately 50% mercury by weight, 35% silver, 13% tin, 2% copper and a trace of zinc⁵. Each tooth restoration has a mercury mass of about 750-1000 mg and should more properly be called a mercury filling. They have a functional life of approximately 7-9 years, after which they are usually replaced with another mercury filling⁶. Hundreds of metric tonnes of mercury are placed into teeth world wide each year and some of this material, as particular waste from the dental office, finds its way into the sewerage and refuse systems.

Within the dental profession, the issue of mercury filling safety has cyclically recurred. After the introduction of the modern dental amalgam in 1812 by a British chemist, a "silver paste", which was a combination of silver filings from coins and mercury, became fashionable for tooth restoration. Since the coins were not pure, expansion of the material often resulted in tooth fracture and/or a high bite.

In America during the 1800s, concern regarding the possibility for mercury toxicity caused the American Society of Dental Surgeons to make mercury usage an issue of malpractice, mandating that its members sign an oath not to use mercury-containing materials. However, mercury fillings usage increased because it afforded an economic advantage to those dentists employing it; it is user friendly, and because of its durability in the mouth.

By 1856, the American Society of Dental Surgeons was forced to disband due to dwindling membership over the mercury filling issue. In its place arose the American Dental Association, founded by those who advocated silver amalgam- mercury use in dentistry⁷.

Again in the 1920s, a controversy erupted after the publication of articles and letters by a German chemistry professor, who attacked mercury filling usage for possible toxic effects.

Today, 182 years later, the American Dental Association has amended its code of ethics to make removal of serviceable mercury fillings an issue of unethical conduct, if the reason for removal is to eliminate a toxic material from the human body and if this recommendation is made solely by the dentist⁸. In the American Dental Association's view, a dentist is "ethical" to place the mercury material and recommend its safety. But, if a dentist suggests that the mercury fillings are potentially harmful or that the exposure to unnecessary mercury can result, then the dentist is acting "unethically". Clinically serviceable mercury fillings can be "ethically" removed if: done for aesthetic reasons; at the request of a physician; or a patient's request (without prompting).

Release of mercury from dental fillings.

Mercury vaporizes continuously from dental fillings, being intensified by chewing, tooth brushing and hot liquids⁹. After mastication or tooth brushing ceases, it takes almost 90 minutes for the rate of vaporization to decline to the lower prechewing level¹⁰. Also, the greater the number of fillings and the greater the chewing surface area, the larger the mercury exposure¹⁰. Thus, the average individual is on a roller coaster of mercury vapor exposure during the day. Breakfast will cause the release rate to increase and just as the rate is slowing again it is time for midmorning coffee brake. Lunch, mid-afternoon coffee or tea, the evening meal, and a snack before bedtime all contribute to the daily exposure to the daily exposure to mercury from dental fillings.

It is estimated that the average individual, with eight biting surface mercury fillings, is exposed to a daily dose uptake of approximately 10 micrograms mercury per day from dental fillings¹¹. Select individuals may have daily doses 10 times higher (100 micrograms per day) because of factors which exacerbate the mercury vaporization. Some of these factors are: frequency of eating, chronic gum chewing, chronic tooth grinding behavior (usually during sleep), consumption of hot foods and drinks, mouth and food acidity. Corroborating human autopsy evidence showed that the brain and kidney tissues contained significantly higher mercury in individuals who had mercury fillings¹². Furthermore, the concentration of brain mercury in subjects with mercury fillings correlated with the number of these fillings present.

The historically espoused opinion of dentistry insists that, once mixed, the mercury is locked into the fillings. Despite these replicated research findings, many national dental trade associations still claim that mercury fillings are safe¹³. They base their conviction on the anecdotal facts that the mercury fillings have been used for over 150 years, billions of fillings have been placed, and they do not see sickness or death from the mercury exposure¹⁴. From the medical perspective, dental amalgam fillings are a significant source, having potential medical consequences.

Recently investigations in sheep and monkey animal models demonstrate that the dental mercury accumulates in all tissues of the adult, being highest in the kidney and liver.

This accumulation is so extensive that it can be visualized on a whole-body image scan¹⁵. Research also shows that a high level of dental amalgam mercury in monkey kidney is still present at one year after mercury filling placement¹⁶.

Also, mercury from dental amalgam will cross the placenta and begin accumulating in the developing fetus within two days after the filling placement in pregnant sheep and is highest in the fetal liver then the kidney. The mother's milk also showed evidence of mercury, suggesting that the newborn would have an additional exposure to mercury¹⁷. Recent human chelation studies show a association between urinary mercury excretion and the presence of mercury fillings¹⁸.

For example, one study showed that, after a chelation challenge with DMPS, urinary mercury excretion is significantly higher from subjects with mercury fillings than from those with no such fillings. It was concluded that at least two-thirds of the excreted mercury originates from the dental restorations¹⁸.

There is now a consensus that the mercury from dental tooth restorations constitutes the largest non-occupational source of mercury in the general population, being greater than all other environmental sources combined.

Pathophysiological consequences of mercury from dental fillings.

During the last several years, medical research has demonstrated a relationship between mercury exposure and pathophysiology in various animal models. In sheep exposed to mercury from in situ tooth fillings, kidney function has been shown to be impaired. After 30 days of chewing the sheep lost 50% of their kidney filtration ability, they began to have difficulty regulating sodium and they demonstrated a reduced albumin excretion. Control sheep treated with non-mercury dental fillings did not show such effects¹⁹.

In a study of 10 humans with mercury fillings, it was demonstrated that the plasma mercury dropped by 50% and the urinary mercury level declined by 25% over a twelve month interval after filling removal compared to pre-removal level. Most notable was the finding that 12 months after filling removal, the urinary albumin level was significantly higher than the level 4 months prior to removal²⁰.

In sheep, the placement of mercury fillings caused a fall in the urinary albumin, signifying renal pathophysiology. In humans, the removal of mercury fillings results in an elevation in urinary albumin, indicating a renal homeostatic readjustment. In a recent collaborative paper between three North American universities, it was demonstrated in a primate model that oral and intestinal bacteria (ex. streptococci) exhibit a significant increase in mercury and antibiotic resistance within two weeks following mercury filling placement²¹.

The mercury resistant bacteria species exhibited resistance to various antibiotics such as, ampicillin, tetracyclines, streptomycin, kanamycin, erythromycin, and chloramphenicol, which they had not demonstrated prior to placement. This occurs because in some bacteria mercury-resistance and antibiotic-resistance are encoded on adjacent small genetic sites within plasmids²². When exposed to environmental mercury, this genetic material is activated to protect the bacteria from the lethal mercury.

The plasmid is also replicated and passed on to other bacteria, insuring species survival. In so doing, the antibiotic resistance also spreads to the other bacteria. Antibiotic resistance is an important issue in medicine today. It has been estimated that 80% of mercury-resistant bacteria strains also show an increased resistance to one or more conventional antibiotics.

Thirty percent of all hospitalized patients in North America receive antibiotic therapy and antibiotics compromise 105 of the total $5! billion drug sales in Canada during 1992²³. Moreover, ten of the top 20 generic drugs prescribed during 1990 in the USA were antibiotics. Yet, antibiotics appear to be losing their clinical potency and stronger antibiotic medications at increasing dosages are necessary to combat many common infections²⁴.

Recently, investigations have suggested that mercury may be involved in common brain pathologies and that the source of mercury is likely the dental fillings²⁵. In a human autopsy study, brain tissue from persons having Alzheimer's disease at death were compared to an age matched group of control brains from subjects without Alzheimer's disease. The only significant difference in metal content between the two groups was mercury, being considerably higher in the Alzheimer group.

The mercury concentration was prominent in the hippocampus, the amygdala and particularly in the nucleus basalis, all brain structures involved in memory function. Other metals examined were not significantly different in the two groups of subjects.

The effect of mercury on central nervous system neuron membrane integrity has been examined and shown that mercury specifically affects tubulin, a brain neuronal dimer protein responsible for proper microtubule formation of brain neurons. Both in vivo and in vitro experiments demonstrated that mercury chelated to amino acids maintains an abnormal polymerization state of tubulin. This effect may produce neurofibrillar tangles.

Such tangles are a recognized lesion of Alzheimer's disease.
Inorganic mercury affects ADP-ribosylation of the rat brain neuronal proteins tubulin, actin and B-50, in both in vivo and in vitro experiments²⁶. ADP-ribosylation is the rate limiting process involved in polymerization of tubulin and actin monomers into the structure of the neuron membrane. It has been demonstrated that ionic mercury and elemental mercury vapor markedly diminishes the binding of tubulin to GTP and thus inhibits the polymerization of tubulin which is essential for the formation of microtubule in the central nervous system. These studies are direct evidence for a connection between mercury exposure and neurodegeneration.

Governmental regulatory action concerning mercury fillings.

In 1987, the government of Sweden commissioned an expert panel to evaluate the available evidence regarding mercury filling safety. The panel concluded that mercury fillings were "unsuitable from a toxicological point of view". Based on this panels advice, the Swedish announced that steps would be taken to eliminate dental amalgam use and recommended that comprehensive mercury filling treatment on pregnant woman should be stopped to prevent mercury damage to the fetus²⁷.

Shortly thereafter, the German Ministry of Health (Bundesgesundheitsamt, BDA) issued a similar advisory.

In October of 1989, the Swedish Director of Chemical Inspection (KEMI), responsible for environmental protection, declared that amalgam would be banned.

In January of 1992, the German Ministry of Health (BDA) informed manufacturers of its intention to ban the production of amalgam. The BDA removed low copper non-gamma-2-amalgam from the market and published a pamphlet recommending avoiding mercury filling use in individuals with kidney disease, children to age 6, and pregnant women.

In August of 1992, the Swedish government suggested a timetable to phase out mercury fillings. Environmental concerns were used as the official reason for amalgam discontinuation, but the government did acknowledge the toxicological risk to patients and stated that mercury fillings should no longer be used in children by July 1993, in adolescent to age 19 by July 1995, and in all Swedish citizens by 1997.

The Austrian Minister of Health announced that the use of mercury fillings in children would be banned in 1996 and discontinued in all Austrians by the year 2000²⁸.

The medical research evidence has been clear for some time. Dental amalgam mercury fillings constitute a significant source of chronic exposure to mercury in the general population.

This exposure is unnecessary and can be justified by the risk/benefit analysis. While incriminating medical research continues to be published, the dental profession persists in placing itself in the untenable predicament of advocating an anecdotal position of mercury filling safety.

The mercury exposure from dental silver amalgam is toxicologically significant and research into its possible effects is at an early stage. Lets hope that we as a human race do not have to face what happened at Minamata Bay to put a stop to the amalgam fillings.

References:

1. Casarett and Doull's Toxicology The Basic Science of Poisons.

2. D'itri, P and D'itri, F Mercury Contamination: A Human Tragedy. New York John Wiley & Sons 1977

3. Mitra, S Mercury in the Ecosystem. Trans Tech Publications Ltd. 1986.

4. Baurer, J.G. and First, H.A., Calif. Dent. Assoc. J., 1982, 10, 47-61.

5. Skinner, E.W. and Phillips, R.W., The Science of Dental Materials, 6^th ed., Philadelphia: W.B. Saundesr Co. 1969, Chapter 20, page 303 & Chap. 22, p.332.

6. Phillips, R.W., Hamilton, A.I. Jendresen, M.D. McHorris, W.H., and Schallhorn, R.G., J. Prosth. Dent., 1986, 55:736-72.14.0pt;mso-bidi-font-size: 10.0pt">

7. Ring, M. Dentistry, an illustrated history. Harryu N. Abrams Inc.,Publisher, New York, 1985.

8. American Dental Association, Principle of ethics and code of professional conduct.

9. Vimy, M.J. and Lorscheider, F.L., Journal Dental Research., 1985, 64, 1069-71.

10. Vimy, M.J. and Lorscheider, F.L., J. Dental Research., 1985, 64, 1072-5.14.0pt;mso-bidi-font-size: 10.0pt">

11. Vimy, M.J., and Lorscheider, F.L., J. Trace Elem. exper. Med., 1990, 3, 111-123.14.0pt; mso-bidi-font-size:10.0pt">

12. Eggelston, D.W. and Nylander, M., J. Prosth. Dent., 1987, 58, 704-707.14.0pt;mso-bidi-font-size: 10.0pt">

13. Truono, E.J., Letter of Importance, J. American Dental Assoc. 1991, 122, 8-14.14.0pt; mso-bidi-font-size:10.0pt">

14. American Dental Association News Release, 1990.

15. Hahn, L.J.., Kloiber, R., Leininger, R.W., FASEB J, 1990, 4, 3256-3260.14.0pt;mso-bidi-font-size: 10.0pt">

16. Danscher, G. Horsted, P. and Rungby, J., Exp. Mol. Path., 1990, 52, 291-299.14.0pt;mso-bidi-font-size: 10.0pt">

17. Takahashi, Y., and Lorscheider, F.L., Amer. J. Physiol., 1990, 258, R939-R945.14.0pt; mso-bidi-font-size:10.0pt">

18. Aposhian, H.V., Bruce, D.C., Alter, W., Dart, R.C., Hurlbut, K.M., FASEB 1992, 6, 2472-2476. 14.0pt;mso-bidi-font-size:10.0pt">

19. Boyd, N.D., Benediktsson, H., Hooper, D.E., Vimy, M.J., American J. Physiology 1991, 261, R1010-R1014.

20. Molin, M. Bergman, B., Marklund, S.L., Schutz, A. Acta Odontol. Scand., 1990, 48, 89-202.

21. Summers, A.O., Wireman, J., Marshall, B., Antimicrob. Agents & Chemotheraoy, 1993, 37, 825-834.

22. Gilbert, M.P. and Summers, A.O., Plasmid, 1988, 20: 127-136.

23. Intercontinental Medical Statistics, Canada, 1992.

24. Cohen, M.L., Science, 1992, 257, 1050-1055.

25. Thompson, C.M., Markesbery, W.R., Ehmann, W.D., Vance D.E., Nerotoxicology, 1988, 9, 1-7. 14.0pt;mso-bidi-font-size:10.0pt">

26. Palkiewicz, P., Zwiers, H., Nuerochem. 1994, 62, 2049-2052.

27. Lundstrom, I.M.C., Int. J. Oral Surgery, 1983, 12, 1-9.