zinc, bismuth, cadmium, nickel, manganese, indium, le ad and aluminium. Depend- ing on the procedure ..... Tinnitus, noises in ears. Gastrointestinai problems.
International Journal of Risk & Safety in Medicine, 3 (1992) 1-22 @ 1992 Elsevier Science Publishers B.V. All Tightsreserved 0924-6479/92/$05.00
1
RISMED 00108
Mercury from dental amalgams:exposure and effects laroPleva
"\
Uddeholm Tooling AB, Hagfors, Sweden (Accepted
1 September 1991)
"'\ Key words: Mercury; Dental amalgam; Toxicity; Alternative materials
~
The risks of mercury exposure arising from the use of dental amalgam fillings are reviewed and discussed. On the basis of both knowledge acQuired in various scientific disciplines and ten years of experience in the field it is concluded that mercury from amalgam may weil contribute significantly to a DumheTof modern health problems and to decreasedQuaIity of life in a large population group in many countries. Erroneous opinion as to "negligible" mercury exposure and lack of cooperation between the dental, medical and other professions are two important factors in the issue. There is both biological and metallurgical evidence that typical Hg-exposure levels produced by amalgam fillings are 5-10-fold higher than what are regarded as safe limits for exposure to mercury from other sources. There is no doubt that dental mercury should be taken inta consideration as a possible etiological factor when considering neurological, immunological and endocrinological diseasesof unknown etiology. Protective measuresduring amalgam removal and prospects for alternative dental materials are discussed.
""'"\
History
\
The era of dental amalgam (DA) dates back to 1818 [1,2]. About 50% of a dental amalgam is mercury (Hg), which can dissolve a number of metais. Silver, copper and tio were the first metals used in various rat ios for dental amalgams, though dentists have been free to add many other metals such as gold, platinum, zinc, bismuth, cadmium, nickel, manganese,indium, lead and aluminium. Depending on the procedure chosen, the precise mercury content of amalgam can vary considerably, from 42% with the conventionai and "dry" method to 60% Hg when using the so-called "wet" techniques. Correspondenceto: Jaro Pleva, PhD, PI 3079, S-68300Hagfors, Sweden.
..
2 From the very beginning, the use of mercury alloy implants has been a matter of debate and struggle. On ODehand, dentists have appreciated the availability of a material capable of helping to preserve decayedteeth which is both cheap and easy to work. Opponents of amalgam have for a long period been convinced that
,
implanting amalgam,which has been observedto sweatout a metal as toxic as
mercury, must be harmful to bot h the living tooth and the rest of the patient's system. Initial resistance to dental amalgam remained strong till about 1860, ODe opponent of its use arguing that unIess it could be shown to have overriding benefits "... the practice must be abandoned as wholly improper" [3]. Many dentists nevertheless continued to use amalgam, and the general argument that it might be detrimental to health slowly receded. It came to the fore once more in the period between the two world wars ("the second amalgam war") and was then forcefully advanced once more during the 1980's("the third amalgam war"). The earliest actual observations of intoxication due to mercury in amalgam had appeared during the second half of the 19th century [4,5]. Between 1926 and 1939
the eminent GermanchemistAlfred Stock publishedhis investigationson amal-
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gam and the properties of mercury as weIl as a very illustrative description of the symptomatology of chronic mercury poisoning [6-8]. Mter 1945 a great deal of specialized research was undertaken into both the material properties of amalgam and the physiological effects of minute amounts of mercury. In the entire interdisciplinary debate, however, ODehas continued to miss an overall synthesis of the various issues, ranging from materials science and corrosion to neurology, immunology and diagnostics; no unambiguous answer as to the biocompatibility of dental amalgam has ever been given.
": i
The conventionai view and the field situation The official position of the dental profession today seems to reflect a large measure of prestigious compromise, reflecting the fact that over a period of 170 years the use of amalgam has become a firmly established tradition. Where ODe
might expect concern or a willingnessto carry out adequateepidemiological investigationsinto the health effects of dental amalgam,ODein fact usually encounters only bland assurancesto the effect that dental amalgam has been used successfullyover such a long period, with favorable experience in billions of fillings [9], or assurancesas to "very low mercury exposure" and the negligible toxicity of inorganic -mercury (as compared to the organic form encountered in fish from a contaminated environment). Unjustified comparisons between the general population and workers occupationally exposed to mercury are also made as a means of proving the safety of amalgam. Oddly, the current situation is also complicated by the fact that the practicing physician is much less familiar with the problems of "mercurialism" than was his predecessor in the days when mercury was widely used in medicine; that can only meaD that a diagnosis of mercury-induced problems is unlikely to be made. At the
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same time, central authorities have sometimes released general information about non-existent risks of adverse effects from dental amalgam, an equal disservice to the community. Outside the official structures the situation is very different. In Sweden, the growing Scandinavian Organization of Dental Patients has acquired over 11,000 members and has established contacts with patients in several other countries. The field experience built up by this group now extends over a period of more than ten years. It comprises in particular the histories of patients with chronic complaints who have been examined by most current methods, sometimes over several years, with out finding the cause of their troubles. Their problems have been resistant to any tradition al treatment and the diagnosis "psychical disorder" is frequent. All too of ten, according to this group, its members encounter from physicians only an attitude of scorn when they raise the subject of amalgam mercury. Some of their case histories and experiencespoint to however is the fact that in the professions, ignorance of the facts which are known, coupled to what ODemight call educated nonchalance and an exaggeratedloyalty to established structures are risk factors in amalgam poisoning. Very consistently, to put it briefly, many of the histories of patients of this type point to a persistence of symptoms so long as amalgam is present and a remarkable recovery after the amalgam has been removed. For the patient who has experienced such symptoms, his or her recovery is obviously more important than a willingness to await the production of the strict scientific proof which would be required by the authorities if they are to become convinced of the existence of the problem. Needless to say, the recovery of such patients is also beneficial to the community and to the economy of the health care system. The existenceof a large DumheTof patients attributing their symptoms to dental amalgam is not specific to Scandinavia, though the degree of severity and DumheT of casesmay for unknown reasons be higher there; hypotheses have been raised relating to a low intake of selenium in Scandinavia or a relatively high level of use of amalgam. As far as the latter point is concerned: the level of use of amalgam in Sweden has until recently been four times higher than in Germany (if ODeuses data relating to what was recently the Federal Republic). An unprejudiced discussion in the professional press has sometimes been arrested by the argument, that the less amalgam-friendly findings would disquiet the broad population who have "silver fillings" [10] - a view which haslittle to do with the evaluation of scientific facts or with the human right to health protection. Another factor obstructing the publication of case historie s is the difficulty in exact and documented diagnosis; complete proof, if that is to include determination of mercltry levels in the blood, urine or a body tissue, and the process of rechallenge, is not possible. Judgements will necessarily have to be based largely on symptoms described by the patient, comparison to known symptoms of mercurialism, the individual's dental status and a history of failure to respond to any form of medical treatment, obviously coupled to a well-documented examination of the responseto amalgam removal. However such judgements will commonly be considered unscientific - for example because of the absence of biochemical confirmation or the impossibility of rechallenge - and for that reason individual casesmay weIl fail to
4 meet the usual requirements applicable to the peer review of material for publication. The manner in which exposure occurs to mercury incorporated in amalgam is in the first instance a question of materials science. The metal is not primarily absorbed from the intact amalgam; it is released by corrosion, abrasion and by metallurgical processes which take place within the amalgam filling. That fact, which may easily go unrecognized by the practitioner of a discipline other than materials science, points to the obstacleswhich can arise from a lack of interdisciplinary co-operation in a field such as this; there is a clear lack of joint effort between dentists (with whom the problem is generated), physicians (to whom the patient with symptoms presents), toxicologists and materials scientists. Nor are the health authorities likely to engage in any such broad interdisciplinary consultation in forming their views; they are likely to be heavily dependent, in issues such as this, on information provided to them by the health professions, in casu the profession of dentistry. An official statement which may be quoted from Sweden that "... a sys~ematicdeterio~atio.n of silve.r a~algam fil~ings has ~ever been
reported" [11] IS for exampleIn dlrect confllct with the evldenceavallablefrom
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materials scientists. Exposure to mercury For the purpose of the present review only the most common form of dental amalgam - the so-called "silver amalgam" - will be considered. A great deal of research has been published on this material, though very little of it has seeped through into clinical practice. For making an initial assessmentof the level of risk, ODecan employ the same approach as that normally used when dealing with issuesof occupational exposure. In the latter situation, exposure is regarded as being proportional to the air content of mercury vapor. At a concentration of 25 JLgHg/m3 (WHO Threshold Limit Value, TLV), and allowing for an aspiration volume/rate of 0.75 1/15 per min during normal working hours, i.e., 8 hours a day, 40 hours a week, the daily exposure will be 135 JLgHg. For the general population, the U.S. EPA (Environmental Protection Agency) National Emission Standard, based on studies of the effects of mercury, is 1 JLg Hg/m3 air. Adopting the above assumptions, this concentration will give an exposure to about 16 JLg Hg a day. The provisional tolerable daily intake is 50 JLgof Hg metal a day (weekly intake 5 JLgHg/kg body weight) [12]. These exposure levels can thus be taken as a starting point for examining the
level of mercuryexposurefrom dental amalgam.The physico-chemical processes underlying total exposure and the fate of amalgam mercury are demonstrated in Fig. 1. Evaporation of mercury accounts, as will be seen, for only a part of the total quantity released. What is released in solid or dissolved form willlargely enter the gastrointestinai tract; animal experiments [13,14,15] have indeed clearly demonstrated that, besides the lungs, important routes of absorption are the teeth and
adjacenttissuesasweIlasthe gastrointestinai tractitself.
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5 Exposure Abrasion - Corrosion
- Phase transformatiOn
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Air
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Symptoms
disease
Sewage
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station, sludge """,
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Hg. vapor
-
Deposition
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-
./ Kidney
Brain
Fetus etc
Absorbed Lung Gut Tooth
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)
dro\ets Not absorbed
Feces
Excretion
feces,urine
;;wage
Fig. 1. Main factors in long-term mercury exposure and the fate of mercury released from dental amalgam(schematic illustration).
The best method to document the total exposure of a patient to dental mercury would clearly be a strictly controlled experiment; one would insert a filling of known weight and Hg-content, and remove it for chemical analysis after a predetermined period. For practical reasons, such a controlled experiment has never been carried out. There are however several other ways of arriving at fair estimates of the level of release of mercury from amalgam. They involve considering and using what is known about the three processes involved, i.e. transformation, corrosion and abrasion.
Transformation '"'\
,
Conventionai silver amalgam typically contains 50% of mercury (Hg), 35% of silver (Ag) and 10% of tin (Sn) by weight, as weIl as traces of copper and zinc. However there can be very considerable variations in composition, as weIl as in particle size and form and in mercury content. As the amalgam sets, three main
metallographicphasescan be recognizedalongsideone another, designatedas gamma-1(Hg + Ag), gamma-2(Hg + Sn) and gamma,which is the unreacted original alloy powderof Ag + SnoThe result of the settingreactionsis dependent on manyfactors,includingthe initial contentof mercury,the overall composition, the form and size of the alloy particles, the trituration time and the insertion techniqueof the dentist employingthe material. The reported formulas of the phasesand their Hg-content are shown in Table 1. From the literature it is obvious,that the setting reactionsare unpredictableand that the resultingstruc-
6 TABLE 1 Reported formulas of the mercury containing phasesand their Hg-content. Formation of beta-1 phase from gamma-1 has been observed in aged fillings Phase
Weight-% Hg
Reference
Gamma-l AgzzSnHgz7 Ag4Hgs Ag3Hg4 Ag\\Hg\S AgzHg3 AgsHgs
68.4 69.8 71.2 71.6 73.5 74.8
25 2 2 2 2 2
Beta-l AgHg
64.9
16,19
Gamma-2 Sn7Hg SnsHg
19.4 17.4
1,2 1,2
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tural phases, most importantly gamma-l, vary considerably as regards their Hgcontent. The impact of the structural instability on Hg-release is weIl illustrated by the presence of the beta-1 phase in fillings as they age. Beta-1 (AgHg) is formed by transformation from gamma-1 (Ag2Hg3), mercury being released in the process [2,16,17].The Hg-content in the original combination present in the phase is 64.9% by weight, but the dental literature gives several later figures which deviate from this: slightly over 50% [1], 60%, 50.9 and 52.9%, or 47.5% in an amalgam specimen which has aged for three years in vivo [16]. Transition of only 1.0 gram of gamma-1 (Ag2Hg3) to AgHg in 10 years will release 170,000 ,ug Hg (8% of the original content), giving an exposure of 46 ,ug Hg a day. This transformation can provide a partiai explanation for the apparent contradiction between cases of long service life of amalgams and the simultaneous high release of mercury, since amalgam in which the transformation has occurred with loss of mercury can continue to give service. One can also easily be misled by the formation of Hg-free corrosion products of unchanged volume and form [18, this paper Fig. 2). A reasonable conclusion is therefore that no dentist can, merely by showing that a filling
continues to give service and appearsunchanged,provide any evidenceas to
whetheror not it haslost mercury,its future performancein an oral environment, or what the individual'scurrent and future exposureto mercuryis likely to be.
.
Co"osion
Most of the known types of corrosion have been observed on amalgam fillings after clinical use: a distinction is drawn between the processesknown as general attack, selective corrosion, crevice attack, galvanic corrosinin contact with dissimilar metals and stress corrosion cracking. The main issue of concem in the dental literature has been the effect of corrosion on the mechanical performance
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Potential E (V SCE) Fig. 2. Anodic polarization curves of a conventionaI silver amalgam in synthetic saliv:. (af ter Marek [21]). Abrasion or contact to gold increase the corrosion rate (current density) up to 2 orders of magnitude. The SEM-micrographs of cross sections show the differente in appearance of corrosion without and with contact to gold. Mercury depleted regions appear dark. (Micrographs of fillings after service in vivo by J. Pleva).
of restorations. There have been observations of the release of free mercury droplets by corrosion [19] or by simple polishing [20], though it should be noted that not even these have triggered any serious appraisal of the resulting exposure level, and its possible health impact. The extent öf corrosion depends not only on the properties of the filling, but also on the aggressivityof the individual oral environment. In the general population, there are obviously considerable variations in the type of faDd consumed, its salt content, pH-valne and temperature, as weIl as in chewing habits (e.g. the pressure exerted on the teeth), the composition of the saliva and the constitution
8
of the bacterial flora. The extent of the influence exerted by these factors can be measured by various techniques. A considerable increase in electrochemical corrosion currents can for example be detected and measured during slight experimental abrasion, comparable in degree to that caused by chewing [21]. The process of
.
corrosionis accompaniedby a correspondingreleaseof metallic mercury,part of
which can be easily monitored as vapor in the expired air. Svare [22] measured on average a 15-fold increase and Patterson [23] a 40~fold increase after chewing and brushing, respectively. There are two possibilities for assessingthe resulting level of patient exposure. The first of these involves making measurements of corrosion depth on fillings which have had in vivo service; this will naturally provide only information on
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processesinvolving the exposedarea and not as to what happenson occlusive surfaces. The second method is based on measurements of corrosion currents in vitro. From the measured polarization curve and free corrosion potentials, Olle can estimate corrosion rates and the amount of metal dissolved [24,25]. Examples of both types of measurement are shown in Fig. 2. The dark layer of mercury-free corrosion products in the upper microphotograph of Fig. 2 shows how contact to gold renders the attack more general. From the mercury free volume and the known service time of the restoration, the daily Hg-exposure can be calculated [18]. General conversion of the filling "b" illustra ted in this figure resulted in the release of 29 J.LgHg/day, i.e. 68 mg Hg in 9 years. Selective corrosion, seen in filling "a", has resulted in release of about 30 J.LgHg/day. In Table 2 calculations of the amounts of mercury released from a surface area of 1 cm2 are shown, based on Marek's measurements[21] and using Faraday's Law [24]. The exposure levels estimated from corrosion measurements are in close agreement with the in vivo fin dings of Vimy et al. in sheep and monkeys [13,14]. In their work, the main part of the mercury released was found in the gastrointestinai tract and it could be monitored in the faeces. The sheep excreted about 9000 J.Lg Hg a day from 12 occlusal fillings, during the first month after insertion. The rate of faecal mercury excretion in monkeys, 4 weeks after amalgam placement, averaged 300 J.LgHg/day. Over the 4-week period, cumulative mercury loss amounted to 0.5% of the total Hg in their amalgams.Urinary excretion of Hg was negligible, attaining less than 1% of that excreted daily in the faeces.
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TABLE 2 Faraday s law. AbrasIon and galvamc corroslon ID contact to sold have been consIdered. Data from Calculat:ons
?f
relea~ed
mercury
fro.m
1
cm2.
fr?m
corrosion
currents
and
potenti~ls
in
Fig.
Corr. current,/LA/cm2 Released Hg, /Lg/day/cm2 Released Hg in 2 h chewing
using
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TerS.21 and 24 havebeenused Abrasion:
2,
No contactto sold no yes 2
87
135
5872
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490
Contactto sold no yes 100 6750
-
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- 700 47250 3937
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9
The above levels of Hg-release, noted with freshly placed amalgam, are much higher than the averagelong term release. Af ter several months in service, the rate of Hg release decreasesconsiderably [26], hut it can rise again after a prolonged period of time. Abrasion An exposure assessmentbased on corrosion data will not reflect the quantities of amalgam mercury released as a result of mechanical wear. Wear rates in a dry artificial mouth have been studied by deLong [27]. In correlation with clinical
observationshe found an amalgamwear rate of 65 JLmper year at points of contact with enamel. For a total contact surface of 1 cm2 the wear will result in the release of 37000 JLgHg per year, i.e. 101 JLgHg a day. Similarly, Angelini et al. [28] found on a conventionaI silver amalgam a loss of a layer 100 JLm thick after 300,000 brushing strokes. For dispersion-type dental amalgam the wear rate was 40 JLm and for a high copper amalgam 30 JLm. On a yearly basis, the corresponding total levels of exposure from 10 cm2 of amalgam surface (the Swedish average) will be 1560 JLg, 624 JLg and 468 JLg Hg a day respectively. The release figures obtained here are much higher than those recorded by deLong, reflecting the fact that these latter experiments were performed in artificial saliva and that corrosion was therefore also involved.
The dose absorbed Because of the dynamic character of the process involved, estimates of the amounts of mercury actually absorbed are difficult. As pointed out earlier in this review, a certain (unknown) doge is absorbed by the teeth [29] and oral mucosa [18]. Up to 80% of inspired Hg-vapor is absorbed in the lungs [30]; Vimy [31] estimated the daily doge absorbed through this latter route at 20-30 JLgHg a day for an average patient, and 8 JLg in subjects with no more than four occlusal amalgams.During the first week after exposure, about 10% of the mercury vapor absorbed in the lungs is re-excreted into the intestines [32]. In rats, the amount retained has been found to be distributed to the kidneys, brain, myocardium, intestine and liver, in decreasing order of magnitude [33]. The rate of absorption in the gastrointestinaI tract is dependent on the chemical form ffi which the metal is present, though as the history of acrodynia shows, even poorly soluble forms of mercury can be absorbed in toxic quantities in the intestinaI environment. The metallic and ionic mercury released from the fillings may be methylated, or organic Hg may be demethylated, by intestine bacteria [35,36]; some metallic mercury will however certainly be present. It is known that organic Hg is absorbed much more strongly than are inorganic salts or metallic Hg. A rough estimate is that in the gut some 2-15% of the latter may be absorbed [34], though following biliary excretion, re-absorption in the gut may occur. What is
10
more: since the Hg content of the faeces has been found to be high [13,14], even a low percentage rate of absorption can result in the absorption of a large amount of mercury. Absorption is also affected by the physical form in which mercury enters the gastrointestinaI tract. Dissolved Hg and amalgam microparticles have a higher availability than do large drops and particles. Chewing of fatty food will result in the production of a weak mercurial ointment, the presence of which is again known to increase substantially absorption through mucous membranes. All these factors need to be considered when discussingmercurial exposure. Knowledge of the different propensity for absorption of the various chemical and physical forms of mercury is as important in considering the amalgam problem
~
as it is in explainingthe largevariationsin sensitivityexhibitedby workersexposed
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to the metal in the course of their occupation. Studies of amalgam can also benefit from phenomena investigated as regards occupational exposure. In the chlor-alkali industry, presence of a small amount of chlorine in the air, for example, protects the workers from a part of the insidious effect of mercury vapor; Hg-vapor is oxidized by chlorine gas to calomel (mercurous chIoride) which is less toxic (being less weIl absorbed) and is also precipitated before it can be inspired [38].
~
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The toxic etTectsof mercury Symptomato!ogy The symptomatology of chronic Hg-poisoning is known mainly from the study of occupational exposure, but also from the history of medical treatment with mercurials (used at various times against syphilis, against intestinaI parasites, in ointments and until a generation ago even in diuretics), and from accounts of exposure resulting from accidents or ignorance. An extensive bibliography on mercury and its effects has been compiled by Hanson [99]. The list of symptoms attributed to the metal is long [40-46]; those most frequently cited and best documented on the basis of chronic mercury exposure are listed in Table 3. Chronic exposure to mercury vapor leads to an insidious, slowly developing
,~ '---
intoxication, which is very difficult to recognize until more marked and more objective signs and symptoms appear. Paradoxically, the drastic exaggeration of symptoms which may be observed after the installation of gold-amalgam restorations will sometimes help dental patients to discover the hitherto obscure etiology of their problems [48].
~ '-~
It is not surprising that in patients suffering from the early effects of mercurial exposure the diagnosis teDdstoare le an heavily on the psychical in the entire picture. The early symptoms largely subjective and, upelements to the present, have often been identified only in the course of a dialogue with the patient. Such symptoms will include abnormal fatigue, depression, shyness, irritability, loss of memory (especially short-term memory) and intellectual exhaustion [8]. With
o.
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11 TABLE 3 Documented, most frequent symptoms in chronic mercury exposure [40-46,831 Nervousness,irritability Shyness,timidity Lack of attention Loss of memory Lack of self controi Loss of self confidence Anxiety Depression General CNS dysfunction Irregular heartbeat Alterations in blood pressure Pain, pressure in chest area Headaches
Vertigo Tinnitus, noises in ears Fine tremors of hands, feet, lips, eyelids Persistent cough, asthma Endocrine disturbances Joint, back pain s Muscle pains and weakness Fatigue Drowsiness Insomnia Dim or double vision Impaired hearing
Dermatitis Gastrointestinai problems Diarrhea Speechdisorders Renal damage Menstruation disturbances Bleeding gums Loosening of teeth Excessivesalivation Metallic taste Stomatitis Sinusitis, chronic cold
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progressing chronic mercurialism, symptoms of a more somatic type appear, but there are large variations in sensitivity and in the pattem of response.It seemsvery probable that, because of a lack of recognition of the early toxicity pattem of mercury, many patients with early symptoms are readily dismissed as suffering from mental disorder. Experience in the field suggeststhat the largest numbers of symptomsand those which are most severe teDd to be observed in patients with gold-amalgam inte rfaces, which are in effect oral galvanic cells. Once they have been informed of the possibility that amalgam may have induced illness, many patients seem able retrospectively to relate the aggravation of their health problems to the installation of such a gold-amalgam "battery" at a slightly earlier date. Other forms of dental treatment too can have an aggravating effect, e.g. the replacement of old fillings by new or endodontics treatments. By far the most undesirable effects seem to result from constructions in which a brass element carries amalgam, covered in tum by a gold crown. Removing this type of dental prosthesis has been reported to result in alleviation of the severe symptoms [48]. There are many wamings in the literature against the lise of gold-amalgam batteries [19,49,50],but Olle cannot gay that the dental profession has taken due notice of these or considered the natural laws which underlie these problems. In the field of molecular biology, research is in progress to elucidate the fate of mercury and other trace elements, whether deleterious or essentiai, in the body.
Resultsof this work, includingsomewhich are disputed,point to possibleinterac-
tions between mercury and other metals in the biological system. Patients with symptoms similar to those of mercurialism ("metal syndrome") have been found to have increased plasma levels of mercury and decreased plasma levels of selenium (Se) and zinc [51]; the activity of the selenium-containing enzyme glutathione peroxidase (GSH-Px) is in such cagesusually decreased. In gingivai biopsies, high concentrations of both Hg, Ag, Sn and Se have been found in subjects with a normal selenium status; in biopsies from symptomatic patients, on the other hand,
12
I
selenium was absent, indicating its possible importance in protection against the
effectsof heavymetaIs.The formation of extremelyinsolubleselenidescan cause
"
depletion of Se,which would in tum result in reduced activity of GSH-Px and thus raise the risk of inadequate protection to lipid peroxidation. Studies of symptomatic individuals have also shown skewed distributions of mercury, zinc, magne-
.'
sium, calcium, iron, manganeseand strontium in the erythrocytes and neutrophil granulocytes [52], as measured by PIXE (Particle Induced X-ray Emission). At this point ODemust consider what consequencesmercury (or interactions in which it is involved) could have for various organ systems,and to what extent these consequenceshave actually been demonstrated. ~
Neurologyand immunology
",-'
It is weIl documented and generally accepted, that the nervous system is ODeof the primary targets for mercury. Many of the symptoms referred to above reflect an influence on the central nervous system (CNS), in combination with endocrine
~
disturbances[53]. In the past, attentionwas directedprimarily to the severeCNS
..-'
damage resulting from methylmercury (MeHg) poisoning, such as that due to consumption of contaminated fish in Minamata, Japan, or of mercury-treated grain in Iraq (Bull. WHO, 1976). Since then, primarily for environmental reasons, interest in the CNS effects of mercury as a metal and of inorganic mercury has become much greater. Depending on the target organs involved, inhaled Hg-vapor can exert effects similar to those of methylmercury; swallowed mercuric chioride, on the other hand, will be localized mainly in the kidneys [43,53]. Both Me Hg and Hg-vapor pass through cell membranes whereas ionic Hg binds to them and coagulates protein. Mercury can cross the blood-brain [54,55] and placental barriers [56,57]. In a fetal sheep, amalgam-Hg appeared in the pituitary glaDd and liver. In man, a correlation between the presence of dental amalgam and the occurrence of mercury in brain tissue has been reported [58]. The correlation found between the Hg content of the pituitary glaDd and individual status as an amalgam carrier [59] or a dentist [60] is of special interest. Nylander found a statistically significant regression between the number of amalgam surfaces and the concentration of Hg in the occipital lobe cortex [59] and in the pituitary [61]. In experiments with
guineapigs,the uptakeof Hg in brain wasfound to be severaltimeshigher after
exposure to Hg-vapor than to an injected inorganic salt, but the pattem of distribution in the brain was similar after both modes of administration [62]. Though seldom considered, there is some evidence that retrograde axonal transport of Hg to the brain may be ODeof the routes of uptake [66].
Mercury seemsto be metabolizedslowly in the brain; the slow alleviationof
psychic symptoms (such as erethism mercurialis) after amalgam removal, as contrasted to the rapid lessening of such somatic symptoms as joint pains is qualita-
tively in agreementwith this finding. In fact the elimination rate of Hg differs between the various regions of the brain, as demonstrated by findings in rats studied by Cassanoet al. [63]. In autopsy brain specimensfrom confirmed victims of
Alzheimer's
disease,
elevated
concentrations
of
Hg
and
Br
have
been
found
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---
13
parts of the brain showing consistent pathological alterations [64,65]. Information on possible links between multiple sclerosis, Hg and selenium can be found in various publications [47,75,83]. Endocrine effects According to Trachtenberg [67], low Hg concentrations markedly increase the functional activity of the hypophyseal-adrenalcortical system,which could explain some of the metal's endocrinological effects. As there is a close relationship between adrenal and thyroid function, thyroid dysfunction can indicate hypophyseal-adrenal disorder. Immune system The immunotoxicity of Hg is weIl known. Both inorganic and organic Hg initiate autoimmune reactions, characterized by the formation of antibodies to a variety of proteins. Trachtenberg [67] concluded that immunological changes occurred prior to the emergence of (latent) toxic effects. Mercury, whether from the working environment [68] or from dental amalgam [69,70] can adversely affect the immune response, e.g. the number of T -lymphocytes. In this context the high frequency of alleviation of various painful joint, back and muscle (fibromyalgia) problems clairned to have been observed following the removal of amalgam is of interest [83], particularly in view of the wide incidence of these conditions with their immunological facets. Renal effects Toxicity studies point to the kidneys as a primary target for the toxicity of inorganic mercury. High levels of mercury are found in sheep and monkey kidneys shortly after application of dental amalgam [13,14]. Impairment of glornerular filtration by mercury derived from dental amalgam has been reported by Vimy et al. [71]. In occupational exposure, Lamm and Pratt [72] found a negative correlation between exposure time and urinary excretion of mercury, which can reflect progressive impairment of the ability of the kidneys to excrete the metal. This could in tum point to progressive failure to excrete Hg as a factor in the development of poisoning. These findings however can also mean that urinary Hg levels 'are of limited value in the diagnosis of poisoning; high urinary levels of mercury can be found in symptom-free subjects, as opposed to low levels in those showing evidence of mercurialism [73]. Diseasesof unknown etiology Bearing in mind the evidence which nowexists for a much higher level of population exposure to this toxic mercury than was previously recognized, the
14
possibleinvolvementof mercury in a number of diseasesof unknown etiology shouldbe reconsidered.Amongthem are a seriesof syndromes, hearingthe names
~
of the workers who first described them. Recently, descriptions of over sixty such name d syndromes the men hind are them have published in the of Swedish Physiciansand [74]; most ofbe these listed inbeen Table 4, alongside theJournal year and
.
the country in which they were described. While the pace of discovery most certainly followed the increasing rate of medical innovation, it would be fair to note that a great many puzzling syndromes were first identified only after the introduction of dental amalgam into European medicine from 1819 onwards despite the fact that mercury exposure occurred (even in medicine) at a much earlier date. One might further add that at the time when many of these syndromes were brought to the fore, amalgams producing a particularly high level of mercurial exposure were in lise; typical amalgamsin lise around 1900, when their properties were first studied by G.V. Black, certainly showed a high propensity to corrosion.
.
~ 'o~'"
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It overall would picture be very rash to claim that every case of the disorders alluded to above
can be traced to amalgam, much rasher to suggest that every patient carrying amalgam will develop these disorders. What is evident, however, is that suspicion has fallen upon amalgam as inducing or triggering a wide range of disorders in sensitive individuals. Some advocatesof amalgam removal have compiled long lists of the conditions which in their view could benefit. Oaunderer [69] has postulated that dental amalgam fiIlings should be regarded as contraindicated in any disorder of the nervous system, multiple sclerosis, morbus Alzheimer, Parkinson's disease, Crohn's disease, amyotrophic lateral sclerosis, sudden blindness or deafness, colitis, anorexia, chronic diarrhea, repeated sinusitis, depressions,paraesthesiaand AIDS.
The case of acrodynia
~
Before dismissing lightly the multiple arguments for a broadly toxic role of the mercury in dental amalgam, one would do weIl to consider the lessons to be derived from the history of that extinct disease, acrodynia [39,77]. Known also as "pink disease", it was characterized by redness and sweIling of the fingers, feet, nose and'ears, loosening of the teeth, salivation, insomnia, sweating, diarrhoea, England, the British Commonwealth and the United States. There were many
weakness
and
apathy.
It
affected
children
up
to
about
9
years
of
age,
mainly
r"'""'I
in
etiological theories, ranging and fromviTal "primary emotionai disorder" to allergy, neurosis, endocrine disturbance infection. Impressive arguments were ad-
..
vanced in favor of one theory or the other, hut they did not bring one closer to
preventionor cure of the disease.Only in the 1950's,after a hundred years of acrodynia, was the etiological role of mercury in every case established. The
),
I
15 TABLE 4 Compilation of syndrome names from ref. 74, their character and origin
""
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~
Syndrome/Morbus
Character
Parkinson Bright Bell Hodgkin Basedow,Grave Addison Meniere von Graefe Down Henoch, Schönlein Horner Robertson Huntington Charcot, Marie, Tooth Morton Quincke Gaucher Hirschschprung Wernicke, Korsakov Menetrier Bechterew Wilms Meige Alzheimer Whipple Cushing Reiter Stevens,Johnson Felty Moschcowitz Hippel, Lindau Melkersson, Rosenthal Forestier
N E N 1 E E N E N, 1 I, N N N N N N I? N N N 1 1 1 N N 1 E,N 1 1 1 N N N 1 1 ? ? ? I? N 1 1 E
'Sjögren Crohn deLange Kartagener Kimmelstiel, Wilson Horton. Cogan Löfgren Luft
N = neurology; 1 = immunology; E = endocrinology.
Described Year
Country
1817 1830 1830 1832 1840 1849 1861 1864 1866 1868 1869 1869 1872 1874 1876 1882 1882 1886 1887 1888 1892 1899 1902. 1907 1907 1912 1916 1922 1924 1925 1926 1928 abt 1930 1930 1932 1933 1933 1936 1939 1945 1946 1958
GB GB GB GB D (G B) GB F D GB D CH GB USA F, GB, F USA D F DK D, Russ F Russ D F D USA USA D USA USA USA D, S S F F USA NL CH D, GB USA USA S S
'J}?
,
children concerned bad been exposed mainly to calomel (HgzClz) in the form of "teething powders" or as a component of sedatives, laxatives or anthelmintics. A smaller number bad been exposedto Hg-ointments or to mercuric chioride in rinse
16
solutions. An estimated Olle in every 500 children exposed developed acrodynia, and about 10% of the patients died. This was an instance in which, despite what the proponents of calomel treatment would no doubt have considered "well-tried and favorable experience" over a period of a hundred years, the harm far outweighed the good.'Calomel prepara-
:; ::
tions were withdrawn from the market, following which the disease disappeared. Unfortunately, there was never a proper analysis and elucidation of the mechanisms underlying mercurial acrodynia, such as could have proved useful in advancing knowledge of individual reactions and susceptibility to drugs in general and mercury in particular. ~ -'
Removal of amalgam and other protective measures As noted by Warkany [77] and confirmed by field experience, current knowledge among medical and dental professionals as to the wide spectrum of adverse reactions to mercury is far less extensive than it was in former generations. In the situation as it currently exists, it is likely to be the amalgam patient himself or herself who will have to assessthe situation and decide for or again st the removal of mercury-bearing fillings. The patient may only be confronted with the issue after having been examined by physicians for many years for signs and symptomswhich mayor may not have been accorded an eponym but which have remained unexplained. Having found a dentist who is open to consideration of the issue itself sometimes a considerable problem the decision to remove amalgam may be taken. If it is, a new conundrum may arise, for uni ess protective measures are taken the process of removal of the amalgam itself may temporarily increase mercury exposure. The patient, who by the very nature of things is likely to be particularly sensitive to the metal, will need to be protected from the increased exposure to Hg during drilling, e.g. by adequate water cooling and high volume evacuation (vacuum cleaning) [78,79], and the swallowing of pulverized fillings needs to be prevented. In Sweden a combination of research findings and field experience has further led to the belief that patients can be afforded additional protection at this time by the administration of selenium (200-400 JLg daily) as weIl as vitamins Bl, B6, C and E and supplements of zinc and magnesium. Aggravation of symptoms hours or days after drilling in an amalgam filling is common (and may be considered as a confirmation of the etiological role of mercury in the sensitized patient) and patients should be warned to anticipate it; patients are further advised to space the replacement sessionsat intervals of not less than a month. Although urinary excretion of mercury is for a time substantially increased during progressive amalgam removal (and mild but acute effects, such as skin reactions, may occur in about 1% of cases), once removal is complete the mercury level in the urine will decline. There are recent reports on a possibility of heavy metal detoxification using 2,3-dimercapto-l-propanesulfonate (DMPS, Dimaval, UnithioI). Daunderer [69] reported 10 years of good experience with over 850 cases, treated intravenously
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n
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;;
~
,
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~
,
17
with DMPS. 98% of patients showed a marked increase in the mercury content of the urine after such mobilization. It may be noted that Zalups et al. [80] reported on good results with this same agent in treating the acute nephrotoxic effects of mercuric chioride. An alternative drug against heavy metal poisoning, which has been very weIl tolerated by children, is 2,3-dimercaptosuccinic acid (DMSA) [81].
Results of amalgam removal The problems in providing incontrovertible evidence of a cause and effect relationship between amalgam mercury and any individual case of disease have been alluded to above. The history of acrodynia - which developed in only one case in 500 exposed to mercury - underlines the fact that the correlation between the causative (or triggering) agent and the diseasecan be far from absolute; it follows that amalgam removal can only be expected to produce results in those cases where mercury has indeed played a role, and that there will be disappointments. For such reasons,onlyasmall number of casesof amalgam poisoning and recovery have been documented in the scientific literature; it is arguable that the great majority have remained undiagnosed. Between those two extremes, however, one has a considerable body of case material, such as that accumulated by the ScandinavianOrganization of Dental Patients, relating to individuals whose history and dental status created a reasonable assumption of cause and effect, and in whom removal of amalgam was followed by recovery. Some of the caseswhich have been published have not surprisingly given lise to controversy. An impressively documented case of amyotrophic lateral sclerosis (ALS) recovering after amalgam removal was described by Redhe [82], but the entire history - including the original diagnosis - was subsequently challenged. Stock's description of his own poisoning [6] is a highly illuminating case. Further caseshave been described in the literature and justify study [8,18,24,48,69,84-93]. What above all calls for attention is the very large amount of anecdotal evidence demanding objective analysis, collected among organized Scandinavian patients. Cases in whom recovery has been recorded include patients with Parkinsonism, Crohn's disease,multiple sclerosis,epilepsy, asthma, scleroderma, paranoia, blindness, and disorders originally thought to be of viraiorigin. Over 500 cases have been briefly evaluated by Hanson [83]. Prospects for alternative materials There ar~ several groups of materials which can provide suitable alternatives to dental amalgam. In the most important group are the compositeresins,filled with hard particles. Initial evaluations in the early 1970's detected problems with leakage and excessivewear. The insertion was also more time-consurning and operator-sensitive than that of dental amalgam. Newly developed posterior composites have improved resistance to wear, fracture and discoloration, and possess
18
improved radiopacity, and when used in conjunction with etching and dentinai bonding they strengthen the restored tooth and resist leakage. The material's manipulation and placement properties have also improved, light-cured composites showing clear advantagesover those which have been chemically cured. Several investigations concluded that these improved posterior composites gave a better clinical performance than amalgams.Bayne [94] examined 17 posterior composite materials over 5-10 years; the failure level for 899 composite fillings at 5 years was 9.2%, which is less than half that for conventionai amalgam (failure rate 20% at 5 years and 50% at 10 years). In another study [95], the 5-year survival of amalgam restorations and composites was 84% and 89% respectively. In addition, study of the marginal breakdown of 432 posterior composites and 73 amalgam restorations showed a marginal crevice in 28% of composite restorations hut in 60% of amalgams;after two years, the marginal integrity of the studied posterior composites was superior to that of an amalgam alloy [96]. Up to now, no serious adverse effects of modem composites have been reported, or observed in the field experience, perhaps making an exception for the hypersensitive amalgam patient. What is essentiai is to avoid some known causesof premature failure with these materials, e.g. contact with phenol compounds even in minute amounts must be avoided, otherwise polymerization will be inhibited. Recent research also supports the view that all dentin should be covered with glassionomer to reduce microleakage [97]. When using light-curing units, care should be taken to ensure that the spectral peak corresponds to the maximum hardening wavelength and that the light intensity is correct; to ensure the best results, the operation of light-curing units should be regularly controlled. The ceramic material group is another very promising Olle in respect of biocompatibility and durability. Materials in this group are available as crowns, and computerized techniques for the preparation of inlays are under development. Titanium (Ti) is increasingly used for implants, in dental practice mainly for screw fasteners. All experience points to good biocompatibility of Ti [98], which is certainly to a large part due to the high corrosion resistance of the material. However, the general fUle that Olle should avoid galvanic contacts with other metals applies to titanium as weIl. Last hut not least, gold alloys have long been suitable materials for dental restorations. In sensitive patients, alloys with a high copper content and ceramic layers applied for better appearance have been observed to cause symptoms, the reason for the latter being unknown. Hypersensitivity problems may arise with any alternative material in severely mercury-influenced patients. Careful selection of a
compatiblematerialis a matter of cooperationbetweenthe dentistand the
~'", ~
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patient. All in all, field experience shows that in terms of life cycle cost {taking into account all the costs associated with the use of a given material}, there are acceptable alternatives to amalgam and that these continue to improve.
..
In this situation, there is today little reason to continue to use amalgam. It is a material with respect to which suspicions of serious health risk are founded upon field experience and evidence from toxicology and materials science and pure
)..
19
theory; those risks are likely to be reflected too in costs, and if that is so then even the economic argument for using amalgam evaporates. An amalgam filling has an unpredictable structure, the setting reactions, the resulting phase composition, performance and the Hg-exposure cannot be controlled. What is, however, more than evident is that the exposure of the average amalgam heaTeTto mercury is several times in excessof the acceptable exposure levels established for mercury from other sources; and there are various common situations in which the level of exposure is further increased. It is bard to see that, with the emergences of reasonable and affordable alternatives, continued exposure to even a theoretical hazard of this degree is defensible. "\
,
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Acknowledgement The author is indebted to Dr Mats Hanson, Veberöd, Sweden,for accessto his extensive mercury bibliography [99] and for valuable discussions. References 1 2 3 4 5
Jörgensen KD. Dentale Amalgamer (in Danish). 2nd ed., Odontologisk Boghandels Forlag 1976. Vrijhoef MMA, Vermeersch AG, Spanauf AJ. Dental Amalgam. Quintessence Publ. Co., Inc. 1980. Letter from prof. Slack, Am. J. Dent. Sci. Jan. 1848; 8:172-178. Barker GT. Meeting of PennsylvaniaAss. Dent. Surgeons.The Dental Cosmos 1861;548-558. Talbot ES. The chemistry and physiological action of mercury as osed in amalgam fillings. Ohio State J. 1882;2:1-12; 1885;5:123-129. 6 Stock A. Die Gefåhrlichkeit des Quecksilberdampfes. Z. angew. Chemie 1926;39:461-488. 7 Stock A. Uber Verdampfung, Löslichkeit und Oxydation des metall ischen Quecksilbers. Z. Anorg. Allgem. Chemie 1934;217:241-253. 8 Stock A. Die chronische Quecksilber- und Amalgamvergiftung. Arch. Gewerbepath. 1936;7:388-413. Zahnärztl. Rundschau 1939;10:403-407. 9 American Dental Association ADA Special Report: When your patients ask about mercury in amalgam. JADA 1990;120:395-398. 10 Pleva J. Corrosion of dental amalgam. Mat. Perl., Sept. 1990;29:60. Controversy exists over mercury release from dental amalgam. Letters to editor from Marek M and from Pleva J. Mat. Perl. Jan. 1991;30:6-7,82. 11 Glantz P-O, Bergman M. Report to The Swedish Social Welfare Board on mercury release from dental amalgams. Umeå University 11.11.1982(in Swedish). See also the critical appraisal of this report (rebuttai to the Attorney- General (in English», Bio-Probe Newsletter June 1986;3:2-7. Edit. office 4401 Real Ct. Orlando, FL 32808, U.S.A. 12 Provision al tolerable weekly intake of mercury for humans. WHO Tech. Rep. Ser. Nos.373,462,505,631and WHO Food Additives Series No.4. FAO Nutrition Meetings Rep. Ser. Nos. '43,48,51. 13 Hahn U, Kloiber R, Vimy MJ, Takahashi Y, Lorscheider FL. Dental "silver" tooth fillings: a source of mercury exposure revealed by whole-body image stan and tissue analysis.FASEB J. 1989;3:26412646. 14 Hahn U, Kloiber R, Leininger RW, Vimy MJ, Lorscheider FL. Whole body imaging of the distribution of mercury released from dental fillings into monkey tissues. FASEB J. 1990;4:32563260. 15 Danscher G, Horsted-Bindslev P, Rungby J. Traces of mercury in organs from prima tes with amalgam fillings. Exp. Mol. Pathol. 1990;52:291-299.
20 16 Mahler DB, Adey JD, van Eysden J. Transformation of gamma-l in clinical amalgam restorations. Ann. Meet. Int. Ass. Dent. Res., 1973;Abstr. No. 190,p.l06.
;.
17 OkabeT. Mercuryin the structureof dentalamalgam.Dent. Mater. 1987;3:1-8.
18 Hanson M, Pleva J. The dental amalgam issue-review.Experientia 1991;47:9-22. 19 Jörgensen KD. The mechanism of marginal fracture of amalgam fillings. Acta Odont. Scand. 1965;23:347-389. 20 Schneider PE, Sarkar NK. Mercury release from Dispersalloy amalgam. IADR 1982;Abstract No. 630. 21 Marek M. Acceleration of corrosion of dental amalgamby abrasion. J. Dent. Res.1984;63:1010-1013. 22 Svare CW, Peterson LC, Reinhardt JW, Boyer DB, Frank CW, Gay DD, Cox RD. The effect of dental amalgamson mercury levels in expired air. J. Dent. Res. 1981;60:1668-1671. 23 Patterson JE, Weissberg BG, Dennison PJ. Mercury in human breath from dental amalgams.Bull. Envir. Contam. Toxicol. 1985;34:459-468. 24 Pleva J. Corrosion and mercury release from dental amalgam. J. OrthomoI. Med. 1989;4:141-158. 25 Gross MJ, Harrison JA. Some electrochemical features of the in vivo corrosion of dental amalgams. J. Appl. Electrochem. 1989;19:301-310. 26 Borinski P. Die Herkunft des Quecksilbers in den menschlichen Ausscheidungen. Zahnärztl. Rundschau 1931;40:223-230. 27 DeLong R, Sakaguchi RL, Douglas WH, Pintado MR. The wear of dental amalgam in an artificial mouth: a clinical correlation. Dent. Mater. 1985;1:238-242.
28 Angelini E, Bianco P, Zucchi F. Influence of brushingand abrasionon the in vitro corrosion resistance of dental amalgams.Surf. Coat. Technol. 1988;34:523-535. 29 Till T, Schubert K. Bericht liber Spurenanalysen an menschlichen Zähnen. Zahnärztl. Welt/Reform 1976;86:66-68. 30 Hursh JB, Clarkson TW, Cherian MG, Vostal J, Mallie RV. Clearance of mercury (197Hg!O3Hg) vapor inhaled by human subjects. Arch. Envir. Hlth 1976;31:302-309. 31 Vimy MJ, Lorscheider FL. Serial measurementsof intra-oral air mercury: Estimation of daily dose from dental amalgam. J. Dent. Res. 1985;64:1072-1075. 32 Cherian MG, Hursh JB, Clarkson TW, Allen J. Radioactive mercury distribution in biological fluids and excretion in human subjects after inhalation of mercury vapor. Arch. Environ. Health 1978;33:109-114. 33 Placidi GF, Dell'Osso L, Viola PL, BerteIIi A. Distribution of inhaled mercury rO3Hg) in various organs. Int. J. Tissue Reac. 1983;V(2):193-200. 34 Chang WL. Mercury. In: Experimental and clinical neuropathology. Ed. Spencer P & Schaumburg HH, Williams and Wilkins, 1980;508. 35 Edwards T, McBride BC. Biosynthesis and degradation of methylmercury in human feces. Nature 1975;253:462-464. 36 Ludwicki JK. Studies on the role of gastrointestinaI tract contents in the methylation of inorganic mercury compounds. Bull. Env. Conto Toxicol. 1989;42:283-288. 37 Sarkar NK, Marshall GW, Moser JB, Greener EH. In vivo and in vitro corrosion products of dental amalgam. J. Dent. Res. 1975;54:1031-1038. 38 Viola FL, Cassano GB. The effect of chlorine on mercury vapour intoxication. Autoradiographic study. Med. Lavoro 1968;59:437-444. 39 Warkany J, Hubbard DM. Acrodynia and mercury. J. Pediatr. 1953;42:365-386. 40 Schulz H. Wirkung und Anwendung der inorganischen Arzneistoffe. G. Thieme, Leipzig 1907. 41 Burgener P, Burgener A. Erfahrungen liber chronische Quecksilbervergiftungen. Schw. Med. Wochenschr. 1952;8:204-210. 42 von Oettingen WF. (Ed.) Poisoning. A guide to clinical diagnosis and treatment. Saunder Co. 1958. 43 Poulsson E. (Ed.) Lehrbuch der Pharmakologie. 6th ed. 1922, 16th ed. 1949. 44 Baader EW. Quecksilbervergiftung. In: Handbuch der gesamtenArbeitsmedizin, 1961;vol.2:158-176. 45 Moeschlin S. Klinik und Therapie der Vergiftungen. 6th ed. G. Thieme, Stuttgart 1980. 46 Weger AM. Veränderungen des Nervensystems bei Arbeitern des Quecksilberbetriebes. Arch. Gewerbepath. Gewerbehyg. 1930;1:522-538.
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21 47 Ahlrot-Westerlund B. Multiple sclerosis and mercury in cerebrospinal fluid. 2nd Nordic Symposium on Trace Elements in Human Health and Disease, Odense, Denmark 17-21.aug.1987. 48 Pleva J. Mercury poisoning from dental amalgam.J. OrthomoI. Psych. 1983;12:184-193. 49 Holland RI. Galvanic currents between gold and amalgam. Scand. J. Dent. Res. 1980;88:269-272. 50 Schoonover IC, Souder W. Corrosion of dental alloys. J. Amer. Dent. Ass. 1941;28:1278-1291. 51 Ahlrot-Westerlund B, Carlmark B, Grönqvist S-O, Johansson E, Lindh U, Theorell H, DeVahl K. Altered distribution pattems of macro and trace elements in human tiggDeSof patients with decreased levels of blood selenium. Nutr. Res. 1985;Suppl.1:442-450. 52 Johansson E, Lindh U. Mercury in blood cells-altered elemental profiles. Toxic events in human exposure. Biol. Trace Elem. Res. 1987;12:309-321. 53 Hanson M. Effects of inorganic mercury on the nervous system. 1st Nordic Neurosci. Meet., 1988, HemsedaI, Norway. 54 Steinwall O. Transport inhibition phenomena in unilateral chemical injury of blood-brain barrier. Progr. Brain Res. 1968;29:357. 55 Chang LW. Neurotoxic effects of mercury - A review. Environ. Res. 1977;14:329-373. 56 Vimy MJ, Takahashi Y, Lorscheider FL. Matemal-fetal distribution of mercury (203Hg) released from dental amalgam fillings. Am. J. Physiol. 1990;258:R939-R945. 57 Clarkson TW, Magos L, Greenwood MR. The transport of elementaI mercury into fetal tiggDes. Biol. Neonate 1972;21:239-244. 58 Eggleston DW, Nylander M. Correlation of dental amalgam with mercury in brain tiggDe.J. Prosth. Dent. 1987;58:704-707. 59 Nylander M, Friberg L, Lind B. Mercury concentrations in the human brain and kidneys in relation to exposure from dental amalgam fillings. Swed. Dent. J. 1987;11:179-187. 60 Nylander M. Mercury in the pituitary glands of dentists. Lancet 1986;1:442. 61 Nylander M, Friberg L, Eggleston D, Björkman L. Mercury accumulation in tiggDeSfrom dental staff and controls in relation to exposure. Swed. Dent. J. 1989;13:235-243. 62 Nordberg GF, Serenius F. Distribution of inorganic mercury in the guinea pig brain. Acta Pharmacol. Toxicol. 1969;27:269-283. 63 CassanoGB, Viola PL, Ghetti B, Amaducci L. The distribution of inhaled mercury (203Hg)vapors in the brain of rats and mice. J. Neuropathol. Exp. Neurol. 1969;28:308-320. 64 Ehmann WD, Markesbery WR, Alauddin M, Hossain TIM, Brubaker EH. Brain trace elements in Alzheimer's disease.NeuroToxicol. 1986;7:197-206. 65 Thompson CM, Markesbery WR, Ehmann WD, Mao Y-X, Vance DE. Regional brain trace-element studies in Alzheimer's disease.NeuroToxicol. 1988;9:1-8. 66 Arvidson B, Arvidson J. Retrograde axonal transport of mercury in primary sensory neurons innervating the tooth pulp in the rat. Neurosci. Lett. 1990;115:29-32. 67 Trachtenberg IM (Ed.). Chronic effects of mercury in organisms. TransI. from Russian. U.S. Dept. of Health, Education and Welfare, DHEW Publ. 74-473, 1974. 68 Bencko V, Wagner V, Wagnerova M, Ondrejcak V. Immunological profiles in workers occupationally exposed to inorganic mercury. J. Hyg. Epidemiol. Microbiol. Immunol. 1990;34:9-15. 69 Daunderer M. Amalgam. Klinische Toxikologie, 46. Ergänzungslieferung 9/89, ISBN 3-60970016-5, 1989. Ecomed Verlagsges. mbH Landsberg, Miinchen, Ziirich. Authors address: Weinstr. 11, D-8000 Miinchen 2. 70 Eggleston DW. Effect of dental amalgam and nickel alloys on T -Iyrnphocytes:Preliminary report. J. P~os!h.Dent. 1984;51:617-622.. . . . . 71 Vlmy MJ, Boyd ND, Hooper DE, Lorschelder FL. Glornerular fIltratlon lmpalrment by mercury released from dental "silver" fillings in sheep. Physiologist 1990;33:A-94,abstract. 72 Lamm O, Pratt H. Subclinical effects of exposure to inorganic mercury revealed by somatosensoryevoked potentials. Eur. Neurol. 1985;24:237-243. 73 Goldwater U. The toxicology of inorganic mercury. Annals NY Acad. Sci. 1957;65:498-503. 74 Mannen bakom syndromet. (The man behind the syndrome.) Läkartidningen (J. of Swedish Physicians),compiled by Kristina Räf, 2nd ed. 1990. In Swedish. ISBN 91-7970-860-9. 75 Baasch E. Theoretische Uberlegungen zur Ätiologie der Sclerosis Multiplex. Die Multiple Sclerose eine Quecksilberallergie? Schw. Arch. Neurol. Neurochir. Psychiat. 1966;98:1-18.
22 76 Schalin G. Multiple sklerosis and selenium. In: Geomedical Aspects in Present and Future Research.J.J.Acrodynia-Postmortem L~g (Ed.), Univ. forl. Oslo, 1980;81-102. 77 Warkany of a disease. Amer. J. Dis. ChiId. 1966;112:147-156.
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1
78 Reinhardt ~W.' Chan KC, Schulein TM. Mercury vaporization during amalgam removal. J. Prosth. Dent. 1983,50.62-64. 79 Richards JM, Warren PI. Mercury vapor released during the removal of old amalgam restorations. Br. Dent. J. 1985;159:231-232. 80 Zalups RK, Delein RM, Cernichiari E. 2,3-dimercapto-1-propanesulphonicacid (DMPS) as a rescue agent for the nephropathy induced by mercuric chioride. The Toxicologist, Feb.1990;10:271,Abstract 1083. 81 Graziano J et al. Oral 2,3-dimercaptosuccinic acid (DMSA) for the management of moderately severe childhood lead poisoning. The Toxicologist, Feb. 1990;10:271,Abstract 1081. 82 Redhe O. Invalidiserande huvudvärk. In Swedish. ISBN91-7810-137-9, p.117. Ed. R-Dental AB, Falugatan 1, S-79171Falun. 83 Hanson M. Changesin health status after removal of poisonous dental filling materials. In Swedish. TF-Bladet (J. of Scand. Dental Patients) 1986;No 1,ISSN 0349-263X. 84 Harndt E. Ergebnisse klinischer Untersuchungen zur Lösung der Amalgam-Quecksilberfrage. Dtsch. Zahnärztl. Wochenschr. 1930;33:564-575. 85 Wesselhaeft WE. A few suggestions about mercurial fillings for teeth. Int. Hahnemann Ass. 86 1896;16:200-209. HyamsBL, Ballon HC. Dissimilarmetalsin the mouth as a possiblecauseof otherwiseunexplain-
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