Reviews Experientia 47 (1991), Birkhfiuser Verlag, CH-4010 Basel/Switzerland 9

The dental amalgam issue. A review

M. Hanson" and J. Plevab

aNils Pgtls viig 28, S-24014 Vebergd (Sweden), and bPL 3079, S-68300 Hagfors (Sweden)

Summary. Using an interdisciplinary approach, the current position in the dental amalgam controversy and the
potential impact of amalgam mercury on human health are reviewed. Aspects of materials science, corrosion, mercury
exposure, toxicology, neurology and immunology are included.
New data on mercury exposure from corroded amalgam fillings in vivo are presented. The exposure can reach levels
considerably over known threshold limit values. Also, measurements of mercury absorption from intraoral air are
presented. The vital importance of avoiding a galvanic amalgam-gold coupling is emphasized. The symptomatology
of a disabled patient, who recovered after amalgam removal, has been included.
It is concluded that discussion of the dental amalgam issue has suffered from the lack of an interdisciplinary
approach. It would be wise to learn from the lesson of acrodynia, and consider amalgam mercury among other
possible factors in neurological and immunological diseases of unclear etiology.
Key words. Dental amalgam; corrosion; mercury release; threshold values; toxicity; neurology; immunology.

1 Introduction enced the dental profession. Surprisingly, no epidemio-

logical evaluation of health status, for example of dis-
Amalgams are, in general, alloys of mercury with other eases such as neurasthenia, has been made in relation to
metals. At the beginning of the 19th century, the idea of the introduction of amalgam 150 years ago.
filling carious teeth cheaply and simply with mercury The medical use of mercury also initiated frequent de-
alloys spread from France and England to the USA and bates. The insidious toxic effects were often very difficult
other countries. The first dental amalgams (ca 1818) were to differentiate from the symptoms of the disease for
based on an alloy of bismuth, lead and tin, which had a which the metal was administered. One of the first careful
melting point around 100 ~ Addition of a small amount descriptions of the symptoms of mercury poisoning was
of mercury decreased the melting temperature to 68 ~ an attempt by Kussmau164. The question was whether
and thus also the suffering of the patient during the filling mercury poisoning produced symptoms distinctly differ-
of the cavity. ent from those of syphilis, for which mercury was the
In 1819, the chemist Bell started production of a silver- preferred treatment. The study was carried out in mirror
based amalgam. Around 1900, Black recommended an factories, where exposures were generally high, but al-
'improved' high-silver alloy, which continued to be used ready Kussmaul noted that sensitivity towards the metal
as a basis for the most extensively used conventional was highly individual and unpredictable.
filling material 130. A pure copper amalgam was also in Today, extreme exposures as in the mirror factories are
use until recently, often to fill children's teeth, in spite of rare, but they do sometimes occur because of ignorance
its strong propensity to corrosion and related unfa- or accidents. Instead, most persons in the western world
vourable performance and toxicity. In the 1970s, new are chronically exposed to lower levels from dental amal-
copper-rich amalgams, called the non-gamma-2 type, gam fillings, often from childhood. In addition, anyone
have been introduced with the purpose of increasing the may be exposed to mercury in vaccines, drugs, contact
corrosion resistance of silver amalgam. lens solutions, cosmetics and, of course, food. Thus no
The use of amalgam for dental implants has been a sub- single source can simply be dismissed as 'not more than
ject of controversy throughout the 150 years of its exten- a given level', but the sum of all sources has to be consid-
sive use. During the 'Amalgam War I' (ca 1830 1856) no ered as a total load.
dentist using amalgam was accepted as a member of the The degree of mercury exposure from amalgam has ap-
Society of Dental Surgeons in the USA. Due to the lack parently been underestimated. A simple consideration of
of alternative cheap filling materials the use of amalgam the amount of mercury in the teeth, compared to the
nevertheless continued, and the 'Amalgam War II' of the daily intake from food, makes it apparent that amalgam
1920s and 1930s revived the debate. would have to be an exceedingly stable alloy in order to
In Germany the distinguished chemist Alfred Stock con- contribute less mercury than the daily amount ingested
tributed to the debate with many publications on amal- with food. With 5 g mercury in the teeth (10 g amalgam),
gam and mercury toxicology and analytical determina- the fillings would last 1370 years if the release is a maxi-
tion, and also with a very informative description of his mum of 10 lag Hg per day. 10 lag Hg is about what most
own chronic mercury poisoning 1~ 111. In spite of its people take in with food, if they do not eat too much fish.
scientific background, Stock's warning that 'the thought- In southern Sweden the average daily intake was found
less introduction of amalgam as a substance for filling to be 5.5 lag, but it was 12.4 lag with diets containing more
teeth was a grave sin against humanity' has not influ- than 75 g fish per day 27. Amalgam fillings will some-
10 Experientia 47 (1991), Birkhfiuser Verlag, CH-4010 Basel/Switzerland R e v i e w s

times:remain in the teeth for 2 - 3 decades, but the aver- comprehensive bibliography is available from the au-
age lifetime is considerably shorter. The 10-year survival thors. As well as reviewing the literature, we include new
rate for fillings in adults ranged from 13 to 74% in one data of our own on mercury exposure, related to symp-
study 78, others reported 50 % replacement within 5 years tomatology, similar to that of chronic mercury poison-
and an average life span of 4 - 8 years 13. In 6-year-old ing, as known from occupational and accidental ex-
children the average survival time for occlusal amalgam posure. Further, measurements of mercury vapor ab-
fillings was2 years and 2 months 132 sorption in the oral cavity are presented.
The terms 'silver filling' or 'amalgam' do not give a lay-
man or non-chemist the important information about the
2 Structure and deterioration of dental amalgams
50 % mercury content. Inorganic mercury has insidious
effects, not readily recognized unless one is aware of the 2.1 Structure
symptoms of chronic mercury exposure. Proper diagno- The conventional silver amalgam contains typically, in
sis will be even more difficult if the exposure is from percentages by weight, 50 parts of Hg, 35 Ag, 10 Sn, Cu,
amalgam fillings. To quote again from Stock 108, 'The Zn. The amalgamation reactions have been studied by
dentists are seldom in a position to recognize the general Espevik 35 and can be described by the equation
effects of amalgam fillings or even learn about them.
Ag3Sn + Hg ~ Ag2Hg 3 + Sn6_sHg
Patients suffering from nervousnessl intellectual exhaus-
tion, catarrh etc. usually do not complain to the dentist; or"
in addition, they are prevented from talking during the
gamma-phase + Hg ~ gamma-I + gamma-2-phase
treatment. They will rather discuss their problems with
the family physician, neurologists, laryngologists and in- The reaction between the alloy powder (gamma) and
ternists'. The physician in turn is completely unaware of mercury does not proceed stoichiometrically. Hence,
dental treatments, and does not suspect mercury from both the composition and the amount of the structural
amalgam. Thus it is not surprising that reports on mer- phases in fillings vary depending o n the overall composi-
cury poisoning from amalgam are relatively rare in the tion, trituration time and insertion technique of the par-
medical literature. However, in the daily press and in ticular dentist. This is illustrated by the varying formulas
magazines there have been numerous descriptions of reported for the gamma-l-phase:
health changes following amalgam removal.
Ag3Hg4, Ag4Hgs, AgzHg3, AgalHg15 and AgsHg813o
There are many descriptions of the symptomatology of
inorganic mercury intoxication, most of them written The Corrosion sensitive phase gamma-2 has been de-
before interest was focused on methyl-mercury. Bio- scribed as SnvHg, SnsHg, Sn7_8 35 and Sn6Hg 74. The
chemists have also provided many studies on the cellular content of the gamma-2 may vary between zero and
and molecular effects of mercury, providing explanations 59% 14, but 15-20% seems to be frequent 89. Normally,
for many symptoms observed in clinical practice. Recent- unreacted particles of the Ag3Sn alloy are found after
ly, the immunotoxic effects of mercury have attracted setting reactions. However, due to complicated and un-
considerable attention. Nowadays, mercury is the best predictable setting reactions, free liquid mercury can also
studied of the substances able to cause autoimmune dis- appear on polished surfaces of silver amalgam 99.
ease. Immune reactions were also considered to be a The preferential corrosion of the gamma-2 phase is part-
factor in acrodynia of children observed after calomel ly responsible for the deterioration of conventional amal-
(mercurous chloride) exposure. The acrodynia epidemic gam restorations. Therefore, attempts have been made to
illustrates the puzzling nature of mercury intoxications. eliminate this phase by adding copper at concentrations
Even more puzzling is mankind's short memory after the of 6 - 1 5 % 36. These high-copper amalgam are called
discovery of the Hg-etiology of acrodynia. 'Man is ap- 'non-gamma-2'. The corrosion-prone phases in this sys-
parently a poor student of history' as Casarett & Doull's tem are CuSn 36 and the Ag-Hg-Sn phase 73.
'Toxicology' says, referring to the use of mercury as a
2.2 Corrosion
medicine.
Deterioration of various types of amalgam by electro-
In this review we will try to give an overall picture of the
chemical corrosion has been described in a large number
documented connections between mercury, especially in
of publications.
dental amalgams, and various possible neurological, im-
munological and orthomolecular effects. The fate of The documented types of deterioration are:
amalgam components other than mercury is not within - crevice corrosion 35
the scope of this review. It is not possible to discuss every - selective corrosion 56, 57,
detail of this cross-scientific issue which touches not only - galvanic corrosion in contact with dissimilar
odontology, but also materials science, toxicology, neu- metals 40, 65, 66,
rology, immunology, physical biology, analytical chemis- - stress corrosion cracking 37, 75,
try and diagnostics. The pertinent literature which we --general corrosion 75,
found to be available includes more than 8000 titleS. This - mechanical wear 26.
Reviews Experientia 47 (1991), Birkh/iuser Verlag, CH-4010 Basel/Switzerland 11

Mateer v5 investigated fifty extracted teeth containing of amalgam to the body burden of mercury. Frykholm
amalgam restorations. Every restoration was attacked by did find increased urine mercury, and migration into
corrosion, resulting in a surface layer of corrosion prod- dental pulp, days and weeks after insertion of amalgam,
ucts. These observations have been consistently con- but he classified the amounts as insignificant.
firmed in the published literature and in clinical prac- Frykholm's anticipation that the exposure to mercury
tice 36, 47, 62, 89, 97,100, 120. Corrosion may have advanced released in mouth can be related to mercury found in the
so that the amalgam has lost most of its strength 56. For excreted urine does not find sufficient support in the
both mechanical and biological performance, avoidance literature. Until now, no defined partition of mercury
of galvanic coupling to gold and other noble metals is of between that excreted and that deposited in various or-
the utmost importance. Galvanic corrosion is also the gans has been measured, so it is not possible to judge the
only corrosion type which it is possible to avoid. The amount of dental mercury released from measuring the
other types of attack, listed above, seem always to be urine concentrations (see section on mercury in blood
present to some extent. The corrosion mechanisms of the and urine). Therefore diagnosis cannot be based on uri-
non-gamma-2 amalgams differ from those of silver amal- nary mercury determination. Frykholm's investigation
gam, but no clear model of their corrosion behavior has of exposure during insertion and for a short time after-
been presented. wards may not be relevant to long-term mercury release
The corrosion products of silver amalgam consist mainly after the onset of corrosion in vivo.
of insoluble hydroxy-chlorides and oxides of tin 97. As Marek 72 observed an up to 56-fold (average 23-fold)
the products have a larger specific volume than the orig- increase of electrical corrosion currents during abrasion
inal alloy, they partly substitute for the released mercury of five brands of fresh amalgams. According to Fara-
and help to maintain the mechanical function of the day's law, the measured corrosion currents corresponded
filling. The crevice between tissue and filling may occa- to a daily release of 60-735 gg of mercury from 1 cm 2 of
sionally become sealed 7s, 131, but the voluminous corro- surface, assuming a total daily chewing time of 2 h 89.
sion products may also cause tooth cracking due to the In vivo, the two processes of corrosion and wear are
high internal pressure 71 interdependent 15, corrosion being strongly promoted by
mechanical wear. To illustrate the possible toxicological
impact of the volume of worn amalgam, it is of interest
3 Mercury exposure
to consider the role of the wear process alone. DeLong 26
A reliable knowledge of the exposure level is a prerequi- studied the wear rates in an artificial mouth, and found
site for any meaningful conclusion about the health haz- a correlation with clinical observations. At points of con-
ard of amalgam in vivo. The traditional opinion of the tact with enamel, a layer about 65 gm thick was worn
dental profession during 150 years has been that amal- away after 250,000 masticatory cycles per year. An as-
gam becomes biologically inert as soon as it is set, i.e. in sumption of a total contact surface in the mouth of I cm 2
a few days 95. A survey of the available data on metal then gives 6.5mm 3 of worn amalgam, containing
release from dental restorations was published in 1986 by 37,000 lag mercury. As the tiny particles will be exposed
Brune 16. The information available is rather sparse, and to dissolution in the acidic stomach environment, the
no investigation has taken into consideration all types of individual might be exposed to 101 lag Hg a day.
deterioration and routes of uptake in order to get the The most complete documentation of total mercury ex-
whole picture of the toxicological impact. Corrosion has posure and uptake up to now is that recently published
been primarily considered with respect to the mechanical by Hahn 48 and Vimy 127. The radioactive labeled mer-
performance of the fillings. Despite the amount of pub- cury from 12 fillings in sheep was determined by whole-
lished information about corrosion of amalgam, the tox- body scanning and measurement in specific tissues. Mer-
icological impact of the released mercury has been dis- cury appeared within 29 days in various organs and
cussed very little. Therefore, the question of mercury tissues and in fetuses. The investigation confirms the
exposure will be treated in greater detail. three main ways of Hg-uptake; in the lung, the gas-
The lack of an interdisciplinary approach has tended to trointestinal tract and through jaw tissue absorption.
lead to underestimates of the mercury released from After one month, the total Hg content of the kidney was
amalgam fillings in vivo. The work by Mayer and 1.86 mg and that of the liver 0.77 mg. Also the brain,
Dieh176 provides an example. The investigators used pituitary, thyroid, pancreas and ovary glands showed
oxygen-free distilled water for measurements of mercury evidence of Hg accumulation from dental amalgam. In
released from amalgam. The elimination of any cathodic addition to the deposited mercury, the sheep eliminated
depolarizer, such as oxygen from the air, effectively re- daily over 9 mg of Hg in 2000 g of feces. The order of
moved the possibility of any corrosion process and led to magnitude is in reasonable agreement with the released
a wrong conclusion about the high corrosion resistance amounts of mercury computed from Faraday's law and
of amalgam under conditions where oxygen is present. in vitro current measurements 89.72. With 2 hour's chew-
The dissertation by Frykholm 43 has been used by dental ing a day, 500-700 lag/cm 2 will be released from fresh
professionals as a proof of the insignificant contribution conventional amalgam, i.e. 5 7 mg from 10 cm 2 surface.
12 Experientia 47 (1991), BirkhS.userYerlag, CH-4010Basel/Switzerland R e n e w s

H a h n ' s findings o f dental mercury in tissues are consis- mercury. Pure Hg emits vapor at the rate o f 2.5 ng/s cm 2
tent with analyses of mercury in autopsied hunaan brains at r o o m temperature and maximum air flow 113. This will
and kidneys by Nylander 82, 83. Subjects with amalgam correspond to about 6 ng/s cm 2 at the oral temperature.
fillings showed significantly increased Hg-contents in the Assuming an amalgam surface of 10 cm z, the highest
pituitary gland, and the concentrations were related to values recorded by A b r a h a m will correspond to the va-
the number of amalgam surfaces. por pressures measured by Brecht-Bergen 14.
Knappwost 60 measured the evaporation rate of mercury
3.1 Mercury vapor
from 0.5 cm 2 amalgam in artificial saliva under static
An amalgam bearer is exposed t o a daily amount of
conditions. The evaporation levels were 0.66 9 10-3 lag/s
mercury released from the fillings in the form of vapor,
without, and ten times as much with contact with gold.
liquid metal and ions. A part o f the released amount will
F r o m amalgam alone, the evaporation rate corresponds
be taken up by the body.
to an average exposure of 57 lag Hg a day. F r o m 10
The main routes of uptake are: fillings of 0.5 cm 2 surface the exposure will be several
- as metal and ions from the bottoms of fillings 120 and hundreds lag a day. This is in good agreement with our
through the mucous membranes, own evaluation based on depth of corrosion 89 (this pa-
- as vapor in the lungs 86' 51, per).
- in all forms in the gastrointestinal tract, The evaporation depends on the vapor pressure, the flow
- by direct transport from the oro-nasal cavity to the of air over the surfaces, abrasion etc. The actual inhaled
brain 110,117 and absorbed amount of Hg is difficult to determine.
However, nose versus mouth breathing does not seem to
The assay of mercury vapor Hg ~ in the expired air of have a central role. To test for a possible direct oral
amalgam bearers is experimentally feasible, and it has absorption, we injected known amounts of mercury va-
been measured in a number of investigations. Stock por into the closed oral cavity of an amalgam- and gold-
demonstrated in 1926 that dental amalgam fillings gener-
free subject with no detectable mercury emission from
ated mercury vapour in the mouth 1~ Chewing and
lungs or oral cavity. After 0 - 3 min, air with the remain-
abrasion 41, 44,118,125, brushing 86 and increased temper-
ing mercury was sucked out and the m o u t h flushed with
ature 121 strongly stimulated corrosion of amalgam and 30 ml of Hg-free air. An immediate extraction - within
evaporation of mercury. Svare lt8 measured on aver-
the first 3 - 5 s - showed an absorption of 5.5 + 4.5 ng Hg
age a 15.6-fold increase o f mercury in the expired air (n = 6). Delayed extraction (1 - 3 min) resulted in steadi-
after chewing, compared to amalgam-free controls. The ly less Hg being recovered. In one series of experiments,
mercury content in exhaled air or in the oral cavity 2.4-ml samples of Hg vapor from the mercury-saturated
after chewing can exceed permissible industrial lev- air over metallic Hg were injected. Mean absorption was
els 86,1 ts, 125. Stock's results inspired Brecht-Bergen 14 to
10.2 -+- 2.1 ng/min (n = 12).
measure the Hg-vapor pressure over amalgam: To obtain information on absorption kinetics, increasing
Ag/Sn/Hg-alloy with 45% Hg: 10.7% compared amounts of H g from 32 to 120 ng were injected and
to pure Hg extracted after 1, 2 and 3 min (a total of 10 injections).
Ag/Sn/Hg-alloy with 54% Hg 25.7% compared The results indicate exponential absorption kinetics
to pure Hg (table 1) and that most of the mercury vapor, generated
Sn/Hg-alloy with 30 % Hg 54.7 % compared from fillings in the mouth, might be absorbed even when
to pure Hg chewing is done with closed mouth and nose breathing.
The further fate of the absorbed mercury is unknown.
Measuring the concentration of Hg in expired air or in Fredin41, using a somewhat different approach, placed
the oral cavity leads to difficulties in calculating how an inverted cup on the buccal oral mucosa and intro-
much Hg is actually inhaled. A b r a h a m 1 introduced
flushing of the mouth for 15 s and measuring the evapo-
Table 1. a) Absorption of mercury vapor in the oral cavity.
ration rate from the fillings. A pre-chewing evaporation b) Absorption kinetics with increasing doses of mercury vapor. (Mea-
during 15 s was found to be 1.0-11.8 ng, i.e. 0.07- surements by M.H.). Mercury determined with a Jerome Gold Film
0.8 ng/s with a mean of 2.24 ng (0.15 ng/s). After 3-min Mercury Analyzer, Modell 51I. For experimental details, see 3.1.
chewing, the emission was 1.2-162.7 ng (0.08-10.8 ng/s) Injected amount Hg Mean absorption/min
with a mean of 18.97 ng (1.27 ng/s). Berglund 9 found ng + SD ng + SD
0.16 ng/s (range 0.04-0.34) for unstimulated Hg-evapo- a) 32.9___1.5 10.2+2.1 n=12
ration. The actual values after chewing might be even b) Non-absorbed Hg, extracted
after 1- 3 min ng Hg
higher than those found by Abraham since the vapor 1 2 3 min
levels continue to increase during 30 min of chewing lz6.
32 14 8 5
Thus the evaporation rates from amalgam fillings in the 42 21 13 10
oral cavity can reach 11 ng/s after chewing 1. A compar- 79 34 31 22
ison can be made with known evaporation rates from 120 . . . . 39
Reviews Experientia47 (1991), Birkh~iuserVerlag, CH-4010 Basel/Switzerland 13

duced k n o w n amounts o f mercury vapor. The results

were similar to those described above. H a h n 48 also re-
ported a high mercury content in the gum mucosa
(323 ng Hg/g) of sheep with a m a l g a m fillings.
3.2 The present authors' data on exposure
Twenty used restorations were investigated using a Scan-
ning Electron Microscope (SEM, J E O L 940), equipped
with an Energy Dispersive X-ray analytical device
(EDX). The donors of the restorations belonged to a
group o f 250 patients with chronic health problems o f
u n k n o w n etiology. I n f o r m a t i o n on age, sex, profession,
medical history and dental treatment was obtained by a
questionnaire. A b o u t 50 of these patients, who had had
all their a m a l g a m fillings removed (with initial aggrava-
tion of symptoms and, after a period ranging from sever-
8
al months up to a year, their alleviation) constituted a
test group for possible mercury etiology. Patients who
did not have their a m a l g a m fillings removed served as
one control group and 10 persons who had never had any
such fillings as a second one. Persons with possible occu-
pational exposure to mercury and those consuming fish
from inland lakes more than twice a week were excluded
from the investigation. A detailed evaluation o f the pa-
tients will be published elsewhere.
F r o m eighteen patients it was possible to recover pieces
o f large a m a l g a m fillings, whole teeth with amalgam, or
gold restorations in direct contact with amalgam. All
were microscopically examined and figures 1 - 3 show
typical examples. The type of corrosion attack was simi-
lar in all investigated a m a l g a m fillings, though the sever-
ity of corrosion varied between specimens, p r o b a b l y
depending on filling quality, age of filling, saliva compo- b
sition and eating and chewing habits. Figure 2. a Cross-sectionthrough a silver amalgam filling after 8 years
Figure 1 shows general corrosion of an a m a l g a m surface in vivo. The dark areas consist of converted amalgam products, free of
mercury. This filling has been giving off 70 gg Hg a day.
1.4 cm 2 in area, under a gold crown. This caused total b Photo 2894: Detail of the micrograph 2892 at a depth of 200 ~tm.The
release of mercury from a layer 100 gm thick, that is white area on the left is a cavity filled with corrosion products.

68 mg in 9 years, i.e. 29 gg Hg a day. In addition, selec-

tive corrosion t h r o u g h o u t the a m a l g a m is estimated to
have released at least another 30 gg H g a day. The total
average exposure from this restoration was a b o u t 60 gg,
and from all the fillings of this patient at least 150 gg per
day.
A n o t h e r example of a strongly corroded filling shown in
figure 2 had released 102 mg of H g in 8 years, i.e. 70 ~tg
a day. Corrosion has penetrated the filling, creating nar-
row channels. The d a r k products in the channels are free
o f mercury, as confirmed by the EDX-analysis. The com-
parison of the spectra o f the bright and d a r k phases is
shown in figure 4. The corrosion products consist mainly
o f tin oxides and hydroxides, but silver, sulphur and
chloride were also found, indicating silver sulphide a n d /
Figure 1. Cross-section through a silver amalgam filling under a gold or chloride.
crown after 9 years in vivo. The dark layer has been converted to corro-
sion products free of mercury. This filling has been giving off around Figure 3 shows the buccal surface o f an a m a l g a m filling
60 gg Hg per day. without contact with gold after 5 years in vivo. The sur-
14 Experientia 47 (1991), Birkh/iuser Verlag, CH-4010Basel/Switzerland Reviews

rather than dissolution. The filling is slowly converted to

products of constantly decreasing mercury content, while
the volume remains substantially constant. The convert-
ed products still fill up the space even when mercury is no
longer present, and no obvious change is apparent to the
eye or on routine examination by light microscopy. The
replacement of amalgam by more voluminous corrosion
products explains the apparent contradiction between
the constant volume of old fillings and the simultaneous-
ly-reported high release of mercury and its health effects.
3.3 Case history
The person from w h o m the fillings illustrated in figures 1
and 2 were removed was a Swedish woman, 58 years old,
a telephone operator, retired at age 40 because of dis-
abling chronic health problems. The syndrome included
Figure 3. Appearance of the buecal surface of a filling after 5 years in
vivo. The mercury-depletedsurfacelayer is 14 ~tmthick, and the selective 24 symptoms of mainly somatic character: diarrhea with
attack has released over 8 ~g Hg a day. strong bleeding, joint-, muscle- and back pains, frequent
inflammations in eyes and upper respiratory passages,
sinusitis, severe fatigue, stress, loss of memory, vertigo,
Sn 5n impaired hearing, increased salivation, bleeding gums,
asthma, irregular heart-beat, heart and chest pains, dis-
DARK PHASE turbed sleep and eczema.
The official diagnosis was Morbus Crohn with rheumatic
CORRODED
Sn and allergic affliction of intestines (organic enteritis),
Ag~j joints, eyes and upper respiratory passages. The etiology
was not known. Dental status: since childhood amalgam
fillings in most teeth; a short time before the severe dis-
ease manifestations she was given gold restorations
which were in contact with amalgam.
When interviewed in 1990, four years after amalgam re-
moval, she reported amazing recovery with only 4 weak

l
BRIGHT PHASE symptoms left: fatigue, eczema, occasional diarrhea and
impaired ability to concentrate. The woman was one of
the 250 patients (see 3.2) with similar symptoms. Three
other cases are described i n Pleva 89.
3.4 Comparison with literature data
Comparison of the above results with published investi-
gations confirms the considerably high mercury release
"0 5',16 ENERGY keV 10,3='- under realistic conditions 15, 48, 60. The c o m m o n denomi-
Figure 4. Energy dispersive X-ray analysis of the corroded (dark) and nator of many published investigations is the use of fresh
bright areas in figure2. The dark areas consist of amalgam which has amalgam, i.e. amalgam which is only at the start of its
been converted to mercury-freecorrosion products. Similar spectra have
been obtained from the dark and bright areas in figure 1. deterioration process 15, 36, 40, 62, 72, 76, 99. The daily re-
lease of 9 mg o f Hg, which was found by Hahn 48 in
All scanning electron micrographsand EDX-spectra by J. Pleva. investigations o f the feces of sheep one month after the
insertion of 12 fillings, would have consumed all the
face has been corroded and totally depleted of mercury to mercury in less than 2 years. As this rate of loss has not
a depth of 14 gm. F r o m 1 cm 2, 9.5 mg Hg was set free in been observed in practice, either the release must decline
5 years, that is 5.2 gg Hg a d a y . The selective attack on after some months, or the filling will loosen and be re-
the gamma-2 phase has been estimated to have given off placed by a new one in a relatively short time.
additionally 3 gg a day. In this patient, the total exposure Considering the strong variations of the Hg-content in
from 10 c m 2 of corroded surface was 82 gg Hg per day, the feces of amalgam bearers 12' 112, mercury excretion
not counting unknown amounts from the abraded layer due t o oral corrosiOn may vary appreciably. Stock 112
and release from fillings in contact with gold restora- reported daily amounts between 10 and 56 gg Hg in feces
tions. and urine, compared to the average 3.5 gg Hg of con-
Figures I and 2 confirm previous findings by Sarkar 97 trols. N o data about number and size of the fillings are
that the corrosion process can be a process of conversion given.
Reviews Experientia 47 (1991), BirkhS.user Verlag, CH-4010 Basel/Switzerland 15

Borinski 12 also states that excretion (urine + feces) of cury, indicating impaired urinary excretion of the metal.
5-10 ~tg Hg a day is frequent in amalgam-free subjects The investigators found a positive relation between time
not exposed to mercury except from food. Borinski dis- at work and subclinical neurological damage. Adminis-
covered the ubiquitous occurrence of mercury. Excretion tration of dimercaptopropane sulphonate (DMPS), a
over 10 lag indicates an exposure level considered to be heavy metal chelator, produced a massive increase of
potentially harmful. After insertion of an amalgam fill- mercury excretion in amalgam exposed patients with
ing, strongly increased excretion of Hg was observed low, 'normal' Hg levels in urine 25. In the Soviet Union,
during some months, after which the excretion de- DMPS is used for diagnostic purposes. An eight times
creased. During the first three months, about half of the increased urinary Hg-excretion after chelation is consid-
test children showed a total daily excretion in the region ered to be indicative of adverse Hg-effects, when symp-
of 10 100 lag, the other half over 100 lag Hg. From toms of 'micromercurialism' are present 42.
Borinski's text it is apparent that most of the test subjects There are several uncertainties regarding the use of
were treated with one filling only. From the above, and B + U Hg-levels as diagnostic tools. Most industrial
from Kozonos' 62 investigations, it is apparent that the studies relate the B + U-levels to the percentage of af-
mercury release is highest in the first months after inser- fected workers, irrespective of the severity of symptoms.
tion and decreases with time. The decrease of the decay The adverse effects of long-term exposure to low levels of
depends on the build-up of corrosion products, impeding mercury - 'micromercurialism' - can be completely dev-
the transport of mercury and other species between the astating for the affected individual, as was vividly de-
inner parts of fillings and a non-abraded surface. Also scribed by Stock in 1926 ~07.
the decreasing concentration of mercury in the filling will Detailed investigations on single blood cells with proton-
lower its diffusion rate to the surface. However, after a induced X-ray emission equipment demonstrated that
longer time the metal release may increase again 62. only some of the thrombocytes and red and white cells in
The Swedish 'standard man' for discussion of dental patients with suspected amalgam poisoning contained
restorations has been defined as an adult aged 40-50 mercury 4. In a healthy control population the mercury
years, with 16 amalgam restorations with a normalized levels in all cells were below the detection limit. Only one
occlusal geometrical surface area of 10 cm 2' 84. A part of controlled study on animals has assessed blood Hg-levels
the hidden surfaces (bottoms of fillings) is subject to in relation to mercury levels in inhaled air 34 Blood Hg
crevice corrosion. Therefore, to obtain the total surface was found to be related exponentially to the exposure
releasing mercury, the occlusal surfaces need to be multi- level. Assuming that a similar situation exists in humans,
plied by a factor larger than 1. blood Hg levels would be expected to show moderate
changes within a broad range of levels of exposure.
3.5 Mercury in blood and urine Chlorine gas reacts spontaneously with Hg ~ vapor in the
'Normal' values for mercury in blood and urine (B + U) air 46. Already in 1904 it was recognized that the best
were found in the sheep with amalgam fillings, whereas method of protecting workers in mercury mirror facto-
the tissue and feces levels were high 48. The first reliable ries was to maintain a low chlorine content in the air 24.
measurements of Hg in B + U demonstrated that blood The elemental mercury is then oxidized to the much less
values remained low until the exposure level became toxic mercurous chloride (calomel). Viola t28 and Viola
high. Little increase was found in the urine, but much and Cassano 129 found precipitated calomel in mercury-
higher levels in the feces a12. Some studies show that using chlorine factories. They also studied rats exposed
amalgam fillings do have a certain effect on blood Hg- to mercury vapor in comparison to exposure to air with
levels lo5 and that removal of amalgam fillings reduces a mixture of mercury and chlorine. Exposure to the mix-
the Hg-level 1~ Other studies found no difference 63. ture in the same proportions as in the chlorine factories,
Amalgam placement causes a transient peak of mercury but at higher levels, was strikingly less toxic than expo-
in the urine 43, 98, 114 sure to Hg alone. Whereas the rats exposed to Hg alone
Human experiments with single doses of swallowed ra- suffered severe neurological symptoms, those exposed to
dioactive ionic or inhaled elemental mercury show that Hg + chlorine only showed mild gastrointestinal disor-
1 - 2 % of the absorbed dose is eliminated in the urine in ders. The difference in symptomatology can be explained
the course of a week after the exposure 21'91. The ob- by the fact that the brains and hearts of the rats exposed
served urinary excretion after amalgam placement thus to both Hg and chlorine had only 8 - 1 0 % of the levels
corresponds to several mg of total absorption. Recent found in rats exposed to Hg only. Total body uptake in
studies show that the number of amalgam fillings is pos- the doubly-exposed rats was 60 % compared to Hg-only
itively correlated with urinary mercury 69. Few measure- rats.
ments of fecal mercury levels have been made. Tompsett
and Smith 122 found levels of 50-180 lag a day, without
4 Amalgam poisoning
considering amalgam fillings as a source. Lamm and
Pratt 67 found a significant negative correlation between Mercury poisoning from amalgam fillings has been de-
exposure time of workers and urinary excretion of met- scribed several times. Stock lo8 relates cases with devas-
16 Experientia 47 (1991), Birkh/iuser Verlag, CH-4010 Basel/Switzerland Renews

tating psychic effects, and also aggravated symptoms number of teeth was used as a corrective variable. Time
when fillings were drilled out without suction. Further factors were not studied, neither was there any informa-
cases have been described by Stock I~ Fleisch- tion on gold-amalgam combinations or other types of
mann 39 reported that conditions for poisoning were dental restorations. It is not likely that middle-aged per-
present in carriers of copper amalgam fillings (as judged sons in Sweden will have many intact teeth. Lavstedt and
from the Hg-values in urine and feces), whereas no con- Sundberg 70 could not find any correlation between the
clusion could be reached for silver amalgam. Fleisch- prevalence of mercury-related symptoms and the number
mann found that the disappearance of symptoms after of amalgam surfaces. Hugoson so found only a few cases
the removal of silver amalgam indicated that poisoning among 100 patients whose symptoms could be attributed
could occur. Harndt 49, studying the same patients, con- to reactions to dental restorative materials.
sidered patients with gold in contact with amalgam as In a study by Jontel154, 62 patients with 'oral galvanism'
self-evident poisoning cases since the enhanced corrosion were studied. The authors conclude that most symptoms
could clearly release enough Hg. Other cases have been could be ascribed to psychosocial factors. Blood mercury
presented by Wesselhaeft 136, Hyams 52, Steffensen 106, measurements showed no differences between the patient
Lain and Caughron 65, Struntz115 Rost94, Zamm 13v, and control groups. Mtiller-Fahlbusch and W6hning 8o
Pleva 88 and Daunderer z5. also ascribed the symptoms of 50 patients, who suspected
Effects of amalgam removal or placement on T-cells in 3 amalgam poisoning, to psychogenic factors. Removal of
patients (one with multiple sclerosis, MS) was measured amalgam led to an aggravation of the symptoms in 28 of
by Eggleston 33, and the acute exacerbation of MS-symp- 29 cases. Three of the patients had new, allegedly im-
toms during removal (pulverization) of one old filling proved, amalgam fillings. There is no information on
was reported by Ingalls 53. Taskinen 119 followed a pa- protective measures during the amalgam removal, on
tient who had fillings ground to form a bar to support a whether the aggravation was immediate, or on later
bridge. In addition, 11 fillings had about 1 m m ground changes in health. In one county in Sweden, 248 patients
away to improve occlusion, and three fillings were re- were referred to the specialist dental clinic for possible
placed during the following session. After a week, the amalgam-related problems. They were questioned after
patient developed stomatitis, a sore throat, a rancid taste 1/2 to 3 years about treatment and possible health
in the mouth, loss of the sense of smell, dizziness and changes. Most of the patients had exchanged the amal-
headache, and later pains in lhe thorax, fever, elevated gam fillings. Total amalgam removal gave significantly
sedimentation rate, weakened sense of touch in her left better results than other types of treatment or no treat-
hand, sensitivity to cold in the fingers, and a weakened ment, the former having hardly any effect at all. Im-
hand grip. The patient felt rather bad, lost 9 kg of weight provements ranged from 85 % for oral symptoms, 75 %
and became anxious and depressed. The fillings had been for headache to 66 % for psychic problems. The authors
removed with extreme caution. The authors find that the consider the improvements real. However, they ascribe
symptoms correspond to those of micromercurialism. them to placebo effects, since so many symptoms disap-
Anorexia hydrargyria was described in a 15-year-old peared 59.
girl 31, who developed headache, joint pains, vertigo, loss
of memory, fatigue, sleep disturbances and hair loss.
Lack of appetite led to loss of weight and symptoms of 5 Mercury toxicity and symptomatology
anorexia nervosa. There were, however, no psychic prob-
lems. The physician noticed that the patient's mouth con- The toxicity of inorganic mercury has been described
tained 10 glittering amalgam fillings. At an early school several times in the course of centuries. The most com-
age, the patient had received 6 - 8 fillings, with no effects mon form of exposure is inhalation of vapor. There is
on her health. In 1986 the fillings were all replaced by general agreement that inhalation leads to a slowly-de-
new ones and new ones added. The girl was treated with veloping and insidious poisoning which primarily pro-
dimercaptopropane sulphonate and the fillings removed. duces psychic effects, and is very difficult to recognize
This treatment brought about a complete recovery. The until more objective symptoms appear. Numerous more-
author of the report considers the current toxicity evalu- or-less extensive descriptions can be found in the litera-
ation by the dental authorities as insufficient. Diffusion ture. Baader 5 has described the major symptoms: Stom-
of mercury through the pulp, the number and quality of atitis, gingivitis, loose teeth, salivation or dry mouth, foul
the fillings and the toxicity of amalgam for pregnant breath, metallic taste, redness in the throat, black line
women, children and adolescents have not been taken along the teeth, diarrhea, speech problems, nephritis,
into consideration. anemia, relative lymphocytosis, pressure over the chest,
Studies of the relationship between the number of amal- irregular heart, circulation disturbances, low blood pres-
gam fillings and impairment of health do not show any sure, increased sweating, disturbed sleeping, tremor,
differences. Ahlqwist 3 studied 1024 women, aged 38-72 shaky handwriting, dull pains in limbs and joints, fatigue,
years. No difference was found between persons with headache, anxious seclusion, uncertainty, shyness, labile
1 - 4 amalgam fillings and persons with more, when the mood, agony, forgetfulness, feeling of intellectual ex-
Reviews Experientia 47 (1991), Birkh/iuser Verlag, CH-4010 Basel/Switzerland 17

haustion, sensory disturbances of skin, irregular men- Oral or subcutaneous mercuric chloride in rats was found
struation, thyroid disorder, eye pigmentation, eczema. to cause a long-lasting but not permanent impairment of
Common misdiagnoses are neurasthenia, hysteria, the blood-brain barrier with extravasation of plasma
schizophrenia. Other symptom descriptions can be found components a9, demonstrating that acute or subacute ex-
in Schulz 1~ Burgener Iv, Oettingen 85, Nordin 81, posure could expose the immune system to neuronal anti-
Moeschlin 79 and Poulson 9o gens.
In addition to the general symptoms of mercury poison- Stock lo7 published one of the few descriptions of how it
ing there are numerous reports on individual cases of less feels to be poisoned by mercury. He emphasized the psy-
common forms of poisoning, which are likely to pass chic effects, which were especially troublesome for an
unnoticed in industry. The largest such study involved intellectual. In addition to a number of somatic symp-
only about 600 workers in the chlorine industry 104. The toms, Stock mentions: 'Intellectual exhaustion and de-
types of symptoms depend on the mercury compound pression, lack of energy and working ability, especially
and the mode of administration. An amyotrophic lateral for intellectual work, increased need for sleep... For a
sclerosis-like (ALS-like) syndrome has been reported af- person with intellectual work, the loss of memory was the
ter exposure to ethylmercury 58, mercury vapor 2 and in- most severe burden. Especially the ability to calculate
haled mercuric oxide 8. Redhe 92 described the complete and to perform mathematical thinking, also to play chess,
recovery of a 29-year-old woman with an official ALS-di- was severely affected. The lowered ability to remember
agnosis, after all amalgam fillings had been removed. and the difficulties in calculating seem to be a special sign
Mercury-neurasthenia has been known for a long time. of insidious mercury vapor poisoning. The intellectual
Various forms of paralysis, affecting different parts of the capacity was depressed in other ways as well, although
nervous system and diagnosed under different names, not as much as the memory. In addition there was psy-
have been reported: polyradiculoneuritis, Guillain- chic depression and painful inner restlessness, with time
Barre' syndrome, and multiple sclerosis 6, 11, 64, 138. If the causing disturbed sleep. By nature fond of company, and
mercury exposure is recognized and interrupted, most enjoying life, I withdrew depressed into myself, avoiding
cases recover, some slowly, but many surprisingly rapid- public relations, people and social contacts. I lost the
ly. love for art and nature. Humor became rusty. Diffi-
When the mercury etiology of acrodynia was clarified, culties, previously cleared with ease, (as they are again
the possibility that MS was an adult form of acrodynia, today), appeared insurmountable. Scientific work re-
and a neuroallergic reaction, was considered. Baasch 7 quired considerable effort. I forced myself into my lab-
recognized the possibility that amalgam fillings could be oratory but could not produce anything of value despite
the responsible source of Hg. He concluded that the all efforts. My thoughts were heavy and pedantic, i had
amalgam mercury etiology could explain the known facts to give up participating in matters of no immediate im-
about MS. Baasch noted the presence or absence of portance. The lectures, previously something I liked, be-
amalgam fillings in 500 consecutive MS patients in came tormenting. The preparation of a lecture, the writ-
Ziirich. All but one (or possibly two) had amalgam fill- ing of a paper, even a simple letter, required immense
ings. However, amalgam fillings are common, so this efforts in handling the contents and language. Not sel-
finding proved nothing. On the other hand, there are also dom I happened to write words in the wrong way or
other sources of mercury. Three cases were described by forgot letters. To be aware of these shortcomings, with-
Baasch. Two of these had their amalgam fillings removed out knowing their cause, seeing no way to get rid of them,
and the patients improved. The third one showed a rapid- expecting further aggravation - that was not nice!'
ly developing disease, starting a few months after she got Three cases among dentists have been described by
her first amalgam fillings at 19 years of age. When 8 years Smith lo3. The first dentist had hand tremor, impaired
old she had been treated with mercury for congenital motor control, indifference towards family and friends
syphilis. and a visual disturbance. The subjects experienced irrita-
Knolle and Giinther 61 described the mercury/amalgam bility, critical excitability, fearfulness, restlessness,
status of 100 MS patients. Eleven of these had previously melancholy, depression, weakness, timidity, fatigue, in-
been treated with mercury ointments. Seven had no teeth, decisiveness and headache. The dentists emphasized that
and the percentage with amalgam did not differ from the mental effects of mercury poisoning were most dis-
that in the general population. The high percentage of tressing and frightening. Being deeply affected by the
mercury-treated patients seems to be remarkable. Stutte feeling of a hopeless situation, depression and futility,
and Groh 116 discuss an acrodynia case with paralysis, they urged the physician to bring the cases to the atten-
caused by the rectal administration of metallic mercury tion of the medical profession.
in vaseline, and the suspected meckanisms behind this
kind of 'idiosyncrasy'. The proposed sequence of events 6 Mercury and immunology
in acrodynia was suggested to be an initial attack by
mercury on the blood-brain/nerve endothelial cells with Mercury is well known to be immunotoxic. Inhalation or
a secondary immune reaction to brain components. swallowing of mercuric chloride or methylmercury, in
18 Experientia 47 (1991), Birkh/iuserVerlag, CH-4010Basel/Switzerland Reviews

doses comparable to industrial exposures or intake in exposure is required than what is needed for following
food, results in the same systemic autoimmune reactions exposures. Later on, symptoms can appear within an
which occur after subcutaneous administration in sus- hour after exposure to much lower levels. If further expo-
ceptible rat strains to. The autoimmune disease is charac- sure is avoided, the sensitivity slowly disappears, more so
terized by antibodies to a variety of proteins, mainly of if the poisoning has been severe and prolonged. Recovery
endothelial origin 96. Outbred animals show a more com- can take years.'
plicated response 28, 93. The effects on the immune sys- Mercury has a strong affinity for sulfhydryl groups and
tem are thought to be mediated by interaction between it is generally assumed that inhaled mercury is rapidly
mercury and T-cells. The result is a genetically deter- ionized in the blood and binds to SH-groups of enzymes.
mined, polyclonal activation of B-cells sv. The Hg-in- Exposure of animals or humans will lead to a measurable
duced autoimmune disease shows the same types of au- reduction of free tissue and blood sulfhydryl groups. A
toantibodies as in a number of human diseases, graft vs simple estimate, however, will lead to the conclusion that
host disease and reactions to some drugs 32. Long-term even with fatal kidney levels of Hg there will not be
exposure of rats and rabbits to low levels of Hg-vapor, enough metal to bind to more than 10 % of available
6 - 1 0 gg/m 3, for 6 h a day, caused first a stimulation of sulfhydryl groups 22. Glutathione levels alone are in the
the immune response and a decline after months 123. millimolar range. A catalytic oxidation of sulfhydryl
Trachtenberg finds that the immunological changes oc- groups by one mercury ion seems to be a plausible expla-
cur significantly earlier than other signs of latent toxic nation. Mercury is known to release calcium from mit0-
effects. chondrial stores 20, an effect of free radical chemistry
A recent study on human granulocytes demonstrated known to involve oxidation of thiol groups to2. Glutathi-
that exceedingly small amounts of Hg are required to one reductase is inhibited up to 15% by 13 ng Hg/ml
stimulate oxygen free-radical production from neu- (67 x 10-9 M), and myelin phosphodiesterase up to 40 %
trophils (PMNs) in vitro, and to depress various other by 100ng Hg/ml 3~ The levels of mercury in the
P M N functions 23. The radical production was increased brains of humans with amalgam fillings are proportional
at 10-17 M, reached a maximum at 10-13 M and almost to the number of fillings, and are within the range men-
disappeared at 10-7 M concentration. In vivo, the pres- tioned 82.
ence of sulfhydryl groups in blood proteins might change
the figures considerably by non-specific binding of Hg.
7 The acrodynia lesson
Also, free radical production and D N A single strand
breaks in hamster ovary cells, induced by mercury, The best studied cases of human mercury poisonings
showed a distinctly nonlinear response 18. Release of ox- come from the now almost forgotten disease acrodynia.
ygen free radicals is suspected of mediating the patholog- This disease, mostly affecting children, was first recog-
ical effects of adverse drug hypersensitivity reactions 124. nized in France in 1828. It reached epidemic forms in
Skin hypersensitivity to mercury has been reported to some parts of the world. The skin on children's fingers
occur in up to 26.6% of the population zg. There is a and toes was particularly affected and peeled off. The
limited number of described cases of skin reactions skin appearance gave the illness the name 'pink disease'.
caused by amalgam fillings. There is no indication that The patients suffered from pains in the limbs and circula-
skin tests for mercury would give any information on tion troubles, and in extreme cases fingers and toes could
systemic or immunotoxic effects of mercury. Stock, who be lost. Extreme weakness of the muscles, weight loss,
was hypersensitive to traces of inhaled mercury, showed sleep and gastrointestinal disturbances, tremor, chorea,
no positive skin reaction. Children with acrodynia sel- sometimes fever and conjunctivitis belonged to the clini-
dom gave a positive reaction 134. Fanconi 38 observed cal picture. Some patients developed salivation, loose
that in children who were exposed to calomel parenteral- teeth and necrosis of the jaw bones. Thousands of chil-
ly, a positive skin reaction could sometimes be shown dren died: Many causes have been suggested: lack of
when the calomel-disease was at its peak. A few weeks vitamins, endocrine disorders, allergy, hysteria, neurosis,
later, a new test was negative. Children with a negative mold poisons and viruses. Mercury etiology was first
patch-test could develop a flare-up at the site of the suggested in 1846. Again in 1922 a physician pointed out
previously negative Hg application when they accidental- the similarities with mercury poisoning. In 1945
ly swallowed another dose of calomel. Some children Warkany 133,134 found that in almost every case of acro-
developed systemic hypersensitivity after calomel treat- dynia, mercury exposure could be demonstrated. The
ment, but some became more resistant to a second dose. most common exposure sources were teething powders
Baader and Holstein 6 report that occupational exposure containing calomel, and calomel-containing prepara-
leads to increased sensitivity towards further exposure. tions against gastrointestinal parasites.
The acquired 'idiosyncrasy' is often the only permanent Warkany and Hubbard, in 1953 t34, and Warkany in
effect of mercury poisoning. Stock 110 describes the slow 1966133, pointed out that although the administration of
development of mercury sensibilization: 'To provoke a these mercury preparations was frequent, only a fraction
first reaction to mercury vapor, a stronger and longer of the exposed children developed acrodynia. They calcu-
Reviews Experientia 47 (1991), Birkh/iuserVerlag, CH-4010 Basel/Switzerland 19

lated the incidence to be a b o u t one in 500. Mercury Table 2. Examples of Threshold Limit Values (TLV or MAC) for mer-
cury in air and food. Exposureamounts of mercury are givenin each case.
excretion was often found in controls as well, although Presumption: respiration volume/rate: 0.75 t/15 per rain. About 80% of
no symptoms were present. Despite the exposure, mer- the respired mercury is taken up in the lungs sl.
cury was not always detected in the urine samples o f Occupational exposure TLV/MAC Exposurecalculat-
acrodynia children. However, careful studies showed 8 h/day, 40 h/week Ixg Hg/m3 ed from respired
mercury exposure in every case. W a r k a n y notes: 'It seems air and Hg level;
gg Hg/day
rather odd that one could not detect the injurious mer-
cury at the entrance to the alimentary canal, whereas it Germany 100 540
Sweden 50 270
could be demonstrated at the end o f the urinary tract.' World Health Organization (WHO) 25 135
Pseudo-acrodynia with some features o f the real disease Soviet Union 10 54
was p r o d u c e d by different treatments in animals. Howev- General population,
24 h/day
er, 'a subtle, complicated, and no d o u b t molecular dis-
EPA, USA 1 16.2
ease was eradicated by such a prosaic measure as remov- Soviet Union 0.3 4.8
ing calomel from old-fashioned teething powders and Exposure fi'om food
w o r m medicines. There were d a t a on electrolyte changes, Sweden 30 gg/day 30
explaining the symptoms o f acrodynia and their allevia-
tion by subtle saline treatments. But these d a t a did not
take into account the one electrolyte that mattered, following m a i n reasons: There is (or should be) regular
namely mercury '133. medical control o f occupationally exposed workers, and
suspected mercury-related problems can be alleviated by
changing the working conditions. TLVs for mercury are
8 Threshold limit values How much mercury is too
based on studies in the electrolytic chlorine industry
much ?
where the workers are to some extent protected by the
Safety evaluations for inorganic mercury are based on oxidative effect o f chlorine on mercury v a p o r (see section
industrial observations, and for a m a l g a m specifically, on on H g in b l o o d and urine). The TLVs m a y therefore be
estimates o f the exposure levels from a m a l g a m c o m p a r e d too high for continuous exposure in chlorine-free air. F o r
to the industrial M A C - v a l u e s ( M a x i m u m Allowable the general population, it is also necessary to consider
Concentration, c o m p a r a b l e with the concept of Thresh- individual sensitivity, chronic diseases, and effects on
old Limit Values, TLV, used in the USA). In the USA, children, pregnant women and elderly people.
most government agencies recommend a m a x i m u m of
50 lag Hg/m 3 in industry, based on the study o f Smith et
9 Conclusion
al. 1~ A review o f the subject ~39 shows that the U.S.
EPA (Environmental Protection Agency) National Emis- The puzzling insidious biological effects of various forms
sion Standard, I lag H g / m 3 for mercury as a hazardous of mercury are often difficult to recognize when correct
air pollutant, is the only air-exposure standard based on d a t a on mercury exposure are not considered. The dis-
studies of the effects of mercury on the general popula- ease of acrodynia may serve as an illustration. Besides the
tion, and not limited to a 40-h week. In the Soviet Union, diagnostic difficulties, the dental a m a l g a m debate has
the corresponding value is 0.3 gg H g / m 3, based on thor- been affected by the lack o f an interdisciplinary ap-
ough studies o f chronic mercury exposures by Trachten- proach. Despite a large number of specialized papers on
berg 123. amalgam, very few attempts have been m a d e to relate
As shown in table 2, estimates of safe industrial exposure clinically observed deterioration and wear of a m a l g a m
levels vary between different countries by an order o f restorations with estimates of metal release, which can
magnitude. In some countries, the safety limits for the also be m a d e from such studies. Corrosion currents have
general p o p u l a t i o n are 30 - 50 times lower than the indus- been measured in vitro, but this has not led to the obvi-
trial limits. ous step o f using F a r a d a y ' s law to calculate the corre-
The MAC-values are defined as: that average concentra- sponding metal release; instead, it has led to a strange
tion in the air which causes no signs or symptoms of discussion on 'oral galvanism' and the possible biological
illness or physical impairment in all but hypersensitive effects of the generated currents. It is clear from known
workers during their working day, on a continuous basis, facts, and using available scientific and technical meth-
as judged by the most sensitive internationally accepted ods, that estimated exposure levels for mercury will be
tests 77. Hypersensitivity is not stated to be evidenced found to be higher than was previously thought. The
only as skin reactions. N o regulation for any mercury conclusion is that such levels could have considerable
c o m p o u n d considers additional exposures, or the possi- toxicological and immunological consequences. A review
bility o f reduced resistance due to low dietary levels of of the controversy indicates a serious deficiency in the
selenium, zinc and other essential substances which are efforts o f the dental profession to test the published
k n o w n to counteract mercury effects. The occupational warnings, for example those of Professor Stock, and to
TLVs are not relevant for the general p o p u l a t i o n for the bring clarity into the issue.
20 Experientia 47 (1991), Birkhfiuser Verlag, CH-4010 Basel/Switzerland Reviews

Recent investigations on the fate of amalgam mercury, 16 Brune, D., Metal release from dental biomaterials. Bimnaterials 7
(1986) 163-175.
using whole body image scans 48, show that in sheep 17 Burgener, P., and Burgener, A., Erfahrungen fiber chronische
mercury release of up to 1 mg a day from one filling is Quecksilbervergiftungen. Schw. med. Wschr. 8 (1952) 204 210.
possible during the first months after insertion. Sheep 18 Cantoni, O., Christie, N. T.; Swann, A., Drath, D. B., and Costa,
M., Mechanism of HgC1 z cytotoxicity in cultured mammalian cells.
were chosen as experimental animals since they use molar Molec. Pharmac. 26 (1984) 360-368.
chewing as do humans 48. Some humans use chewing- 19 Chang, L. W., and Hartmann, H. A., Blood-brain barrier dysfunc-
gum or exhibit bruxism (grinding of the teeth), and might tion in experimental mercury intoxication. Acta neuropath. 21
(1972) 179-184.
abrade their fillings as much as sheep fed two meals a 20 Chavez, E., and Holguin, J. A., Mitochondrial calcium release as
day. Further; investigations of amalgam restorations af- induced by Hg 2+. J. biol. Chem. 263 (1988) 3582-3587.
21 Cherian, M.G., I-Iursh, J. B., Clarkson, T.W., and Allen, J., Ra-
ter a known time in vivo show that the amount of mer- dioactive mercury distribution in biological fluids and excretion in
cury released can reach levels several times higher than human subjects after inhalation of mercury vapor. Arch. envir. Hlth
accepted threshold values. The corrosion process may 33 (1978) 109 114.
22 Clarkson, T. W., The pharmacology of mercury compounds. A. Rev.
not be apparent to the eye, as it is a matter of amalgam Pharmac. 12 (1972) 375 406.
conversion rather than dissolution. The extensive pub- 23 Contrino, J., Marucha, P., Ribaudo, R., Ference, R., Bigazzi, P. E.,
lished knowledge about mercury toxicology indicates and Kreutzer, D. L., Effects of mercury on human polymorphonu-
clear leukocyte function in vitro. Am. J. Path. 132 (1988) 110-118.
that toxic effects from amalgam mercury cannot be ex- 24 Cremer, E, (Ed.), Die Fabrikation der Silber- und Quecksilber-
cluded. Immunological disorders can appear at consider- Spiegel. I-Iartlebens Verlag, Wien/Leipzig 1904.
25 Daunderer, M., Amalgam. Klin. Toxikologie 46 (1989) 1 54.
ably lower exposures than those from dental amalgam. 26 DeLong, R., Sakaguchi, R. L., Douglas, W. H., and Pintado, M. R.,
Comparison with occupational threshold limits for mer- The wear of dental amalgam in an artificial mouth: a clinical corre-
cury suggests that amalgam bearers should be under reg- lation. Dent. Mater. I (1985) 238-242.
27 Dencker, I., and Schfitz, A., Kvicksilverinneh~llet i kosten.
ular medical surveillance in the same way as mercury-ex- L/ikartidn. 68 (1971) 4031-4033.
posed workers. 28 Dieter, M. P., Luster, M. I., Boorman, G. A., Jameson, C. W., Dean,
A comprehensive bibliography with over 8000 titles on J. H., and Cox, J. W, Immunological and biochemical responses in
mice treated with mercuric chloride. Toxic. appl. Pharmac. 68 (1983)
mercury and its health effects can be obtained from the 218.
authors. 29 Djerassi, E., and Berova, N., The possibilities of allergic reactions
from silver amalgam restorations. Int. dent. J. 19 (1969) 481-488.
30 Domanska-Janik, K., and Bourre, J. M., Effect of mercury on rabbit
1 Abraham, J. E., Svare, C. W., and Frank, C. W., The effect of dental myelin CNP-ase in vitro. Neurotoxicology 8 (1987) 23-32.
amalgam restorations on blood mercury levels. J. dent. Res. 63 31 D6rffer, U., Anorexia hydrargyra. Kasuistik a u s d e r Praxis.
(1984) 71 73. Monatschr. Kinderheilk. 137 (1989) 472.
2 Adams, C. R., Zieg!er, D. K., and Lin, J. T., Mercury intoxication 32 Druet, P., Hirsch, E, Sapin, C., Druet, E., and Bellon, B., Immune
simulating amyotrophic lateral sclerosis. JAMA 250 (1983) 642- dysregulation and autoimmunity induced by toxic agents. Transpl.
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The human leukemia cell line, THP-1 : A multifacetted model for the study of monocyte-macrophage
differentiation

J. A u w e r x

Laboratory o f Experimental Medicine and Endocrinology, Department o f Developmental Biology, Campus Gasthuis-
berg, KULeuven, B-3000 Leuven (Belgium)

Summary. T H P - 1 is a h u m a n m o n o c y t i c l e u k e m i a cell line. A f t e r t r e a t m e n t w i t h p h o r b o l esters, T H P - I cells

d i f f e r e n t i a t e i n t o m a c r o p h a g e - l i k e cells w h i c h m i m i c n a t i v e m o n o c y t e - d e r i v e d m a c r o p h a g e s in several respects.
C o m p a r e d t o o t h e r h u m a n m y e l o i d cell lines, s u c h as H L - 6 0 , U 9 3 7 , K G - 1 , o r H E L cell lines, d i f f e r e n t i a t e d T H P - I
cells b e h a v e m o r e like n a t i v e m o n o c y t e - d e r i v e d m a c r o p h a g e s . B e c a u s e o f these c h a r a c t e r i s t i c s , t h e T H P - 1 cell line
p r o v i d e s a v a l u a b l e m o d e l f o r s t u d y i n g t h e m e c h a n i s m s i n v o l v e d in m a c r o p h a g e d i f f e r e n t i a t i o n , a n d f o r e x p l o r i n g
t h e r e g u l a t i o n o f m a c r o p h a g e - s p e c i f i c genes as t h e y r e l a t e to p h y s i o l o g i c a l f u n c t i o n s d i s p l a y e d b y these cells.
Key Words. A t h e r o s c l e r o s i s ; cellular d i f f e r e n t i a t i o n ; g e n e e x p r e s s i o n ; f o a m cells; l i p o p r o t e i n s ; p h o r b o l esters; t r a n -
s c r i p t i o n factors.

The mononuclear-phagocyte system

T h e ' m o n o n u c l e a r - p h a g o c y t e s y s t e m ' c o n s i s t s o f tissue t h e i r c o m m o n origin, t h e i r s i m i l a r m o r p h o l o g y , a n d t h e i r
m a c r o p h a g e s a n d t h e i r p r e c u r s o r cells, m o n o c y t e s 1~ common functions, including rapid phagocytosis. This
T h e s e cells a r e c o n s i d e r e d t o b e a ' s y s t e m ' b e c a u s e o f ' s y s t e m ' is d y n a m i c a n d is r e p r e s e n t e d i n a l m o s t all tis-