Abstract
OBJECTIVES:
The purpose of this study was to evaluate treatment of patients
suffering from chronic ill health with a multitude of symptoms
associated with metal exposure from dental amalgam and other
metal alloys.
SETTING
AND DESIGN: We included 796 patients in a retrospective study
using a questionnaire about symptom changes, changes in quality
of life as a consequence of treatment and assessment of care
taking.
METHODS:
Treatment of the patients by removal of offending dental metals
and concomitant antioxidant therapy was implemented according
to the Uppsala model based on a close co-operation between
physicians and dentists.
RESULTS:
More than 70% of the responders, remaining after exclusion
of those who had not begun or completed removal, reported
substantial recovery and increased quality of life. Comparison
with similar studies showed accordance of the main results.
Plasma concentrations of mercury before and after treatment
supported the metal exposure to be causative for the ill health.
MAIN
FINDINGS: Treatment according to the Uppsala model proved
to be adequate for more than 70% of the patients. Patients
with a high probability to respond successfully to current
therapy might be detected by symptom profiles before treatment.
CONCLUSIONS:
The hypothesis that metal exposure from dental amalgam can
cause ill health in a susceptible part of the exposed population
was supported. Further research is warranted to develop laboratory
tests to support identification of the group of patients responding
to current therapy as well as to find out causes of problems
in the group with no or negative results
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ABBREVIATIONS
ANOVA
-- Analysis of variance
bcl-2 -- Anti-death gene
DTT -- Dithiothreitol
GABA -- gamma-aminobutyric acid
GSH -- Glutathione, reduced
Hg -- Mercury
hSkM1 -- Gene product of SCN4a (sodium channel a-subunit) being
the human homologue of rSkM1, the tetrodotoxin-sensi tive sodium
channel characteristic of adult rat skeletal muscle
ICP-MS --- Inductively Coupled Plasma Mass Spectrometry
IL -- Interleukin
IRE -- Iron responsive element
IRP-1 -- Iron regulatory protein 1
MAP -- Mitogen activated protein
MELISA® -- Memory Lymphocyte Immuno Stimulation Assay
Ras -- One of a family of guanosine nucleotide-binding proteins
RIC -- Restoration with Individually Compatible Dental Materials
RID -- Removal of Incompatible Dental Materials
ROS -- Reactive Oxygen Species
TNF -- Tumor Necrosis Factor
Introduction
Dental
amalgam was used very early in China. “Silver paste”
is mentioned in the materia medica of Su Kung in 659 A.D. The
name used is probably the historical reason why this material
in some countries is called “silver amalgam” although
its main ingredient always has been mercury. French chemists
and dentists experimenting with various mixtures of metals in
the end of the 18th century initiated the use of amalgam in
the western world. Introduction of dental amalgam is usually
ascribed to the French brothers Crawcour in 1831. They used
a mixture of mercury and filings of French silver coins. Two
years later the Crawcour brothers introduced the filling material
in New York and they falsely pretended to be dentists.
Discussions
about the rationale in using mercury as the main component in
dental amalgams have been going on more than 160 years. In fact,
the debate started immediately after the introduction of the
material in the U.S.A. American medical-dentists at that time
started a merciless crusade against their foreign rivals. They
declared that not only was silver amalgam a lousy filling material
but it also caused mercury poisoning. This had among other things
the consequence that professional dentists started a dental
association (The American Society of Dental Surgeons) in New
York in 1840 to “increase the standing of the profession
and to counteract charlatanry”. The first amalgam war had
begun.
Almost
ignored were the results of studies in which warnings were issued
for negative health effects associated with exposure to mercury
from dental amalgams [1, 2]. Later during the 1920s, the German
chemist Alfred Stock warned about the danger with mercury vapor
[3, 4]. As late as in 1939 he issued enhanced warnings [5].
The latest phase in these amalgam wars started in the late 1970s
and has been especially intense in Scandinavia but also in the
U.S.A. and Germany. Various attempts to estimate risks from
dental amalgams have been published advancing conclusions of
increased risk of disease [6] as well as no correlation between
amalgams and health problems [7]. The latter study, however,
demonstrated negligence of combinations of gold and amalgam
causing increased corrosion and mercury vapor emission. Richardson
[8–10] concludes that a significant portion of all age
groups exceeds the proposed reference dose for mercury exposure
(0.98 mg Hg/day – tolerable daily intake) more than fives
times due to dental amalgam. He also concludes that data suggest
that approximately 19 to 20% of the general population may experience
sub-clinical central nervous system and/or kidney function impairment
as a result of the presence of amalgam fillings. Berlin [11]
arrives at the conclusion that the prevalence of side effects
from mercury in amalgam on the nervous system, immune system
and kidneys should fall in the interval 0.1–10% with the
highest probability of 1%. This makes the probable side effects
from amalgams a significant health problem.
Documented
effects of amalgam removal appeared already in 1842 [1]. However,
probably the first comprehensive study was published in 1928
as a consequence of Stock’s warnings [15]. Seven patients
with a completed treatment reported substantially improved health
or complete health. Fleischmann [15] interpreted the symptoms
as an expression of “hypersensitivity” and recommended
dentistry to abandon copper amalgam of that time immediately
and silver amalgam when equivalent materials were available.
Several contemporary studies have been published dealing with
implications, both in general health, oral pathology and laboratory
medicine, of removal of dental amalgam [16–35]. A drawback
of most of these studies is, however, that there are few indications
of the treatment quality.
The
rationale for highlighting clinical effects of chronic low-dose
mercury exposure is the advancement of modern research in the
behavior of mercury in tissues. This metal has a lot of potentially
toxic effects on various levels in a living organism. Mercury
exposure decreases the DNA content and increases collagenase-resistant
protein formation in synovial tissues. This leads to an increased
risk for reduced joint function and decreased ability to repair
joint damage [36] partly explaining the joint problems in the
patient group.
Decreased amounts of available selenium are also a consequence
of exposure to heavy metals, in particular mercury, which compounds
the oxidative burden on the body [37]. Mercury also decreases
levels of glutathione (GSH) in the body [38]. Mercury binds
irreversibly to GSH causing the loss of up to two GSH molecules
per mercury ion. The GSH-Hg-GSH complex is excreted via the
bile into the feces. Part of the irreversible loss of GSH is
due to the inhibition of GSH reductase by mercury, which is
used to recycle oxidized glutathione and return GSH to the pool
of available antioxidants [39]. At the same time, mercury also
inhibits GSH synthetase, so a lesser amount of new GSH is created.
Since mercury promotes formation of hydrogen peroxide, lipid
peroxides and hydroxyl radicals, it is evident that mercury
sets up a scenario for a serious imbalance in the oxidant/antioxidant
ratio of the body [40].
Central
nervous affection by exposure to mercury may in part be explained
by that Hg0 and Hg2+ are accumulated in motor neurons and Purkinje
cells in the brain [41]. Important intracellular effects of
mercury are intimately connected to enzymes. All enzymes with
sulfur amino acids as well as selenocysteine are open for attack
by Hg2+ with a probable outcome of impairment of function. Cells
presented with Hg0 will not be able to stop penetration through
membranes due to the lipophilicity of uncharged mercury atoms.
This opens for a multitude of possible symptoms from various
organs in the body. First order thiol binding constant of Hg2+
is 1030–40, which demonstrates the extreme affinity of
mercury for thiol groups [42]. Additionally, the ligand exchange
rate constant of Hg2+ among thiol groups is among the highest
known (109 s–1), again showing the extreme properties of
the mercuric ion [43].
Exposure
of workers to 0.0058 mg m–3 mercury vapor (0.007–0.021
mg m–3) affected the chemotaxis of polymorphonuclear leukocytes
significantly [44]. This exposure is in good agreement to what
could be expected from a “normal” set of amalgam fillings
[45]. A sensitive subgroup of the population, therefore, has
to be expected to suffer from impairment of circulating blood
cells. Furthermore, neutrophil activity has been shown to be
inhibited by mercury [46]. Even damages to DNA has been attributed
to mercury exposure [47].
Mercury interacts with the GABAA receptor by way of alkylation
of thiol groups of cysteinyl residues found in GABAA receptor
subunit sequences [48]. This has the consequence that the binding
site of benzodiazepine is modulated.
Structural
alteration of the mitochondrial inner membrane with consequent
dissipation of membrane potential and disruption of oxidative
phosphorylation is another cellular effect of mercuric ions
[49–51]. The intracellular calcium homeostasis is altered
by mercury inducing mitochondrial release of calcium [51, 52].
Cellular influx of calcium also seems to be a consequence of
human exposure to mercury and other metals from dental amalgam
[13]. Mercury-induced stress may transform innocuous astrocytes
into potentially lethal sources of cytotoxic oxygen free radicals
[53].
Low
levels of mercuric ions alter the normal pattern of protein
tyrosine phosphorylation in B-lymphocytes during antigen receptor-stimulated
signal transduction, suggesting that low levels of mercuric
ions interfere with signal transduction pathways that are mediated
by receptor-associated tyrosine kinases [54]. Additionally,
Mattingly et al. [55] showed that low concentrations of mercuric
ions interfere with the normal activation of Ras and MAP kinase
during antigen receptor-mediated signal transduction in T lymphocytes.
The regulation of cell growth is interfered by low and non-toxic
levels of ionic mercury [56]. Mercury-induced apoptosis seems
to be species dependent in human lymphoid cells in a comparison
between the effects of methylmercuric chloride and mercuric
chloride [57]. Each of the mercurial species trigger the apoptotic
cascade, however, there are profound differences in the mechanism
of action at the mitochondrial level. This disparity of mode
of action may be linked to differential effects on the anti-death
gene, bcl-2. Low-dose exposure to silver, copper, mercury and
nickel ions alters the metabolism of human monocytes [58]. These
authors conclude that the levels of metals released from dental
alloys may be significant to monocytic function.
Mercury
as well as cadmium binds iron regulatory protein 1 (IRP-1) with
high affinity, compared with iron. These metals may cause the
disruption of iron metabolism by inhibiting posttranscriptional
regulation of iron-related proteins, such as ferritin and transferrin
receptor. The effects of these toxic metals on inactivation
of IRP-1/IRE binding and activation of aconitase may explain
part of the cell toxicity [59]. Even ion channels may be adversely
affected by mercury exposure. Divalent mercury blocked human
skeletal Na+ channels (hSkM1) in a stable dose-dependent manner
in the absence of reducing agent. Dithiothreitol (DTT) significantly
prevented Hg2+ block of hSkM1 and Hg2+ block was also readily
reversed by DTT [60].
Mercury
is additionally well known to have adverse effects on the immune
system with increased IgE in blood and deposits of immune complexes
in the renal mesangium [61, 62]. Immunomodulation is but one
of the facets of mercury exposure. Experimental animal studies
and observations in humans indicate that immunomodulatory properties
of metals such as mercury are heterogeneous and are not restricted
to contact allergy [63]. Mercury causes induction of oligoclonal
T cell responses skewed toward type-2 reactions [64]. There
are numerous studies showing the induction of autoimmunity by
mercury exposure [65–69]. Even neurological diseases have
been hypothesized to be, at least partly, due to induction by
exposure to heavy metals such as mercury [70–72].
During the last twenty years an increasing number of patients
have sought dental and/or medical care for problems possibly
associated with dental amalgam. These patients have observed
a relationship in time between odontological treatment and occurrence
or increase of their symptoms. The metal syndrome was conceived
by our group as a collective term describing such patients with
a series of symptoms for which no other etiologic diagnosis
could be found in spite of thorough examination and laboratory
tests [12]. Most other possible causes, except for metal exposure
from amalgams, for the disease of these patients have been excluded
by meticulous investigations performed by several specialist
physicians. A differential diagnostic procedure had thus been
thoroughly implemented. These patients suffered from several
general, neurological, psychiatric and oral symptoms.
Soon
additional laboratory tests were included in these studies.
Nuclear microscopy of single isolated blood cells revealed that
patients, in contrast to healthy controls, displayed distorted
profiles of trace elements in blood cells [13]. In addition,
changes of trace elements in blood plasma assessed by X-ray
fluorescence were observed.
Hypersensitivity or allergy to metals comprising dental alloys
was suspected rather early. To avoid potential side effects
of traditional patch testing, an in vitro test was applied.
This test being called MELISA® (MEmory Lymphocyte Immuno
Stimulation Assay) is a development of the common lymphocyte
transformation test. MELISA® applied to 3000 patients with
suspected side effects from metals in dental restorative materials
in three analytical centers demonstrated a reasonable degree
of conformity [14].
The
aim of the present study was to evaluate the treatment of patients
at the former Department of Clinical Metal Biology at the University
Hospital in Uppsala, Sweden. A questionnaire comprising questions
about symptoms, quality of life as well as care-taking assessment
was constructed and sent to patients. The study design was,
therefore, a before-after design in which patients constituted
their own controls and was undertaken in retrospect and longitudinally.
This design has the attractive advantage of setting aside genetic
differences between cases and controls. Even if the study had
been prospective, it would not have been possible to adopt a
double-blind placebo-controlled design for obvious reasons.
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