Review

Environmental Exposure to Mercury and Its Toxicopathologic

Implications for Public Health

Paul B. Tchounwou, Wellington K. Ayensu, Nanuli Ninashvili, Dwayne Sutton

Cellomics and Toxicogenomics Research Laboratory, NIH Center for Environmental Health,
School of Science and Technology, Jackson State University, 1400 Lynch Street,
Box 18540, Jackson, Mississippi 39217, USA

Received 23 February 2003; revised 20 March 2003; accepted 20 March 2003

ABSTRACT: Mercury is a toxic and hazardous metal that occurs naturally in the earth’s crust. Natural
phenomena such as erosion and volcanic eruptions, and anthropogenic activities like metal smelting and
industrial production and use may lead to substantial contamination of the environment with mercury.
Through consumption of mercury in food, the populations of many areas, particularly in the developing
world, have been confronted with catastrophic outbreaks of mercury-induced diseases and mortality.
Countries such as Japan, Iraq, Ghana, the Seychelles, and the Faroe Islands have faced such epidemics,
which have unraveled the insidious and debilitating nature of mercury poisoning. Its creeping neurotoxicity
is highly devastating, particularly in the central and peripheral nervous systems of children. Central
nervous system defects and erethism as well as arrythmias, cardiomyopathies, and kidney damage have
been associated with mercury exposure. Necrotizing bronchitis and pneumonitis arising from inhalation of
mercury vapor can result in respiratory failure. Mercury is also considered a potent immunostimulant and
-suppressant, depending on exposure dose and individual susceptibility, producing a number of patho-
logic sequelae including lymphoproliferation, hypergammaglobulinemia, and total systemic hyper- and
hyporeactivities. In this review we discuss the sources of mercury and the potential for human exposure;
its biogeochemical cycling in the environment; its systemic, immunotoxic, genotoxic/carcinogenic, and
teratogenic health effects; and the dietary influences on its toxicity; as well as the important consider-
ations in risk assessment and management of mercury poisoning. © 2003 Wiley Periodicals, Inc. Environ
Toxicol 18: 149 –175, 2003.
Keywords: mercury exposure; systemic toxicity; immunotoxicity; health risk assessment; management

Correspondence to: Paul B. Tchounwou; e-mail: paul.b.tchounwou@

jsums.edu.
Contract grant sponsor: National Institutes of Health, through Biomed-
ical Research Infrastructure Network–Mississippi Functional Genomics
Network, contract grant number: 5P20RR16470-02/USM-GR00978-04.
Contract grant sponsor: U.S. Department of the Army; through the
MACERAC program, contract grant number: DACA-42-02-C-0057.
Published online in Wiley InterScience (www.interscience.wiley.com).
DOI 10.1002/tox.10116

© 2003 Wiley Periodicals, Inc.

149
150 TCHOUNWOU ET AL.

CONTENTS

1. Abstract ........................................................................................................................................................ 149

2. Keywords ..................................................................................................................................................... 149
3. Abbreviations ............................................................................................................................................... 150
4. Introduction .................................................................................................................................................. 151
5. Sources of Mercury and Potential for Human Exposure ........................................................................... 152
6. Biogeochemical Cycling of Mercury .......................................................................................................... 153
7. Production and Uses of Mercury ................................................................................................................ 154
8. Health Effects Associated with Mercury Exposure ................................................................................... 154
8.1. Elemental Mercury (Hg0) .................................................................................................................... 154
8.2. Inorganic Mercury Compounds .......................................................................................................... 155
8.3. Organic Mercury Compounds ............................................................................................................. 156
9. Immunotoxic Effects of Mercury ................................................................................................................ 157
9.1. Mercury-Induced Immune Responses ................................................................................................. 157
9.2. Mercury-Induced Immune Responses and Apoptosis ........................................................................ 160
9.3. Significance of Mercury-Induced Autoimmunity ............................................................................... 161
10. Genotoxic, Carcinogenic, and Teratogenic Effects of Mercury ................................................................ 163
11. Dietary Influences on Mercury Toxicity and Counter Effects on Diet ..................................................... 164
11.1. Minerals ............................................................................................................................................. 165
11.2. Vitamins ............................................................................................................................................. 165
11.3. Combined Nutrient Effects ................................................................................................................ 165
12. Mercury Risk Assessment and Management .............................................................................................. 166
12.1. Minimum Risk Levels ....................................................................................................................... 166
12.2. Diagnosis of Mercury Intoxication ................................................................................................... 167
12.3. Treatment Schedules .......................................................................................................................... 168
13. Conclusions .................................................................................................................................................. 168
14. References .................................................................................................................................................... 169

Abbreviations: Ab—antibody; Ag—antigen; ALS—amyotropic lateral sclerosis; AMG—autometallography;

AnoAbs—antinucleolar autoantibodies; APC—antigen-presenting cells; BBB— blood– brain barrier; CCB—
calcium channel blockers; CNS— central nervous system; DN— double negative; DR— death receptors; EtHg—
ethylmercury; GBM— glomerular basement membrane; H-2—murine histocompatibility complex; HgIA—
mercury-induced autoimmunity; HgICD—mercury-induced cell death; HRBC— horse red blood cells; ICGN—
immune-complex glomerulonephritis; Igs—immunoglobulins; I-Hg—inorganic mercury; mAb—monoclonal
antibody; MeHg—methylmercury; MHC—major histocompatibility complex; mg/kg b.wt—milligram per kilo-
gram of body weight; NMDA—N-methyl-D-aspartate; PCA—polyclonal cell activation; PCD—programmed cell
death (apoptosis); PNS—peripheral nervous system; ppm—parts per million; PWM—pokeweed mitogen; RfD—
reference dose; SLE—systemic lupus erythematosus; snRNP—small nucleolar ribonucleoprotein particles;
ww—wet weight

INTRODUCTION
Although mercury has no known beneficial effect in human
physiology, it is estimated that an average man weighing 70
kg has an amount equivalent to 13 mg of mercury in his
system (Pier, 1975). It is a highly reactive molecule that
produces toxic effects by binding highly to sulfhydryl and to
a lesser degree to hydroxyl, carboxyl, and phosphoryl
groups. It is widely distributed as an environmental and
industrial pollutant. In humans high mercury levels are
found in the skin, nails, hair, and kidneys. The earth’s crust
contains 0.5 parts per million of mercury. The prominent
sources of human exposure to mercury nevertheless come
from dental amalgams, pharmaceuticals, cosmetics, and
food, primarily contaminated fish (Eley, 1997).
Three forms of mercury are found in the environment.
Each has specific solubility, chemical reaction, and toxicity
characteristics (Clarkson, 2002; Goldman and Shannon,
2001). Quicksilver, or elemental mercury, is released via
degassing from the earth’s crust and oceans, and the com-
bustion of fossil fuels releases elemental mercury to the
environment (ATSDR, 1999). Inorganic mercurous (calo-
mel) and mercuric salts have been utilized for medicinal
purposes through the centuries and employed as detonators
in explosives, respectively (Klassen, 1990).
Microorganisms in streams and rivers are capable of
biomethylating mercuric compounds to form organic spe-
cies of mercury, including the methyl, ethyl, and phenyl
types that find their way into the industrial environment.
The uses of these forms of mercury as biocides, pesticides,
and household antiseptics have contributed to the wide
distribution of this heavy metal into the environment.
Therefore, it is not surprising that despite efforts to control
its use and release into the atmosphere, mercury continually
accumulates in waters and rivers.
Methylmercury, the most toxic of the organic forms, is
taken up by fish species, providing a route to move high up
the food chain to enter the diet and cause concerns about
public health (Tan and Perkin, 2000). The methylmercury
content of fish varies, by species, by size, and by harvest
location. Fish caught in Lake St. Clair, Canada, with mer-
cury levels of 0.07– 0.11 ␮g/g in 1935 had mercury con-
centrations of 0.2–7.0 ␮g/g of body weight by 1970. Tuna
has an average mercury concentration of between 0.13 and
0.25 ␮g/g of body weight (Dales et al., 1971; Hammond,
1971). The daily absorption of all forms of mercury from
fish and seafood is estimated to be 2.3 and 0.3 ng per day
from all other foods and air and water (Goyer, 1996).
The problems associated with mercury poisoning were
not recognized until the occurrence in Japan of what is now
popularly known as Minamata disease (Clarkson, 1997). A
chemical plant in Minimata Bay used an inorganic mercury
compound as a catalyst in a chemical process, unaware that
this process resulted in the catalytic conversion of the chem-
ical to an organomercurial. Years later a large number of
ENVIRONMENTAL EXPOSURE TO MERCURY 151
people exhibited symptoms of mercury poisoning. It was
finally discovered that the organomercurial was being con-
centrated in marine animals that were part of the staple diet
of the local population. Since then similar situations have
arisen in Sweden, in a population living on fish collected
from water contaminated by an organic mercury compound
used as a pesticide (D’Itri, 1972); in Iraq in 1974, among
people exposed to mass mercury poisoning from rice treated
with pesticide (Amin-Zaki et al., 1981); and in Ghana,
where ethylmercury-treated maize was consumed by a local
community, with 20 of the 144 cases of mercury poisoning
ending in fatalities. In China in the 1970s cases of ethyl-
mercury poisoning were reported. The exposure pathway
was the same as in Iraq, where farmers consumed ethylmer-
cury chloride–treated rice (Goldman and Shannon, 2001).
Mercury damages DNA (Sager et al., 1984), impairs
mitosis, and disrupts neuronal migration (Hammond, 1971).
It is therefore neurotoxic during prenatal and postnatal
periods. However, the effects of mercury intoxication are
very pronounced on the fetus. The net results of mercury
intoxication include mental retardation, cerebral palsy, sei-
zures, and ultimately death (WHO, 1990). The kidneys
among all the organs are highly susceptible to mercury salts.
Nephrotoxicity manifests itself clinically as acute tubular
necrosis and immunologic glomerulonephritis (Hultman et
al., 1998; Tominack et al., 2002). Arrhythmias and cardio-
myopathy have also been associated with mercury toxicity.
Cardiomyopathic patients have been found to have very
high concentrations of mercury in their hair, thousand of
times above those of controls (Frustaci et al., 1999).
Phenylmercury, once used as a fungicide in diaper rinses
and in latex paint, has been reported to cause acrodyna with
painful extremities in infants (Agocs et al., 1990), peripheral
neuropathy, and hypertension with renal tubular dysfunc-
tions (Roman-Franco et al., 1978; Langford and Ferner,
1999). In adults a severe neurogenic pain syndrome requir-
ing inpatient pain management is a problem that can de-
velop into a type of severe motor neuropathy that has the
signs and symptoms of both axonal degeneration and Güil-
lain-Barré-like illnesses (Schwarz et al., 1996). The litera-
ture also contains numerous case reports of reversible neu-
rologic conditions associated with mercury exposure
characterized as amyotropic lateral sclerosis–like illness
(ALS; Adams et al., 1983; Schwarz et al., 1996). Despite
such presentations it is difficult to determine the reference
dose (RfD) of mercury, the highest dose that the body can
tolerate over a lifetime without any side effects. The reason
for this difficulty is partly attributed to how poorly under-
stood is the individual susceptibility that is presumably
related to variations in dietary habits among different pop-
ulations.
Certain individuals are genetically susceptible to devel-
oping spontaneous autoimmune diseases. The etiology and
pathogenicity of these, mostly systemic, autoimmune states
have been difficult to trace. Recent immunological findings
152 TCHOUNWOU ET AL.
confirm that most origins of these idiopathic autoimmune
diseases can be traced to the contamination of the biosphere
with xenobiotic compounds, among which mercury has
been strongly implicated. Low levels of mercury exposure
(⬍40 ␮g/kg body weight) in adults may be unsafe in pa-
tients who have a predisposition to develop systemic lupus
erythematosus (SLE). Acute renal tubular lesions and im-
munosuppression follow exposure to large doses, whereas
chronic administration of smaller doses of mercury leads to
the development of SLE (Bariety et al., 1971; Roman-
Franco et al., 1978; Kasturi et al., 1995). Mercury-induced
autoimmunity (HgIA) shares the same pathogenicity and
clinical manifestations seen in patients suffering from SLE
(Hirsch et al., 1982; Dubey et al., 1991; Mathieson et al.,
1992); the symptomatology is also the same (Jiang and
Möller, 1995; Biancone et al., 1996; Kono et al., 1998).
The experimental development of HgIA relied not only
on the amount and duration of the metal exposure, but also
on the genetic background of the exposed animal (Hultman
et al., 1992; Hultman et al., 1993; Jiang and Möller, 1995;
Kono et al., 1998; Hanley et al., 2002; Pollard et al., 2002).
Murine experiments have demonstrated that autoantibody
specificities and susceptibility to immune complex genera-
tion depend on the H-2 haplotype of the mouse. Evidence
has also pointed to the involvement of non-MHC genes in
HgIA susceptibility. The major histocompatibility complex
(MHC) genes, which in humans are on chromosome 6, are
represented in mice by the H-2 region, found on chromo-
some 17. Immunological studies of various haplotype
strains of mice have revealed significant differences in
susceptibilities to mercury. For example, BALB/c mice of
the H-2d haplotype are highly susceptible to HgIA lympho-
proliferation, although they fail to produce immune-com-
plex glomerulonephritis (ICGN; Jiang and Möller, 1995).
B10.D2 mice are capable of lymphoproliferation and de-
velop less severe ICGN than BALB/c mice, whereas the
DBA/2 strain of mice, also of the H-2d haplotype, is resis-
tant to both lymphoproliferation and ICGN (Hultman et al.,
1992; Jiang and Möller, 1995; Kono et al., 1998; Takeuchi
et al., 1995). It has also been conclusively demonstrated that
lupus-prone strains are particularly sensitive to the induc-
tion of SLE-like disease following exposure to mercury
(Hultman et al., 1992; Takeuchi et al., 1995; Hanley et al.,
2002).
The discovery of potential SLE inducibility on mercury
exposure in humans offers the opportunity for comparison
with data from murine models of SLE. This means that the
identification of potential SLE susceptibility loci in humans
offers the chance to compare data from murine models of
SLE induced by xenobiotics such as mercury. Most SLE
susceptibility loci have been mapped in New Zealand hy-
brid models; at least 12 of which are located outside the
interval containing the murine major histocompatibility
complex, H-2. Three regions commonly noted by linkage
studies in New Zealand models are found on murine chro-
mosomes 1, 4, and 7 (Kono et al., 1994; Morel et al., 1994;
Drake, 1995); these have equivalent syntenies in human loci
(Duits et al., 1995; Salmon et al., 1996; Moser et al., 1998)
that seem to be ethnically distinct (Duits et al., 1995;
Salmon et al., 1996). This finding probably foretells that in
dealing with xenobiotics like mercury, surprises are likely in
genetic MHC and non-MHC SLE susceptibility among dif-
ferent racial groups, and so treatments should be scheduled
accordingly.
Evidence is gradually emerging from HgIA studies that
xenobiotic compounds have a characteristic like mercury
that induces autoimmunity in genetically predisposed indi-
viduals. Because of the public health significance associated
with environmental exposure to mercury, developing a
health advisory/criteria document for this toxic and hazard-
ous metal is important. In this research report we provide
and discuss relevant information on the sources of mercury
and the potential for human exposure; the general health
effects associated with exposure to elemental, inorganic and
organic forms of mercury; immunotoxic, genotoxic, carci-
nogenic, and teratogenic effects of mercury; and dietary
influences on mercury toxicity; as well as important con-
siderations in mercury risk assessment and management.
Such information is critical in developing efficient and
effective strategies for dealing with the health hazard asso-
ciated with mercury exposure.
SOURCES OF MERCURY AND POTENTIAL
FOR HUMAN EXPOSURE
Potential Sources of Mercury
Mercury occurs naturally. However, natural phenomena
such as the erosion of mineral deposits and volcanoes and
human activities such as metal smelting, coal production,
chemical synthesis and use, and waste disposal may lead to
substantial contamination of the environment. Mercury is
present in nature as metallic mercury, mono- and bivalent
inorganic compounds, and organic alkyl, aryl, and alloxy-
alkyl compounds. Three main forms of mercury are found in
the environment: elemental mercury, or quicksilver (Hg0),
inorganic mercury (Hg⫹ and Hg2⫹), and organic methyl-,
ethyl- and phenylmercury. They are widely distributed in
the environment as a result of human activities. Each form
has a different solubility, reactivity, and toxicity (Goldman
and Shannon, 2001; Clarkson, 2002). Between 2700 and
6000 tons of elemental mercury is released per year via
natural means to the biosphere through degassing from the
earth’s crust and oceans. Industrial wastes and the combus-
tion of fossil fuels add up to an additional 2000 –3000 tons
of mercury to the environment (ATSDR, 1999).
Industrial discharges of mercury to waterways as ele-
ment or inorganic salts have been common practice. It was
universally thought that these discharges were innocuous

because mercury appeared to sink and remain bound to
sediments. Later it was discovered that certain microorgan-
isms in these deposits are capable of converting metallic
mercury as well as inorganic salts to organomercuric com-
pounds by methylation process (ATSDR, 1999). Methyl-
mercury (MeHg), which is a common organic form of
mercury, tends to bioaccumulate in successive order in the
aquatic food chain: from plankton and algae to herbivores
and finally to the top fish predators such as sharks and
fish-eating marine mammals. A similar sequence exists in
freshwater bodies, with such species as pike and bass having
some of the highest levels of MeHg contamination. Recent
use of the autometallography (AMG) technique by Woshner
and group (2002) confirmed that marine mammals do con-
centrate inorganic elements, particularly mercury, in their
tissues to the point of toxicosis. Although this technique is
considered semiquantitative (Danscher et al., 1994), using it
with beluga whales showed they had significantly higher
hepatic concentrations of total Hg [mean total Hg ⫽ 23.49
and 4.97 ␮g/g wet weight (ww) in liver and kidney, respec-
tively; n ⫽ 24] than did bowhead whales, which had
consistently low Hg levels [mean total Hg ⫽ 0.06 ␮g/g ww;
n ⫽ 55]. The disparity in patterns of tissue Hg accumula-
tions between the two whale species was attributed to dif-
ferences in the trophic levels they occupy (Woshner et al.,
2001). Liver sections of beluga whales exhibited AMG Hg
granules with marked zonal distribution, clearly reflecting
initial accumulation around portal triads with progressive
dissemination around all 3 lobular zones as hepatic Hg
concentrations increased with age. This contrasted with
similar studies in sledgedogs, which demonstrated greater
Hg-catalyzed AMG granule aggregation in the centrilobular
regions of the liver (Hansen and Danscher, 1995). This
finding suggests the existence of interspecific variation in
mechanisms of mercury deposition. The outcomes from
most studies in this field indicating the cellular and intra-
cellular pattern of AMG granule deposition and the absence
of granules in hepatocytic nuclei suggest that the majority of
Hg present was originally in organic form, a finding very
consistent with other food web sources (Rouleau et al.,
2000). It was also found that macrophages contain aggre-
gates of AMG granules, attesting to the importance of these
cells in Hg toxicodisposition (Woshner et al., 2002). It has
been calculated that in belugas a total Hg level of up to
⬃5 ␮g/g ww can be detected in the mesenteric lymph
nodes, yet among ringed seals, nodal total Hg was found to
be minimal (Woshner et al., 2002). The results of these
studies have led to the belief that the reticuloendothelial
system might represent the main site for degradation of
MeHg to inorganic Hg (Suda and Takahashi, 1990).
The potential for bioaccumulation in aquatic food chains
was demonstrated in two outbreaks of human poisoning in
Japan (Clarkson, 1997). Methylmercury released into a
large ocean bay bioaccumulated to such an extent that the
local fish population contained levels of MeHg that proved
ENVIRONMENTAL EXPOSURE TO MERCURY 153
to be lethal to the consumers (CHA, 2001). Organomercuric
compounds are vastly more toxic than metallic or inorganic
mercury because they are lipophilic and can penetrate the
blood– brain barrier (BBB) to cause toxicity to the nervous
system (ATSDR, 1999).
Biogeochemical Cycling of Mercury
Through the processes of biomethylation and bioaccumula-
tion, MeHg finds its way to most species of fish and fish-
consuming animals (Clarkson, 1997; CHA, 2001). Many
anthropogenic sources have been identified (Fitzgerald and
Clarkson, 1991). Chloralkali plants discharge inorganic
mercury as waste into rivers, lakes, and ocean bays. Paper
pulp factories likewise discharge a variety of mercury com-
pounds used as slimicides. Contamination of aquatic sedi-
ments now occurs worldwide because of extensive gold-
mining operations (Cleary, 1990). Large quantities of liquid
mercury are used to extract the sedimentary gold found in
riverbeds. Pure gold is recovered when the mercury is
evaporated from the amalgam by heating. It has been esti-
mated that more than 130 tons of mercury have been re-
leased annually into the Amazon basin alone (Cleary, 1990).
The global cycling of mercury begins with the evapora-
tion of mercury from land and sea surfaces. Volcanoes can
be an important natural source (Cleary, 1990; Richardson,
1992). The burning of fossil fuel, especially coal and mu-
nicipal waste incineration, is a major anthropogenic source
to the atmosphere. Mercury vapor, a chemically stable
monoatomic gas, is estimated to have a residence time of 1
year in the general atmosphere (Clarkson, 2002). It is there-
fore globally distributed even from point sources. Through
processes yet to be fully clarified, the vapor is oxidized in
the upper atmosphere to water-soluble ionic mercury, which
is returned to the earth’s surface in rainwater. This global
cycling of mercury results in the distribution of mercury to
the most remote regions of the planet.
Lichens have been utilized as biomonitors of mercury
pollution from gaseous emissions (Richardson, 1992) as
well as from wet and dry depositions (Bargagli et al., 1987).
Lichens take up appreciable amounts of mercury within 4
weeks and accumulate levels close to equilibrium within
8 –16 weeks (Bargagli et al., 1987). The concentration of
mercury in lichens has been used to make an overall esti-
mation of mercury deposition and vapor absorption at point
sources over an extended period. Seasonal influences such
as temperature variation and wind direction affect levels of
mercury in lichens. High levels of this pollutant are found in
lichens gathered close to the source, with a near-exponential
decline in levels within a short distance followed by a
slower decline to background levels (Barghigiani et al.,
1990). Barghigiani and his group found that mercury con-
centrations in lichens are higher than in soil when ambient
mercury concentrations are low, but lower in Hg-mineral-
154 TCHOUNWOU ET AL.
ized (cinnabar) areas; mercury concentrations were found to
vary also between lichen species (Barghigiani et al., 1990).
This indicates that mercury is stable in soil and that the
atmosphere is a rich source of mercury absorbed by lichens.
Concentrations of mercury at any given location are higher
in epiphytic lichens than in mosses and many other life
forms (Loppi and Bonini, 2000). Other investigators, in-
cluding Steinnes and Krog (1977), pointed out that chlor-
alkali plants constitute major sources of Hg emissions to the
air. Sampling from lakes and rivers around the United States
in 1970 found that about 19% of the waterways are con-
taminated with mercury, with a low median value of less
than 0.5 parts per billion (Nriagu and Pacyna, 1988).
Production and Uses of Mercury
Methyl- and ethylmercury compounds were first synthe-
sized in London in the 1860s (Nriagu and Pacyna, 1988). In
the late 1880s diethylmercury was first used in the treatment
of syphilis, a practice that was later stopped because of the
toxic properties of this agent. However, early in the 20th
century the discovery of the fungicidal properties of the
short-chain alkylmercury compounds led to commercial ap-
plications in agriculture. These compounds were especially
effective in treating a plant root disease in wheat caused by
Telletia triticia. By 1914 many different organic mercury
compounds were in use primarily to prevent seed-borne
diseases of cereals and seed grains (WHO, 1990; Clarkson,
1997). The ethylmercury fungicides were used effectively
and safely for several decades. However, a number of
outbreaks of poisoning occurred in some developing coun-
tries; two outbreaks happened in rural Iraq in 1956 and 1960
from the misuse of ethylmercury toluene sulfonilamide (Je-
lili and Abbasi, 1981).
Thimerosal, a form of ethylmercury (EtHg), commonly
known under various household names as methiolate, mer-
bromin, or mercurochrome, was routinely used as an anti-
septic (Hammond, 1971; Tan and Perkin, 2000) and for
topical applications (Pier, 1975). It was also used as an
effective vaccine preservative and as biological agents for
medical therapy as well (Zhang, 1984). The EtHg in thimer-
osal undergoes a fast dissociation in the presence of endog-
enous thiol groups within cells and tissues. Research has
shown that the types of anions attached to the alkylmercury
radical make little difference to its ultimate disposition in
the body (ATSDR, 1999). These include anions such as
hydroxyl-, cyanide-, and even thiol-containing propane di-
olmercaptides. Such findings suggest that mercury radical
rapidly dissociates from anions in the parent compounds to
attach to ligands in tissues, which may partly indicate the
role of the methyl group in the high lethality associated with
MeHg poisoning (ATSDR, 1999). The discovery of these
properties of mercury compounds led to the assumption that
the administration of thimerosal also resulted in the imme-
diate release of the EtHg to tissues. Such presumptions
prompted the idea that adjuvant-containing vaccines were a
threat to public health. It was calculated that exposure from
a single vaccination dose potentially could exceed federal
guidelines for the mercury reference dose. Routine immu-
nizations could possibly yield a cumulative dose of up to 75
␮g of mercury by 3 months of age and 187.5 ␮g by 6
months of age. Therefore, the American Academy of Fam-
ily Physicians, the Advisory Committee on Immunization
Practices, and the U.S. Public Health Service issued a joint
recommendation that thimerosal be removed from vaccines
(CDC/AAFP/AAP/ACIP, 2000), and its use as a preserva-
tive in vaccines for childhood immunization schedules has
been banned.
In the United States phenylmercury compounds have
been used as pesticides to prevent mildew growth on walls
and as preservatives in latex paints to prevent discoloration
from the growth of microorganisms. Phenylmercury and
EtHg continue to be used as bacteriostatic agents for various
topical pharmacologic preparations (Zhang, 1984). Dimeth-
ylmercury is used only in research laboratories. It is highly
toxic and can cause death at low levels of exposure (Nier-
enberg et al., 1998).
HEALTH EFFECTS ASSOCIATED WITH
MERCURY EXPOSURE
Elemental Mercury
Physical and Chemical Properties
Elemental mercury (Hg0) has the following characteristics:
valence of 1 or 2; atomic number of 80; atomic weight of
200.59; melting point of ⫺38.87°C; boiling point of
356.58°C; and density of 13.546 g/mL at 20°C (ATSDR,
1999). It is liquid at room temperature and is not well
absorbed in the gastrointestinal tract. It has a silvery-white
shiny appearance and at 20°C has a high vapor pressure,
enough to equilibrate in air to reach concentrations 130
times the maximal industrial allowance of 0.1 mg/m3 (Hu,
2000). Only 6 ␮g of mercury in the air is required to reach
ASTDR’s minimal risk level of 0.2 ␮g/m3 in a 10-ft2 (ca. 30
m3) room. Depending on individual susceptibility and ex-
posure time in such a room, health problems become ap-
parent at a mercury volume of between 40 and 400 nL of
vaporized liquid. Hence, it is a potent, toxic biohazard at
room temperatures. Inhaled vapor easily crosses the pulmo-
nary alveolar membranes to enter the circulatory system,
where it invades primarily red blood cells, the central ner-
vous system, and the kidneys (Clarkson, 1997). Its partial
conversion to HgCl2 allows it to be retained in the kidneys
and the CNS for years. Outside occupational settings expo-
sure to metallic mercury results from broken fever ther-
mometers, but the amount of mercury liberated is usually
small (0.5–2 g mercury, ⬍ 0.15 mL; Tominack et al., 2002).

Large quantities of elemental mercury can be spilled in
school science laboratories, and the attractive nature of
mercury invites pilfering. The greatest biohazard, however,
lies in occupational exposure from the heating procedures
used for its extraction from mercury-rich ores such as cin-
nabar (ATSDR, 1999).
Clinico-Pathological Effects
Inhalation of volatilized vapors of metallic mercury leads to
chemical pneumonitis. Exposure to high levels produces
acute necrotizing bronchitis and pneumonitis with symp-
toms of cough, dyspnea, and chest tightness. Diffuse infil-
trates seen in early chest radiographs progress to pulmonary
edema, respiratory distress, and desquamation of bronchio-
lar epithelia that can end in death from respiratory failure.
The most common signs of toxic presentation in children
are diffuse pruritic rash, believed to be contact dermatitis.
Originally known as acrodyna, this rash is an idiosyncratic
hypersensitivity reaction to mercury at onset of the exposure
(Mathieson et al., 1980; Langford, 1999). It develops into a
painful, poorly defined erythematous papulovesicular erup-
tion, with edema and induration of the palms, soles, and
face. This progresses over a period of weeks into desqua-
matous ulceration, often accompanied by diaphoresis and
increased heart rate and blood pressure. Enhanced hypoto-
nia, itching, burning and severe pain of the extremities,
alopecia, ptyalism or profuse secretions, insomnia, apathy,
and irritability have been observed in children. Painful back
spasms and urination are also common complaints (Clark-
son, 1997). Poor sleeping, sore throat, night sweats and
sweating when not hot are noted symptoms. Pustular follic-
ulitis develops later, followed by a painful groin; severe
constipation and impotence in adults have also been ob-
served. By contrast, less than 0.1% of elemental mercury is
absorbed from the gastrointestinal tract when ingested
(Mathieson et al., 1980).
In contact with tissue and in inhalation, elemental mer-
cury is oxidized to its mercuric ion (Hg2⫹) by the catalase
enzyme within the blood (Pier, 1975). Mercuric ions do not
cross the blood– brain barrier (BBB) very well. This means
they also diffuse less out of the brain. Long-term exposure
to mercury vapor primarily leads to CNS defects (Aschner
et al., 1997). Early nonspecific signs including insomnia,
forgetfulness, loss of appetite, and mild tremor may be
misdiagnosed as psychiatric illness. Continued exposure
leads to progressive tremor and erethism, a syndrome char-
acterized by an intention tremor, excitability, memory loss,
insomnia, timidity, and sometimes delirium, once com-
monly seen in workers exposed to mercury in the felt-hat
industry, giving rise to the expression “mad as a hatter”
(Bittner Jr. et al., 1998). Red palms, emotional lability,
salivation, excessive sweating, and hemoconcentration are
accompanying peripheral and autonomic signs. The urine
and feces are the main excretory pathways of metallic and
ENVIRONMENTAL EXPOSURE TO MERCURY 155
inorganic mercury in humans (Dales et al., 1971; Tan and
Perkin, 2000).
Inorganic Mercury Compounds
Physical and Chemical Properties
Some of the most important mercury salts are mercurous
chloride (Hg2Cl2, or calomel), occasionally used in medi-
cines; mercuric fulminate [Hg(OCN2)], a detonator in ex-
plosives; and mercuric sulfide (HgS, or vermillion), a high-
grade paint pigment (Klassen, 1990). Some inorganic
compounds have been used for generations for antibacterial,
antiseptic, cathartic, and diuretic purposes. They also have
been exploited in a number of consumer products ranging
from teething powders to skin-lightening creams. In the
United States such uses have been prohibited, but these
products are still available on the world market.
Both metallic- and organic mercury– containing com-
pounds are oxidized to inorganic mercury in the liver,
preferentially utilizing hydroxyl radical production. The
intestinal flora can also convert organic mercury to its
inorganic form (Suda and Hirayama, 1992). However, or-
ganic mercury is not transformed appreciably in the body.
Rats and mice treated parenterally with HgCl2 have been
found to exhale metallic mercury vapor (Hammond, 1971;
Rowland et al., 1980). Although only about 10% of ingested
mercury salt is absorbed, it tends to be extremely caustic to
the GI tract. A small amount of dermal absorption occurs as
well. In adults the half-life of ingested mercuric salt is about
40 days. Excretion is mostly fecal. Urinary excretion is
negligible, on the order of 10% or less of total elimination
from the body (Clarkson, 2002), but with chronic exposure
urinary excretion is somewhat greater (Dales et al., 1971;
Tan and Perkin, 2000).
It is known, however, that elemental mercury crosses the
placenta and concentrates in the fetus of a pregnant woman
(Pier, 1975; Koos and Longo, 1976; Aschner et al., 1997);
its conversion to inorganic forms or to making combinations
with sulfur compounds can occur in vivo (Koos and Longo,
1976; Aschner et al., 1997). Studies among pregnant Swed-
ish women indicated a high risk to the fetus. While under-
going dental amalgam treatment in the course of antenatal
management, these women were monitored for exposure to
inorganic mercury (I-Hg) until delivery. In that same period
the dietary intake of freshwater fish, a possible source of
bias, was found to be very low and a negligible source of
mercury intoxication (Ask et al., 2002). The results indi-
cated that the median concentration of I-Hg in the placenta
at the time of delivery was 4 times higher (up to 7 ␮g/kg
b.wt) than that in the maternal blood circulation, and it
increased considerably with an increasing number of dental
fillings. The implication is that I-Hg that bound to the
placenta probably originated from Hg0 released from amal-
gam fillings and oxidized to Hg2⫹ by catalase in the blood.
156 TCHOUNWOU ET AL.
The Hg2⫹ ion may bind to metallothionein that is rich in
cysteine in the placenta (Aschner et al., 1997). In vitro
studies suggest that Hg2⫹ has an effect on the transfer of
amino acids (Kerper et al., 1992), on placenta oxygen con-
sumption (Aschner et al., 1997) and enzyme activity, and on
hormonal secretion (Boadi et al., 1992; Kerper et al., 1992).
Inorganic mercury also accumulates in kidneys, and occu-
pational exposure can cause renal damage. Amalgam fill-
ings and diet are the main sources of exposure in the general
population.
Clinicopathological Effects
The toxic effects of mercurials are universally dependent on
the degree of solubility and specifically rely on the ability to
combine with functional sulfhydryl (-SH) groups in impor-
tant enzymes. The principal syndrome of acute mercury salt
poisoning is stomatitis, or digestive upset. Mercury salts are
very toxic to the kidneys, causing acute tubular necrosis,
immunologic glomerulonephritis, or nephrotic syndrome.
Hence, excessive exposure leads to renal injury. Chronic
exposure primarily involves the CNS, ultimately causing
permanent damage. Symptomatologies of chronic toxicity
include progressive anemia, gastric disorders, salivation,
metallic taste in the mouth, inflammation, and tenderness of
gums and tremors (Urbach et al., 1992; Hu, 2000). Central
neuropathy can also occur from mercury salt exposure.
Acrodynia (painful extremities) was also reported among
infants exposed to calomel teething powders containing
mercurous chloride (Mathieson et al., 1980; Suzuki et al.,
1973). Darkening and loss of teeth may be the final toxicity
associated with some mercury compounds. Common symp-
toms, however, are renal complications, with extensive al-
terations in behavior (Suzuki et al., 1973; Bittner Jr. et al.,
1998).
Organic Mercury Compounds
Physical and Chemical Properties
Naturally occurring mercury derives from the divalent form,
Hg2⫹ which is more stable in association with sulfur in the
mineral ore cinnabar and in fossil fuels such as coal and
petroleum. Once discharged into the atmosphere through
mining and industrial activities, mercury undergoes a vari-
ety of transformations (Tan and Perkin, 2000; Goldman and
Shannon, 2001). Bacteria in lakes, streams, and ocean sed-
iment can convert elemental mercury to its organic com-
pounds, which may accumulate in fish and in the food chain
(Clarkson et al., 1988; Langworth et al., 1991; CHA, 2001).
The methyl, ethyl, and phenyl series are the main organic
forms that have been marketed as industrial compounds,
primarily as biocides and as pesticides. They are also found
in two once-common household antiseptics: mercuro-
chrome (merbromin) and merthiolate (thimerosal; Mathie-
son et al., 1980; Elferink, 1999). Methylmercury is the
best-known organic mercurial because it is the predominant
form of organic mercury found in the environment and has
been known to be toxic for centuries (Goyer, 1996). Con-
sumption of contaminated fish is the primary route of hu-
man exposure to organic mercury. Methylmercury appears
in human milk. In the blood MeHg has a mean half-life of
40 –50 days (range: 20 –70 days) for adults from atmo-
spheric inhalation or ingestion. Ninety percent of MeHg is
excreted in feces through bile (Zhang, 1984). Phenylmer-
cury is rapidly metabolized. Its effects are similar to those of
mercury salts (Suzuki et al., 1973; Urbach et al., 1992;
Bittner Jr. et al., 1998; Hu, 2000).
Clinicopathological Effects
It has been known for centuries that methylmercury is toxic
(Mathieson et al., 1980; Sager et al., 1984; WHO, 1990). In
addition, it has been reported to be neurotoxic, particularly
in children. It inhibits in vitro microtubule formation and
protein synthesis in neurons, alters membrane activity, and
disrupts DNA synthesis (Goyer, 1996). Within cells it im-
pairs mitosis and interferes with neuronal migration (Goyer,
1996). Prenatal or postnatal exposure to MeHg adversely
affects the CNS but seems to be most neurotoxic prenatally
in the course of brain development (Choi et al., 1978;
Albers et al., 1988). Exposure to high levels of MeHg
causes mental retardation, cerebral palsy, seizures, and ul-
timately death (WHO, 1990; Bittner Jr. et al., 1998). The
toxicity of organic mercury compounds depends on the
specific compound, route of exposure, dose, and age of a
person at the time of exposure. The overt clinical effects
resulting from toxic exposure to mercury have been de-
scribed. Fatal ingestion usually is either inadvertent or with
suicidal intent. Gastrointestinal ulceration, perforation, and
hemorrhage rapidly occur, followed by circulatory collapse.
Breakdown of intestinal mucosal barriers leads to extensive
mercury absorption and distribution to kidneys, causing
severe kidney damage (Eley, 1997; Goldman and Shannon,
2001; Clarkson, 2002; Hanley et al., 2002; Hultman et al.,
1998; Pollard et al., 2002).
The nervous system is more sensitive to mercury toxicity
than any other system in the body. Mercury has also been
associated with arrhythmias and cardiomyopathy. Hair anal-
yses of patients with mercury-induced cardiomyopathy
measured mercury levels 20,000 times higher than in con-
trols (Harada et al., 1998; Frustaci et al., 1999). Other
neurological problems such as tremors, insomnia, polyneu-
ropathy, paresthesia, emotional lability, irritability, person-
ality changes, headache, weakness, blurred vision, dysar-
thria or speech impairment, slowed mental response, and
unsteady gait have been observed (Chang et al., 1995;
Marsh, 1995; Myers et al., 1995; Urbach et al., 1992; Chan,
1998). Many cases have been reported of infants exposed to
phenylmercury used as fungicidal diaper rinse and of chil-

dren exposed to mercury in interior latex paint (Agocs et al.,
1990; Langford and Ferner, 1999). A maculopapular rash,
swollen nodes and painful extremities, peripheral neuropa-
thy, hypertension, and renal tubular dysfunction developed
in affected children (ATSDR, 1999). However, individual
susceptibility to organomercury is poorly understood.
Thimerosal, an ethyl derivative of mercury, has been in
use for many decades, but very little information exists in
the literature regarding its toxicological effects. Most esti-
mates of health risks from thimerosal found in vaccines
stem from extrapolations from findings with methylmercury
(CDC/AAFP/AAP/ACIP, 2000; Bell et al., 2001). Dimeth-
ylmercury requires specialized storage and handling be-
cause of toxicity and penetrating characteristics. Latex
gloves do not afford an effective barrier, and it is absorbed
through the skin. Exposure to only a 400-mg dose can lead
to degeneration in the CNS, particularly in the cerebellum,
to end in death (Nierenberg et al., 1998). Despite the noted
toxic effects of MeHg, there is no consensus among health
professionals as to what constitutes a safe level of exposure
(Bell et al., 2001).
IMMUNOTOXIC EFFECTS OF MERCURY
Mercury-Induced Immune Responses
Many metals, including mercury, have potent cytotoxic
effects on specific types of cells, including those of the
immune system. Exploitation of the cytotoxic property of
metals in medicine has been very well utilized in the past,
especially in the management of rheumatoid arthritis (gold
therapeutic formulations) and in the early treatment of syph-
ilis. Mercury is not only capable of inducing immunosup-
pression but is also able to produce immunostimulatory
signals in many species, humans and rodents included (Pol-
lard et al., 1999). Exposure to mercury causes cell death by
a nonapoptotic process primarily based on cellular morphol-
ogy (Kass et al., 1990). The prelethal phase imitates oncosis
and occurs within the first 2 h of exposure (Pollard et al.,
2002). Proteolytic degradation of fibrillarin is characteristic
of the prelethal phase of HgIA. Fibrillarin is a 34 kDa
protein component of small nucleolar ribonucleoprotein
particles (snRNPs), and its degradation takes place in mac-
rophages. The most likely source of novel fibrillarin cleav-
age products is phagocytes that accumulate necrotic debris
after toxic contact with mercury. Mercury concentrates in
such an environment and causes cell death. Cleavage by cell
proteases perpetuates the rise of new antigens. Further
phagocytosis leads to the potential processing and presen-
tation of antigens to T cells to elicit autoimmunity. T-cell
proliferation and cytokine release, including IL-1 secretion
by peritoneal macrophages, following HgCl2 exposure have
been observed (Biancone et al., 1996). It has also been noted
that necrotic rather than apoptotic cell debris is activated in
ENVIRONMENTAL EXPOSURE TO MERCURY 157
murine macrophages and dendritic cells; this supports the
idea that HgCl2-induced cell death (HgICD) contributes
immunogenic complexes capable of breaking immunologi-
cal self-tolerance (Biancone et al., 1996).
Mercury-Induced Antibody Synthesis
Hirsch and colleagues (1982) isolated a range of antibodies
after injecting Brown-Norway (BN) rats with 0.1 mg of
HgCl2/100 g of body weight 3 times weekly for variable
periods ranging from 11 to 25 days. The antibodies detected
included antiglomerular monoclonal antibodies (mAbs) of
IgM isotype mAbs of IgE, mAbs against mitochondrial
antigens, antinuclear antibodies of IgM isotype, IgE mAbs
of no detectable specificities, and others that reacted with
single-stranded DNAs (ss-DNA; Hirsch et al., 1982). Other
investigators have confirmed that mercury can induce a
large spectrum of autoantibodies through polyclonal B-cell
activation (Frustaci et al., 1999). Features associated with
HgIA are not dissimilar from the manifestations of SLE;
these include lymphocyte proliferation (Hirsch et al., 1982),
high association with specific class II MHC gene expression
(Dubey et al., 1991), hypergammaglobulinemia (Bariety et
al., 1971), polyclonal Abs to self Ags, production of anti-
nuclear Abs, AnoA Abs (Bariety et al., 1971; Hirsch et al.,
1982; Dubey et al., 1991), ICGN (Bariety et al., 1971), and
necrotizing vasculitis (Mathieson et al., 1992). Autoanti-
bodies similar to those that lead to glomerulonephritis in
humans have been found in drug and substance abusers
(Clarkson, 1972; Pollard et al., 1999). Most findings on the
role of mercury in such immune reactions have been in the
murine species (Biancone et al., 1996; Pollard et al., 1997;
Kono et al., 1998; Pollard et al., 1999; Hanley et al., 2002;
Pollard et al., 2002), however, and clinical manifestations of
HgIA are also similar to spontaneous SLE in humans
(Hirsch et al., 1982).
For induction of the autoimmune state, it has been de-
termined that T cells, CD40/CD40 ligands, and B7/CD28
costimulatory molecule interactions are required (Biancone
et al., 1996; Kono et al., 1998). HgIA susceptibility is also
strongly influenced by the MHC, with specific class II
haplotypes determining autoantibody specificity and disease
severity (Fillastre et al., 1988; Dubey et al., 1991; Hultman
et al., 1993). Some of the susceptibility genes map to the
MHC region (Hultman and Enestrom, 1987). RT-1n rats are
susceptible, whereas rats with RT-11 haplotypes are resis-
tant (Sapin et al., 1984; Eneström and Hultman, 1995).
A.SW mice and others that carry the H-2s haplotype show
high susceptibility to Hg-induced autoantibodies, whereas
C57BL/6 strains (H-2b) are less susceptible. DBA/2 mice
strains bearing H-2d haplotypes are not responsive, whereas
H-2k-bearing mice show intermediate susceptibility (Dubey
et al., 1991; Hultman et al., 1993; Jiang and Möller, 1995;
Kono et al., 1998). The AnoA Abs response directed against
fibrillarin is one of the most representative manifestations of
158 TCHOUNWOU ET AL.
HgIA linked to H-2s (Hanley et al., 2002; Hultman et al.,
1992; Hultman et al., 1993; Pollard et al., 2002) and, more
specifically, to the class II I-As molecule by analysis of H-2
congenic mice (Pollard et al., 2002).
Other genes are believed to participate in the process,
which is highly supported by only certain strains of rats and
mice being subject to the induction of autoimmune reactions
with mercury (Hultman and Enestrom, 1987). Although
several studies have clearly shown genetic susceptibility to
autoimmune induction to be partly controlled by MHC-
linked genes (Sapin et al., 1984; Dubey et al., 1991; Hult-
man et al., 1992; Hultman et al., 1993; Jiang and Möller,
1995; Biancone et al., 1996), the detailed mechanism of the
involvement of another, non-MHC genetic control of re-
sponsiveness is still speculative. A strong genetic control
exists for the development of autoimmune manifestations
both in rats and in mice injected with HgCl2 (Sapin et al.,
1984; Hultman et al., 1992; Eneström and Hultman, 1995).
However, DBA/2 mice of the H-2d haplotype that do not
respond at all to HgCl2 manipulations because of failure to
generate autoimmune reactions (Hultman et al., 1992; Jiang
and Möller, 1995; Takeuchi et al., 1995; Kono et al., 1998)
can still be induced in spleen cultures to yield a low prolif-
erative response with HgCl2 injections (Hultman et al.,
1992). Although BALB/c (H-2d) mice fail to produce anti-
nuclear Abs under HgCl2 treatment, they do develop auto-
immune reactions measurable by significantly increased
levels of Igs in serum and high renal immune complex
deposits, including granular mesangial and systemic vessel-
wall IgG and deposits of C3, the third and central comple-
ment protein (Eneström and Hultman, 1995). This means
that BALB/c mice are actually high responders to mercury
(Hultman et al., 1992). The contradiction is that both DBA/2
and BALB/c mice share the same H-2d haplotype. There-
fore, their respective opposite susceptibilities to autoim-
mune disorders after HgCl2 injections and different respon-
siveness under in vitro stimulation indicate that genetic
susceptibility is influenced not only by the MHC loci but
also by the involvement of other genes present outside the
MHC complex. The non-MHC background genes obviously
differ a lot between the two strains; and the effects of
environment need to be elucidated (Hultman et al., 1992).
Jiang and Möller (1995) determined that the significant
difference in the in vivo induction of autoimmunity between
the responder BALB/c strain and the nonresponder DBA/2
strain could be attributed to the ability of their T-cell sub-
populations to undergo transformations with HgCl2 expo-
sure. Only CD8⫹ T cells undergo transformation in DBA/2
spleen cells on stimulation with HgCl2, whereas both CD4⫹
and CD8⫹ T cells enlarge in BALB/c spleen cells (Hultman
et al., 1992; Jiang and Möller, 1995). Transformed TH cells
play critical roles in the development of autoimmunity
induced by mercury; and these helper TH cells may further
assist in inducing B cells to produce autoantibodies and
finally immune complex-mediated glomerulonephritis. In-
jections of HgCl2 in murine species can cause differential
appearance of TH1/TH2 cell populations, with TH1 high in
responders and TH2 increases in nonresponders (Hultman et
al., 1992). These TH1/TH2 cells are CD4⫹ T lymphocytes
(helpers) that arise in response to antigenic stimulation
(Sapin et al., 1981; Pietsch et al., 1989). TH1 cells produce
IFN-␥, IL-2, and TNF-␤. They have receptors for IL-12R␤
on their membrane surfaces; and they promote cellular
immune responses (Kono et al., 1998; Szabo et al., 1997).
Helper TH2 cells produce IL-4, IL-5, IL-6, IL-10, and IL-13,
express IL-4-related GATA-3 transcription factor, IFN-␥R
␤ (Hultman et al., 1993; Zheng and Flavell, 1997), and the
CCR3 chemokine receptor (Sallustro et al., 1997), and pro-
mote humoral immune responses. Therefore, the dominance
of one or the other of the TH pathways in an immune
reaction results in either a predominantly cellular (TH1-
mediated) or a mainly Ab (TH2-mediated) response. Both in
vitro (Mosmann et al., 1986; Pelletier et al., 1986) and in
vivo (Mosmann et al., 1986; Bottomly and Constant, 1997;
Hultman et al., 1998) shifts to either of these responses have
been reported, although most immune responses involve the
participation of both TH1 and TH2 responses, depending on
the immunogen used.
Mercury-induced autoimmunity is one of the autoim-
mune models in which TH1/TH2 imbalance has long been
thought to play a critical role (Hirsch et al., 1982; Sapin et
al., 1984; Mirtcheva et al., 1989; Dubey et al., 1991; Jiang
and Möller, 1995; Biancone et al., 1996). Although the
mechanism by which mercury modifies the immune system
is obscure, it is known that cationic mercury has a high
affinity for sulfhydryl groups as its principal site for binding
and also has a substantial affinity for amines and phospho-
ryl, carboxyl, and hydroxyl groups (ATSDR, 1999). Mer-
cury therefore can form ligands with proteins and can form
complexes capable of activating the immune system. Some
of the modified proteins may have epitopes closely resem-
bling self-immunogens, easily leading to autoimmune dis-
orders in predisposed individuals (Takeuchi et al., 1995;
Pollard et al., 1997; Pollard et al., 2002). The activation of
CD4⫹ and CD8⫹ T cells requires a prior induction of
antigen-presenting cells (APC; Jiang and Möller, 1995).
Mercury binds to molecules on accessory APC cells and
transform molecules on these cells to superantigens capable
of activating T cells with a particular set of V␤ Ag-binding
receptors (Jiang and Möller, 1995). Mercury-induced auto-
immunity therefore utilizes a different mechanism from that
induced by polyclonal cell activators (PCAs), such as
pokeweed mitogen (PWM), where T-helper cells are not a
prerequisite. The presence or absence of IFN-␥ on re-
sponder or nonresponder TH1 and TH2 cell types, respec-
tively, is thought to be a necessity for whether the response
occurs or does not occur, respectively (Kono et al., 1998). It
is contended that the balance between TH1 and TH2-type
responses does not contribute directly to autoimmune sus-
ceptibility. IFN-␥ is required for the activation of the im-

mune system to respond to poor antigenic determinants,
including both self and nonself Ags involving humoral and
cellular autoresponses. Differences in the dose levels of
IFN-␥ appear to contribute directly to disease susceptibility.
Immunization with high doses of Ag and a strong adjuvant
tend to bypass the IFN-␥ requirement (Ferber et al., 1996;
Jones et al., 1997). Similarly, a strong genetic predisposition
may decrease the threshold for susceptibility enough to
outweigh the IFN-␥ requirement (Abbas et al., 1996). Sus-
ceptibility to autoimmune disease therefore is a multistep
process with many stages or checkpoints, considering the
clinical findings in SLE patients (Andre et al., 1996; Hult-
gren et al., 1996; Manoury-Schwartz et al., 1997; Vermeire
et al., 1997). The IFN-␥ requirement for autoantibody pro-
duction, as an example, defines a checkpoint at the initiation
of the autoimmune process with the potential to distinguish
self from nonself. Understanding the complex lupus genes
by probing into the biology and mechanisms of lupus patho-
genesis will certainly provide important opportunities for
enhancing diagnostic procedures, therapeutic treatments,
and the possible means of preventing this genetically com-
plicated autoimmune disorder. Murine studies that have
induced autoimmunity with mercury therefore have a pro-
pensity to contribute to the understanding of the self/nonself
recognition system within the range of immune responses.
Mercury-Induced Immunosuppression
A peculiar feature of HgIA is that polyclonal B-cell activa-
tion spontaneously disappears despite continuous injection
of mercury (Roether et al., 2002). The mechanism or mech-
anisms are not well clarified for autoregulation of HgIA in
susceptible rats and mice. HgIA normally has the charac-
teristics mentioned previously, that is, T-cell-dependent
polyclonal B-cell activation that culminates in increased
serum levels of immunoglobulin (IgG1 and IgE), produc-
tion of antibodies of different specificities, and development
of renal IgG deposits. In testing for and analyzing the source
of the spontaneous downregulation of mercury-induced im-
mune/autoimmune responses, it has been found that the
inhibition of HgIA is not a result of general immunosup-
pression because the experimental animals were still capa-
ble of responding to different or unrelated antigens (Roether
et al., 2002).
Mercury-susceptible SJL (H-2s) and -resistant DBA/2
(H-2d) mice were injected with mercury for 4, 10, 15, and
17 weeks. Immune and autoimmune responses were moni-
tored in these mice. Thereafter, the mice injected with
mercury for 17 weeks were further immunized with horse
red blood cells (HRBC) in order to monitor the subsequent
humoral immunosuppressivity if any, to a foreign antigen.
Except for IgG1 antinucleolar antibody production and re-
nal IgG1 deposition, other characteristics of HgIA were
downregulated in the SJL (H-2s) mice after chronic treat-
ment with mercury (Roether et al., 2002). However, com-
ENVIRONMENTAL EXPOSURE TO MERCURY 159
pared with naive mice, these mice did not show any decline
in the number of spleen plaque-forming antibody-secreting
cells and/or diminution of serum titers of specific IgM,
IgG1, and IgG2 anti-HRBC antibodies in response to
HRBC (Hanley et al., 1997). Similarly, in mercury-resistant
DBA/2 (H-2d) mice, chronic treatment with mercury did not
suppress total specific antibody responses against HRBC.
Immunosuppression appeared to be under MHC gene con-
trol because there was no general immunosuppression;
rather, it was found to be an intrinsic property of B cells
(Hanley et al., 1997, 2002). This was reinforced by recent
findings that F1 generation of hybrid mice carrying the s and
b haplotypes are resistant to HgIA because they fail to
synthesize antifibrillarins, which are antinucleolar autoanti-
bodies (AnoAbs) induced with mercury injections (Hanley
et al., 2002). The F1 generations were the result of crosses
between sensitive H-2s and resistant H-2b haplotypes. The
results contradicted theoretical expectations because the I-A
molecule is codominantly expressed in F1 mice; and in other
autoimmune models heterozygosity of class II was found to
enhance autoimmunity or moderately affect Ab titers (Nyg-
ard et al., 1993; Hultman et al., 1995a,b). The F1 hybrids of
the H-2s/b strains were found to be resistant to AnoAb
production when injected with mercury. From results of
adoptive bone marrow transfer studies this resistance to
mercury appeared to be an intrinsic characteristic of H-2s/b
(heterozygous) B cells in relation to AnoAb production
(Hanley et al., 2002).
In the DBA/2 strain of mice that are resistant to HgIA
despite expressing a susceptible H-2 (H-2d) haplotype, for
example, the expression of the Hmr1 locus genes has been
shown to be very complex. The Hmr1 locus, a single major
quantitative trait locus on chromosome 1, contains several
lupus susceptibility genes (Kono et al., 2001). The com-
plexity is thought to be an intrinsic property of the B cells’
resistance to HgIA (Hanley et al., 2002). This information
supports that non-MHC genes are involved in HgIA because
the genes for MHC expression in mice are on chromosome
17. It has also been shown that epistatic interaction of the
Sle1, also found on chromosome 1 of the New Zealand
model of SLE, and FASlpr, the CD95 genes, has an additive
production of lymphosplenomegaly with increased numbers
of activated CD4 T cells, CD4⫺CD8⫺ double negative
(DN) T cells, and B1a cells and high levels of IgG and IgM
antinuclear (including anti-ssDNA, anti-dsDNA, and anti-
histone/DNA) and antiglomerular autoantibodies (Shi et al.,
2002). The Sle1 itself is a potent locus that triggers the
formation of IgG antihistone/DNA antibodies when ex-
pressed on the B6 background as a congenic interval (Shi et
al., 2002). Above all, histological and clinical evidences of
glomerulonephritis induced in NZM2410 strains of mice
resulted in more than 80% being fatalities within 5– 6
months; this confirms the presence of non-MHC genes with
the added influence of susceptibility and resistance genes to
HgIA (Stiller-Winkler et al., 1988; Pollard et al., 1997). It is
160 TCHOUNWOU ET AL.
highly probable that xenobiotic compounds in general and
mercury in particular induce autoimmunity in genetically
predisposed individuals. More investigations are needed to
define genetic alterations and mechanisms responsible for
the Hmr1 phenotype in order to deduce the relationship
between the environment and genetic susceptibility in-
volved in autoimmune diseases.
A marked increase in IL-4 production is also a known
feature of HgCl2-treated mice (Ochel et al., 1991; Van Vliet
et al., 1993; Gillespie et al., 1995). T-cell help is required in
this model because nude mice with an H-2s background fail
to develop autoantibodies (Hultman et al., 1992, 1995a).
High levels of IL-4 messenger RNA (mRNA) have been
detected in the splenic CD4⫹ T cells of HgCl2-treated H-2s
mice, whereas those of H-2d mice showed only a weak
increase (Van Vliet et al., 1993). Treatment of H-2s mice
with anti-IL-4 mAbs did not stop AnoAb production but
only altered the isotypes of the autoantibodies (Ochel et al.,
1991). Despite possible noncognate help via cytokines, it
has been demonstrated that B cells require specific MHC
signals from T cells to produce AnoAbs (Hanley et al.,
2002). Lack of responsiveness in HgIA is therefore a prob-
able intrinsic regulatory property of B cells because of
MHC-guided determinant capture arising from MHC mol-
ecules competing for determinants in APC Ag processing
(Sercarz et al., 1993).
Mercury-Induced Immune Responses
and Apoptosis
Abnormal accumulation of autoreactive lymphocytes be-
cause of defective termination of lymphocyte activation and
growth via apoptosis characterizes numerous systemic au-
toimmune diseases (Theofilospoulos and Kono, 1999).
Studies of rodents have clearly indicated a link between
mercury exposure and autoimmune disease. Human case
reports have connected accidental mercury contamination
and autoimmunity (Leonard et al., 1983a; Röger et al.,
1992; Pollard and Hultman, 1997). The characteristic fea-
tures associated with HgIA in rodent models have already
been mentioned. Lymphoproliferation, autoreactive CD4⫹
T-cell generation, T-cell-dependent polyclonal B-cell acti-
vation, hypergammaglobulinemia, high serum IgE levels,
and the synthesis of autoantibodies that proceed on to im-
mune complex–mediated tissue injury and glomerulone-
phritis have all been detected (Bariety et al., 1971; Roman-
Franco et al., 1978; Hirsch et al., 1982; Leonard et al.,
1983a; Röger et al., 1992; Theofilospoulos and Kono, 1999;
Shi et al., 2002).
The mechanism or mechanisms linking mercury and
autoimmunity are poorly understood. Normally cell death
occurs after proteolysis of intracellular proteins, including
nuclear autoantigens. Apoptosis, programmed cell death
(PCD), is a morphological description of cell death that
occurs when there is exposed to many stimuli, including
high levels of mercury and UV light or viral infections.
Apoptosis results in nuclear fragmentation and the accumu-
lation of nuclear autoantigens into cell surface blebs, or
apoptotic bodies (Casiano et al., 1996) and ends up in the
release of intracellular immunogens to the surrounding tis-
sue, which leads to self-Ag presentation and autoimmunity.
Apoptotic bodies contain several self-epitopes, as well as
many components comprising autoantigenic macromolecu-
lar complexes (Pollard et al., 1997; Pollard et al., 2002), and
these molecules are targets for multiple autoantibody re-
sponses. But apoptosis is believed to be a noninflammatory
process (Pollard et al., 2002), and the processing and pre-
sentation of self-Ags as a result of apoptotic cell death
probably contribute more to deletion and tolerance than to
stimulation of autoreactive cells (Roether et al., 2002).
Autoimmunity therefore is considered more likely to be
associated with defective PCD, such as the acceleration of
systemic autoimmunity found in mice with the lpr or gld
mutations (Pollard et al., 2002). That does not exclude
nonapoptic cell death, and the dose of mercury plays an
important role as well.
CD95, also called Fas, is a transmembrane protein that is
a part of the tumor necrosis factor receptor (TNFR) super-
family, whose members are defined by having cysteine-rich
extracellular domains and a homologous cytoplasmic se-
quence termed the “death domain,” capable of interacting to
bring about PCD and/or the mediation of functions that are
distinct from or even that counteract apoptosis (Ashkenazi
and Dixit, 1998). Dysregulation of Fas-mediated apoptosis
is a known factor contributing to the rise of autoimmune
disorders (Takahashi et al., 1994; Casiano et al., 1996).
Some of these proteins are death receptors (DR) associated
with the initiation of apoptosis (Ashkenazi and Dixit, 1998).
The importance of CD95 in immunoregulation is evidenced
by the homozygous CD95 defect in the lpr and gld genes in
mice. Homozygous mutations of the Fas or FasL genes,
affect Fas-induced PCD and cause respectively, lymphopro-
liferation and a generalized autoimmune disease state.
MRL⫹/⫹ mice have autoimmune proliferative syndrome
indicated by massive lymphadenopathy and lupuslike im-
munopathology (Takahashi et al., 1994). The pathogenesis
of the disease is more severe and detected early in MRL
lpr/lpr mice, those with the homozygous CD95 defects
(Watanabe-Fukunaga et al., 1992; Takahashi et al., 1994).
Similarly, humans who have CD95 mutations with an lpr-
like genetic constitution also suffer from a variety of lym-
phoproliferative autoimmune diseases (Fisher et al., 1995;
Le Deist et al., 1996; Dianzani et al., 1997; Puck and
Sneller, 1997; Whitekus et al., 1999). These patients also
have defects downstream in the CD95 death pathway. CD95
and CD95L also are implicated in pathological suppression
of immune surveillance, that is, elimination of tumor-reac-
tive immune cells by certain tumors that constitutively
express CD95L. Thus, defects in the apoptotic-signaling

pathway appear to be linked to autoimmune disease suscep-
tibility.
Mice injected with low concentrations of mercuric chlo-
ride (⬍ 40 ␮M and definitely ⱕ 10 ␮M) end up with
disruption in the CD95-mediated apoptotic cell death path-
way (Whitekus et al., 1999). Mercury has been found to
attenuate CD95-mediated apoptotic cell death; the molecu-
lar target for mercury appears to localize downstream of
agonist binding to CD95 and upstream of caspase-3 activa-
tion. Mercury as Hg2⫹ with its high affinity for free protein
sulfhydryls (Clarkson, 1972) can associate with critical thi-
ols in CD95; by so doing it is likely to inhibit agonist
binding and subsequently affect signal transduction events
(Whitekus et al., 1999). But Hg2⫹ is not known as a com-
petitive inhibitor of CD95 binding, nor does it interfere with
the TNF-/TNF-R interaction (Casiano et al., 1996). The
functional importance of the cysteine-rich sequences in the
extracellular domains of both CD95 and TNF-R is believed
to depend on receptor trimerization required for the appro-
priate propagation of the death signal (Ashkenazi and Dixit,
1998). Like other TNF family members, CD95L is a ho-
motrimeric molecule, and crystal structure studies of its
complexed forms with TNF1 suggest that each CD95L
trimer binds three CD95 molecules (Ashkenazi and Dixit,
2002), leading to clustering of the receptor’s death domains,
which initiates the death process.
Pollard and coworkers (1997, 2002) demonstrated that
mercury-induced cell death (HgICD) led to a proteolytic
cleavage of fibrillarin that was specific to this xenobiotic;
but the generation of a unique (19 kDa) proteolytic cleavage
fragment did not need interaction between mercury and
fibrillarin. Instead, HgICD was associated with a novel
protease activity not detected in other forms of induced cell
death. It was found that xenobiotic-induced cell death pro-
duced novel protein fragments that stimulated self-reactiv-
ity, quite different from that elicited by the full-length
protein (Pollard et al., 2002). Above all, xenobiotic-induced
autoimmunity characterized by autoantibody responses
against native self-Ag did not require preinteraction be-
tween xenobiotic and Ag. The genetically restricted antifi-
brillarin autoantibody response of HgIA was not found to be
directed against a fibrillarin–Hg complex, although a metal–
protein interaction occurred (Pollard et al., 2002). This
finding provides evidence buttressing a longstanding belief
that SLE-prone patients could generate autoantibodies spon-
taneously, even without any physical presence of observ-
able inducers of autoantigens (Pollard et al., 1997, 2002).
From further studies with HgCl2 and VP-16, which is an
apoptosis-inducing etoposide, it was demonstrated that cell
death occurs via both nonapoptotic and apoptotic activities
of proteases that were sensitive to the same inhibitors; but
the cleavage patterns of fibrillarin were different enough to
suggest the action of different proteases (Casiano et al.,
1996; Pollard et al., 1997; 2002). This indicates that the
cleavage patterns for a number of autoantigens differ be-
ENVIRONMENTAL EXPOSURE TO MERCURY 161
tween nonapoptosis (HgCl2, heat, ethanol) and apoptosis-
(anti-Fas) induced cell death (Casiola-Rosen et al., 1995;
Pollard et al., 1997). From such studies it is becoming
apparent that an MHC-restricted autoantibody response and
interaction with HgCl2 are characteristics that differentiate
fibrillarin as an autoantigen in HgCl2-induced autoimmu-
nity. The observation that specific cleavage fragments of
fibrillarin result from HgCl2-induced death and not other
forms of cell death means that novel cleavage fragments
probably act as autoimmunogens. In addition, other effects
of mercury on the immune system including specific cyto-
kine requirements (Ochel et al., 1991; Van Vliet et al., 1993;
Gillespie et al., 1995) and inhibition of Fas-mediated cell
death are possible means of terminating self-tolerance, lead-
ing to the equivalent of the SLE state (Whitekus et al.,
1999).
It was long ago determined that in humans the predom-
inant characteristic of SLE is formation of antinuclear an-
tibodies, particularly against double-stranded DNA
(dsDNA; Berden, 1997). This autoimmune response is T-
cell- and (auto)-antigen dependent. But dsDNA is very
weakly immunogenic. It has been found, however, that the
nucleosome is the principal autoantigen in SLE and that
DNA circulates in SLE patients as nucleosomes. Nucleo-
somes in vivo, on the other hand, are generated through
apoptosis. There is also increasing evidence that apoptosis is
disturbed in human SLE patients (Berden, 1997). Nucleo-
somes have a high affinity for heparin sulfate in the glo-
merular basement membrane (GBM). Through complexes
with nucleosomes, antinuclear antibodies (both nucleo-
some-specific and anti-dsDNA autoantibodies) acquire a
high affinity for GBMs. This is an initial key event in the
development of lupus nephritis. It has been demonstrated
that the pentapeptide Asp/Glu-Trp-Asp/Glu-Tyr-Ser/Gly is
a molecular mimic of dsDNA (DeGiorgio et al., 2001). This
sequence is also found in the extracellular domain of murine
and human NMDA (N-methyl-D-aspartate) receptor sub-
units NR2a and NR2b. The NR2 has been shown to cross-
react with both murine and human anti-DNA antibodies to
mediate the apoptotic death of neurons in vivo and in vitro
(Berden, 1997). Lupus antibodies cross-react with DNA and
NMDA receptors, cross the BBB, and probably mediate
nonthrombotic and nonvasculitic abnormalities of the cen-
tral nervous system (Berden, 1997).
Significance of Mercury-Induced
Autoimmunity
Systemic Autoimmunity
Autoimmune diseases may appear as organ-specific or sys-
temic pathology affecting all tissues of the body, particu-
larly the kidneys. Both forms can be associated with nu-
merous immune pathologies (Theofilopoulos, 1995; Aten et
al., 1998). Epidemiological data have indicated that SLE
162 TCHOUNWOU ET AL.
affects 15–50 of every 100,000 people. The male-to-female
ratio is 3:1 (Hahn, 1994). Between 40% and 50% of SLE
patients, compared to 15% in many healthy ethnic control
groups, have a defective C4AQO, a HLA class III allele that
fails to encode the C4A protein, necessary for the function
of the complement system of proteins (Arnett Jr., 1993;
Hahn, 1994). In some populations specific haplotypes,
B8.DR3.DQ.2 and C4AQO, predispose people to SLE. The
strongest association involves the class II DQB for which
high titers of IgG anti-DNA are associated with lupus ne-
phritis, especially in such combinations as DQ␤1*0201,
0602, and 0302 with DR2 or DR3 (Arnett Jr., 1993). Anti-
bodies to Ro/La (SS-A/SS-B) are associated with dermatitis
of subacute cutaneous lupus and with certain DQA and DQB
genes inherited with DR3 and occasional DR2 (Arnett Jr.,
1993).
Twin studies of SLE patients have confirmed that al-
though genetic predisposition may be required for the de-
velopment of the disease, environmental exposures are im-
portant for its full expression (Deapen et al., 1992; Pollard
et al., 2001). In both animal models (Hirsch et al., 1986;
Pietsch et al., 1989; Guery et al., 1990; Mathieson et al.,
1992; Hultman et al., 1994; Kono et al., 1994; Arnett et al.,
1996; Aten et al., 1998; Pollard et al., 1999) and epidemi-
ological studies (Deapen et al., 1992; Theofilopoulos, 1995;
Pollard et al., 1997) environmental agents such as mercury
have been shown to induce or trigger the autoimmune state.
There is a need to develop and implement appropriate
management and treatment protocols. Animal model studies
help to identify sites for possible drug therapies.
The immunoactivating properties of mercury have been
grouped into three major pathologic sequelae: lymphopro-
liferation, hypergammaglobulinemia, and the development
of systemic autoimmunity manifested as production of au-
toantibody and immune complexes (Pollard and Hultman,
1997). Exposure to Hg accelerates autoimmunity in BXSB
mice (Guery et al., 1990; Pollard et al., 2001). The results of
dose–response studies suggest that environmentally relevant
tissue levels of mercury are able to exacerbate systemic
autoimmunity (Pollard et al., 2001). These studies support
the concept that low-level (⬍ 40 ␮g of Hg/kg of body
weight) exposure to mercury can accelerate idiopathic sys-
temic autoimmunity in genetically susceptible hosts. In ad-
dition, exposure of BXSB mice to either a short course of
high-dose mercury or lower doses over a long period could
trigger systemic autoimmunity. For female BXSB mice,
both the age of initial exposure and the dose of mercury
have been shown to influence the degree of disease exacer-
bation, particularly for antichromatin antibodies (Hultman
et al., 1994; Pollard et al., 2001). Studies with MHC-
identical MRL⫹/⫹ and AKR mice (Pollard et al., 1999)
suggest that both MHC and non-MHC genes contribute
significantly to mercury toxicity. MHC and non-MHC
genes also have both been confirmed to contribute to the
expression of idiopathic systemic autoimmunity (Hirsch et
al., 1982; Theofilospoulos and Kono, 1999). The mecha-
nisms of susceptibility and resistance, though, are still eva-
sive.
Pathogenesis of Autoimmunity by Mercury
Research has shed more light on the mechanisms whereby
mercury induces antibodies against self-antigens. Subtle
differences in the type of immune response generated by
murine species seem to depend on the dose, form, and route
of administration of Hg (Hirsch et al., 1982; Pollard et al.,
1997; Pollard et al., 2002). Mercuric chloride (HgCl2) salt
administered subcutaneously at levels of 40 ␮g of HgCl2 in
PBS twice a week for 10 weeks in SJL/J mice induced the
formation of autoantibodies to fibrillarin (Pollard et al.,
2002).
Analyses of the autoantibody responses to fibrillarin in
murine models of autoimmunity against fibrillarin are sim-
ilar to antifibrillarin responses in a subset of human sclero-
derma disease (Guery et al., 1990; Deapen et al., 1992;
Kasturi et al., 1995; Takeuchi et al., 1995) that also show
genetic restriction (Arnett et al., 1996). It is mapped to the
H-2A region of the MHC complex of H-2s mice (Pollard et
al., 2002; Shi et al., 2002). These antibodies arise via B-cell
responses (Pollard et al., 1999). This finding assists in
probing into the mechanism whereby HgCl2 elicits an au-
toantibody response that is directly targeted to a single
intracellular protein autoantigen. To do so means HgCl2
directly interacts with fibrillarin and/or fibrillarin-containing
snRNPs (the immunogens) by gaining access to the nucle-
olar milieu (Pollard et al., 1997, 2002). This occurs by
cellular toxicity that is nonapoptotically induced by mer-
cury. Mercury-induced cell death has been closely linked to
the loss of fibrillarin antigenicity and an alteration in the
migratory property of fibrillarin from a 34- to a 32-kDa
immunogen under nonreducing sodium dodecyl-Polyacryl-
amide Gel Electrophoresis (SDS-PAGE) conditions (Takeu-
chi et al., 1995; Pollard et al., 1999); this indicates that the
immunogen is somehow modified to a smaller molecule of
32 kDa with a new epitope (Pollard et al., 1999, 2002). The
modification was presumably caused by mutation of cys-
teines to form a disulfide bond in fibrillarin (SOHgOS), a
conformational change that resulted in a neoepitope with a
different antigenicity. The modified 32-kDa immunogen
was found to be a source of T-cell inducers in the process of
generating self-antibody (Pollard et al., 1999, 2002). The
inference is that in the course of metal induced–autoanti-
body formation, especially in HgIA situations, different
types of autoantibodies can be produced, some B-cell de-
rived and others via T-cell help. In genetically predisposed
patients, the generation of autoantibodies may be different
from that generated by nongenetically prone patients. Treat-
ment plans and management schedules therefore are bound
to vary. More work is needed to help to understand and
elucidate the mechanisms leading to genesis of systemically

induced autoimmune states as found in the fibrotic pro-
cesses in scleroderma and the development of SLE disease
in man. Studies with mercury may assist in probing the
pathogenesis of these diseases in humans.
Susceptibility and/or Resistance
to Autoimmunity
Gene analysis has recently partially revealed the complexity
of regulatory mechanisms of autoimmune susceptibility and
resistance. The actual mechanisms whereby genetically sus-
ceptible individuals initially enter into the autoimmune
phase need to be elucidated. Environmental factors are
known to play a major role in the induction phase of
autoimmunity. Xenobiotics including heavy metals such as
mercury (Mathieson et al., 1992; Takeuchi et al., 1995; Shi
et al., 2002), silver (Hultman et al., 1994; Hultman et al.,
1995a), and gold (Pietsch et al., 1989; Schuhmann et al.,
1990) are potent environmental immunostimulants that in-
duce the production of a number of immunopathologic
morbid conditions described earlier: A lymphoproliferation,
hypergammaglobulinemia, and overt systemic autoimmu-
nity; they also promote the production of antifibrillarin
autoantibodies in H-2s haplotype mice (Hultman et al.,
1995a,b). In mice and other experimental animals the MHC
and non-MHC genes, as well as susceptibility to spontane-
ous lupus, influence the predisposition to such metal-in-
duced immunopathology. Of the various mouse strains, the
DBA/2 uniquely lacks susceptibility to HgIA, despite ex-
pressing a susceptible H-2 haplotype (H-2d). In SDF2 inter-
crosses between the DBA/2 strain with either SJL or NZB
strain, both of which are highly susceptible to HgIA, a
single major quantitative trait locus on chromosome 1, the
Hmr1, has been shown to be common to both crosses. The
region also contains several lupus susceptibility loci. Hmr1
has been linked to glomerular immune complex deposits,
not to autoantibody production (Morel et al., 1994; Drake et
al., 1995; Hogarth et al., 1998; Kono et al., 2001). This
suggests that the DBA/2 strain’s resistance to HgIA proba-
bly involves primarily the later genes of disease pathogen-
esis. Research indicates that DBA/2 resistance appears to be
multigenic and largely a result of the effects of the Hmr1
gene and, to a lesser extent, a locus on chromosome 7 (Kono
et al., 2001). Interestingly, the DBA/2 strain is also resistant
to both silver- and gold-induced autoimmunities (Schuh-
mann et al., 1990; Hultman et al., 1995b). These findings
indicate a probable relationship of Hmr1 resistance to mer-
cury-induced disease to broad xenobiotic agents.
GENOTOXIC, CARCINOGENIC, AND
TERATOGENIC EFFECTS OF MERCURY
Mercury is a highly deleterious environmental pollutant
with recognized mutagenic and teratogenic effects, although
ENVIRONMENTAL EXPOSURE TO MERCURY 163
data on the mechanisms of such effects are very sparse and
controversial in the available literature (Leonard et al.,
1983b; Ariza et al., 1994). Mutagenic studies with AS52
cells showed that noncytotoxic concentrations (0.1– 0.4
␮M) of Hg2⫹ mercury caused an increase in mutations of
the gpt gene. These results suggest there may be risks
associated with exposure to noncytotoxic levels of Hg2⫹
(Boffetta et al., 1993). Both genotoxic and nongenotoxic
mechanisms probably contribute to the renal carcinogenic-
ity of mercury (Inouye et al., 1972; Akiyama et al., 2001).
Whitekus and collaborators have shown that in Jurkat cells
cultured in the presence of a CD95 agonist under exposure
to noncytotoxic concentrations of HgCl2 (1–10 ␮M), the
cells continued to proliferate instead of dying (Whitekus et
al., 1999). Although this is interpreted in light of autoim-
mune induction, it also has significance in tumor induction,
or oncosis. It was established that CD95-mediated apoptosis
is attenuated rather than enhanced by inorganic mercury at
the low concentrations specified (ⱕ 10 ␮M) (Whitekus et
al., 1999). It appeared that concentration as well as distri-
bution (ie., extracellular vs. intracellular) of Hg2⫹ are quite
important in evaluating the effects of mercury compounds
on lymphocyte function. Organomercurials such as MeHg
are more membrane permeable than Hg2⫹ and are therefore
more toxic to lymphocytes (Clarkson, 1997); the mecha-
nisms for this toxicity might be different from those work-
ing to decrease the CD95 death pathway by inorganic mer-
cury. Bivalent inorganic mercury (Hg2⫹) binds to multiple
cell surface receptors via free sulfhydryl groups and results
in nonspecific receptor clustering, dysregulated signal trans-
duction, and disorders of cellular function. In fact, the
cytotoxicity of Hg2⫹ has been found to increase markedly
under culture conditions such as supplementation of 2-mer-
captoethanol in which the availability of Hg2⫹ to intracel-
lular targets is facilitated (Whitekus et al., 1999). Therefore,
interference with apoptosis by mercury supports findings
showing that autoimmune diseases are often caused by a
failure to delete autoreactive lymphocytes. Obviously, if
lymphocytes accumulate as lymphomas, then there is a link
to carcinogenesis. Results of recent studies in our laboratory
show that mercury induces cytotoxicity and transcription-
ally activates a significant number of stress genes in human
liver carcinoma cells, including those involved in cell cycle
regulation and apoptosis (Sutton et al., 2002; Tchounwou et
al., 2002).
Heavy metals such as lead and mercury, organic sol-
vents, alcohol, and ionizing radiation are confirmed envi-
ronmental teratogens (Harris et al., 1973). Animal studies
have shown that low levels of mercuric chloride or phenyl
mercuric acetate enter fetal tissues and result in abortion,
growth retardation, subcutaneous edema, encephaly, and
anophthalmia (Nierenberg et al., 1998). Teratogenic effects,
such as cleft lip and palate, rib fusions, and syndactylies
have been seen. Methylmercury compounds are known to
be teratogenic in multiple organs in rats, hamsters, and mice
164 TCHOUNWOU ET AL.
(Harris et al., 1973; Myers et al., 1995). Skeletal malforma-
tions, rib defects, abnormal skeletal calcification, cleft lip
and palate, micrognathia, and clubfeet have all been seen
after mercury intoxication during the fetal period. In non-
pregnant rats methylmercury accumulates in nerve cells
(neuroglia) and nerve fibers. The dorsal root ganglia are
well invaded, whereas the Purkinje cells of the cerebellum,
ventral horn motor cells, and cerebellar granule cells show
fewer invasions. In contrast, mercuric chloride intoxication
is highest in the dorsal root ganglia, followed by the ventral
horn motor neurons, calcarine cortical neurons, and the
granule cells of the cerebellum (Chan, 1998).
DIETARY INFLUENCES ON MERCURY
TOXICITY AND COUNTEREFFECTS
ON DIET
Epidemiological data on the routes of Hg exposure in hu-
man populations indicate that the major sources of MeHg
exposure arise from fish and marine products (Davidson et
al., 1998). It is estimated that fish and fish products contrib-
ute a range of 20%– 85% of the MeHg intoxication in
various populations. Drinking water, cereals, vegetables,
and meat are believed to make important contributions to
MeHg burden in man (Galal-Gorchev, 1993). Dental amal-
gams have been more or less implicated in the release of Hg
vapor (Roberts et al., 2001). The general consensus is that
the daily intake of MeHg comes from its concentration in
foodstuffs and that the naturally present inorganic Hg in the
hydrosphere and biosphere because of acid rain and indus-
trial mining activities and the follow-up biomethylation of
this Hg is a risk for global Hg exposure, which is on the
increase (Fitzgerald and Clarkson, 1991). These reports
mean that for any population the mechanism of total Hg
intake and its effects may be multifactorial and probably
relies heavily on dietary habits for that population (Chap-
man and Chan, 2000). The duration and timing of exposure
to MeHg have been found to be significant critical factors as
well. For instance, the effects of prenatal exposure have
been determined to be more important than the effects of
exposure via breast-feeding in mice (Nielsen and Andersen,
1995). The role of nutrition on MeHg toxicity has generally
been approached from two areas: effects of nutrients on Hg
metabolism and vice versa (Galal-Gorchev, 1993).
Methylmercury is absorbed throughout the intestine; up
to 90% of MeHg crosses most biological membranes (Nors-
eth, 1970). It binds in vivo to proteins such as albumin and
sulfur-containing proteins (Yasutake et al., 1990; Adachi et
al., 1994). In adults recycling occurs in the enterohepatic
system (Norseth, 1970). It is secreted into bile and partly
reabsorbed into portal circulation and thereby returned to
the liver. A fraction of biliary mercury is converted by
microflora to inorganic mercury, which is reabsorbed only
to a small extent (ATSDR, 1999). Massive and prolonged
retention of metallic mercury may facilitate the conversion
of metallic, elemental mercury to divalent mercury and its
subsequent absorption, with the development of hepatic
dysfunction (Lin and Lim, 1993). Most MeHg is eliminated
from the body by demethylation and by excretion of the
inorganic form in the feces. The processes of biliary secre-
tion and demethylation by microflora do not occur in suck-
ling animals. The role of these two processes in suckling
human infants is unknown.
Nutritional factors, not the primary absorption site,
vastly influence the reabsorption rate of MeHg (Yannai and
Sachs, 1993); and a vast variety of foods and nutrients alter
MeHg metabolism. The alkalinity of the environment has
been associated with increased absorption of mercury in the
form of Hg2⫹ ions. Milk may also promote the reabsorption
of MeHg after enterohepatic circulation (Endo et al., 1984).
It is likely that diet affects the absorption of organic and
inorganic Hg (Nielsen and Andersen, 1995) via combina-
tions of different mechanisms. Nutrients do interact with the
metabolism of MeHg at the physiologic level. Nutrients
play important roles in the bioavailability, toxicity, and
dissemination of molecules throughout the organs that are
susceptible. They also influence the biochemical, immuno-
logic, or cytotoxic responses to Hg. Data are lacking, how-
ever, on the mechanism of MeHg toxicity; nutritional mod-
ifiers of mercury toxicity are not well studied. Nutritional
factors, including selenium (Mykkanen and Metsanitty,
1987; Magos, 1991), vitamin C (Solomons and Viteri,
1982), vitamin B (Levander and Cheng, 1980; Bender,
1984), and essential minerals (Levander and Cheng, 1980;
Chowdhury and Chandra, 1987; Zorn and Smith, 1990;
Lugea et al., 1994) have also been implicated in the modi-
fication of MeHg toxicity. However there is not general
agreement on the role these supplements play in the toxicity
of MeHg. No protective or antagonistic effects of dietary
supplements on the toxicity of MeHg to humans have been
clearly established.
Experimental data on animal models have been the main
sources regarding the role of nutrients on MeHg intoxica-
tion. Ethanol is generally known to have a synergistic effect
in the toxicity of MeHg. Mortality from MeHg intoxication
with superimposed ethanol action is known. Ethanol pro-
motes kidney pathogenesis by decreasing the activities of
amino acid transferases and creatine phosphokinases (Rum-
beiha et al., 1992). Selenium absorption is reduced in Se–Hg
interactions (Mykkanen and Metsanitty, 1987), suggesting
that Hg reduces the transfer of selenite from the intestine to
the body but not the transfer of selenium-methionine (Se-
Met). Rather, MeHg disrupts nutrient transport such as the
exchange of Met and Se through the BBB (Aschner and
Aschner, 1990). Fetal uptake of nutrients such as Se, vita-
min B12, and Zn in mice (Danielsson et al., 1984) and
humans (Lin and Lim, 1993) is altered by mercuric ions
(Hg2⫹) during pregnancy. The binding of Hg2⫹ to trans-
membrane thiol groups has been implicated in the decline of

the sugar-Na⫹ phlorizin-sensitive cotransport system, lead-
ing to the inhibition of galactose absorption in rats (Fujinka
and Zasshi, 1987); cysteine reversed this interaction. Cys-
teine is believed to act synergistically with MeHg neuro-
toxicity (Lugea et al., 1994). Methylmercury is transported
in the circulation bound to serum proteins such as albumin
and mercaptoalbumin and enters major organs like the kid-
neys, liver, and brain (Mokrzan et al., 1995) as well as the
placenta and fetus in pregnancy (Davidson et al., 1998). Red
blood cells and epithelial tissues are also invaded in signif-
icant amounts (Norseth and Clarkson, 1970).
L-Leucine, L-methionine, and 2-amino,2,norborane car-
boxylic acid may inhibit the uptake of MeHg through the
amino acid transport system (Mokrzan et al., 1995). MeHg
enters the brain in the form of an L-Cys complex by the
amino acid transport system (Aschner and Aschner, 1990).
Cystine has been implicated as one nutrient that may in-
crease MeHg neurotoxicity, although it can enter other
organs by any one of several transport systems, including
the facilitated D-glucose and the Cl⫺ ion transport system
(Norseth and Clarkson, 1970). The association of MeHg
with small-molecular-weight thiol compounds enhances the
transport of MeHg both into and out of cells (Mokrzan et al.,
1995). In general, diet composition has been shown to affect
the distribution and toxicity of MeHg (Hojbjerg et al., 1992;
Adachi et al., 1994; Hojbjerg, 1996). The percentage of
fiber in the diet affects the retention of Hg; pectin, wheat
bran, and cellulose can alter the ability of microflora to
demethylate MeHg and therefore affect its reabsorption rate.
For example, wheat bran enhances fecal excretion of Hg
after MeHg exposure by increasing the demethylation rate
of MeHg in intestinal flora. Sufficient protein intake pro-
longs survival after oral MeHg dosing (Rowland et al.,
1986).
Minerals
Selenium (Se) plays a protective role against MeHg toxicity
(Mykkanen and Metsanitty, 1987; Magos, 1991). However,
fish and marine mammals, the main sources of Hg in the
diet, also contain a rich source of Se (Mykkanen and Met-
sanitty, 1987; Cuvin-Aralar and Fumess, 1991). Epidemiol-
ogists therefore consider Se an important but unproven
modifier of MeHg intoxication (Tan and Perkin, 2000).
Sufficient intake of Se and Zn may protect against MeHg
toxicity. Selenium, in particular, is found to counteract the
toxicity of other heavy metals including cadmium, thallium,
and silver (Mykkanen and Metsanitty, 1987). Selenium is
believed to delay rather than prevent intoxication from
MeHg (Magos et al., 1984). The mechanisms for delaying
both inorganic and organic mercury intoxication implicate
the formation of Hg–Se complexes, GSH–Se–Hg and bis
selenide (methylmercuric selenide), respectively (Myk-
kanen and Metsanitty, 1987; Magos, 1991). It has been
ENVIRONMENTAL EXPOSURE TO MERCURY 165
suggested that Se modifies MeHg so that the latter is re-
leased from blood proteins (Magos et al., 1984). Zinc has
the effect of reducing lipid peroxidation by enhancing the
activities of enzymes such as GSH peroxidase to repress
mercury-induced neurotoxicity (Gale, 1984; Fukino et al.,
1986). Iron, on the other hand, is noted for reducing MeHg
toxicity; dexoferoxamine, an iron chelator, has been found
to inhibit the MeHg-induced formation of excess reactive
oxygen species in rats’ brains (LeBel et al., 1992).
Vitamins
Vitamins E and C have antioxidant properties and are ex-
pected to negate the formation of active oxygen species
produced in the course of MeHg metabolism (Chang et al.,
1978). Vitamin E protects against ataxia, paralysis of the
hind limbs, and necrosis in the brains of rats and hamsters
(El-Begearmi et al., 1976; Chang et al., 1978); it protects
animals against the effects of organic mercury toxicity but
not against Hg2⫹ toxicity (Chang et al., 1978), and the
protection afforded to animals extends from parent to off-
spring (El-Begearmi et al., 1976; Chang et al., 1978). The
role of vitamin C in mercury toxicity is contradictory at
best. The recovery of enzyme (alpha- and beta-galactosi-
dase) activity after vitamin C treatment of MeHgCl-exposed
mice was found to be incomplete and seemed to be organ
dependent (Vijayalakshmi et al., 1992). There were indica-
tions that although susceptible organs such as the kidneys or
the liver may be relieved of Hg burden, neurotoxicity in
other organs such as the brain is enhanced. Vitamin A was
not found protective against in vivo treatment of MeHg
toxicity; rather, it enhanced MeHg toxicity in in vivo studies
with rats (Bapu et al., 1994).
Combined Nutrient Effects
Research on Hg2⫹ methylation found that simultaneous
exposure to folate, vitamin B12, and ascorbate increases
MeHg in the liver and in hair, whereas the combination of
vitamin C and vitamin B12 increases MeHg in the brain
(Welsh, 1977). Vitamin E and Se seem to have an additive
antioxidant interaction. At low Se concentrations the two
combinations afford synergistic protection against MeHg
(Bender, 1984; Welsh and Soares, 1975). These findings are
now used generally in the management of Hg toxicity.
Doses of 400 IU/day of vitamin E have been shown to have
a protective effect when the brain is exposed to methylmer-
cury (Chang et al., 1978; King and Soares, 1981). Doses of
200 – 400 ng/day of Se are utilized particularly for mercury
elimination in the most intoxicated patients to facilitate the
function of glutathione in mercury detoxification (Levander
and Cheng, 1980; King and Soares, 1981; Hirsch et al.,
1982; Mykkanen and Metsanitty, 1987).
166 TCHOUNWOU ET AL.
Mercury inhibits protein synthesis in general by inacti-
vating enzymes such as aspartate and alanine amino acid
transferases, although MeHg appears to stimulate protein
synthesis in the brain (Solomons and Viteri, 1982;
Kuznetsov, 1987). Mercury exposure is found to alter the
lipid profiles including fatty acid and cholesterol production
(Chowdhury and Chandra, 1987; Bano and Hasan, 1989).
Triglyceride levels declined in the central nervous system of
MeHg-exposed rats, whereas tocopherol levels increased in
serum (Chowdhury and Chandra, 1987). Many enzymes in
carbohydrate metabolism, including glucose-6-phosphatase,
amylase, maltase, and lactase, are inhibited by exposure to
Hg2⫹ (Rana and Sharma, 1982). Calcium channel blockers
(CCBs) alleviate the toxic effects of MeHg on the serum
electrolytes sodium and potassium via their blocking action
(Chowdhury and Chandra, 1987). Sakamoto and colleagues
determined that CCBs prevented a decline in body weight
and neurologic symptoms in rats (Sakamoto et al., 1996).
MERCURY RISK ASSESSMENT AND
MANAGEMENT
Minimum Risk Levels
Currently, health authorities are concerned with the risk
associated with mercury exposure. Because of the possible
teratogenic effects of mercury on humans, health authorities
are faced with the decision of deriving the highest possible
level of oral mercury exposure, the reference dose (RfD),
the level considered to present no risk to the public in
general and to pregnant women in particular. Using an
excretion rate of 1% per day, it was computed that for a
70-kg person a daily Hg intake of 0.3 mg/day would yield
a blood value of 0.2 ␮g/mL, corresponding to the lowest
blood level known to be toxic (ATSDR, 1999). The RfD can
be taken as the dose that can be ingested daily for a lifetime
without a significant risk of adverse effects. With a safety
factor of 10, the daily intake of MeHg was set at 0.03
mg/day for a 70-kg person, corresponding to 0.025 mg/day
for a 60-kg woman. For pregnant women the suggestion is
not to consume fish containing greater than an arbitrary
MeHg concentration of 0.25 ␮g/g and that women of child-
bearing age should not work in areas at risk to MeHg (alkyl)
exposure (ATSDR, 1999).
In general, air concentrations in the workplace above 50
␮g Hg/m3, corresponding to steady-state urinary excretion
rates of creatinine of 60 ␮g Hg/g are associated with fine
tremors in the extremities that frequently are not noticed by
the worker (Kulig, 1998). Slowed nerve conduction velocity
is another preclinical effect found at these lower levels.
Studies on dentists have suggested adverse effects at air
concentrations lower than 50 ␮g Hg/m3 (U.S. EPA, 1997).
Average air concentrations as low as 14 ␮g Hg/m3 were
associated with decreased performance on psychomotor
tests. Follow-up studies of workers previously exposed to
high levels of mercury vapor but not exposed for 10 or more
years prior to being examined revealed that adverse effects
may persist on the nervous system. Mathiesen and col-
leagues examined 70 workers who had been exposed for a
period of 1–35 years, with a mean of 12.7 years. The
average yearly exposure was measured as 8 –584 ␮g Hg/m3
(ATSDR, 1999; Dewailly, 1997). Compared to the perfor-
mance in a control group, these workers showed decreased
performance in a number of neuropsychologic attributes.
Despite these high exposure levels, no residual effects were
observed on general intellectual ability or ability to reason
logically.
Epidemiological evidence derived from studies of the
effects of the environment on the toxic susceptibility of
different communities to MeHg has come from the Amazon
(Lodenius and Malm, 1998), the Seychelles Republic
(Marsh et al., 1995), and the Faroe Islands (Clarkson, 1991;
De Flora et al., 1994). Through the consumption of fish and
other seafood, many populations have been exposed to
equivalent doses of MeHg (Sweet, 2001). Some populations
showed subsequent neurotoxic effects, and others did not
(Gilbert and Grant-Webster, 1995). This observation has
prompted a search for the role of nutritional status of vari-
ous populations in combating or evading drastic toxicolog-
ical effects of MeHg intoxication (Chapman and Chan,
2000). Up to now there has been no clear data as to the best
in vivo nutritional modifier of MeHg toxicity. However, it is
worth noting that MeHg attains its highest concentrations in
the tissues of long-lived edible predatory fish (Inouye et al.,
1972). It is a toxic compound that is well absorbed from the
diet despite having no demonstrable biologic requirement in
humans (Sweet, 2001). This diet has been presumed to be
the main source of exposure in human populations
(ATSDR, 1999). Daily intake of MeHg seems to depend to
a large extent on its concentration in foodstuffs and on the
dietary habits of the consumer.
Currently, the Food and Agriculture Organization (FAO)
and the World Health Organization (WHO) have set levels
considered a tolerable intake as 3.3 ␮g/kg/week or 200
␮g/week of methylmercury based on the level at which
paresthesia presents in adults (Chapman and Chan, 2000).
But the fetus is particularly sensitive to MeHg, even at a
concentration that results in few or no clinical signs of
maternal toxicity (Sweet, 2001). High levels of prenatal
MeHg exposure can induce cerebral palsy, mental retarda-
tion, low birth weight, and early sensorimotor dysfunction
(Gilbert and Grant-Webster, 1995). This has prompted a
further review of reference doses for MeHg in view of its
prenatal developmental effects, infant exposure, and the
important objective of establishing the highest level that can
be considered tolerable for human exposure (Inouye et al.,
1972; Stem, 1993; Chapman and Chan, 2000).
Many regulatory agencies have utilized findings from
two large longitudinal studies of effects of prenatal Hg

exposures from seafood consumption on child neurodevel-
opment; these studies were conducted in the Republic of
Seychelles, where 85% of the population lives on ocean fish
(De Flora et al., 1994; Davidson et al., 1998), and in the
Faroe Islands (Cernichiari et al., 1995; Clarkson, 1991;
Davidson et al., 1998). The Seychelles studies reported
mean maternal hair total Hg level of 6.8 ppm and mean
child hair total Hg level at 66 months of age of 6.5 ppm
(Davidson et al., 1998). No adverse pathology at 66 months
was correlated with prenatal or postnatal MeHg exposure.
The second study, of 1022 singleton births, revealed that at
approximately 7 years of age some of the children in the
study still showed no Hg-related damage after exhaustive
clinical neurophysiological tests (Marsh et al., 1995; Myers
et al., 1995; Davidson et al., 1998). However, subsamples of
112 and 217 children whose mothers had hair Hg concen-
trations of 10 –20 ppm and 7.1 ppm, respectively, were
compared to a subsample of children whose mothers had
hair mercury below 3 ppm. Mild decrements were noted in
the former samples, especially in the domains of motor
function, language, and memory (Davidson et al., 1998).
Based on such findings, Health Canada revised the tolerable
limit of daily Hg intake for women of childbearing age and
infants to 0.2 ␮g/kg of body weight/day (Galal-Gorchev,
1993). The U.S. Environmental Protection Agency (EPA)
set the reference dose for MeHg at 0.1 ␮g/kg of body
weight/day (Stem, 1993; U.S. EPA, 1997; Rice et al., 1999).
The nervous system seems to be most affected in mer-
cury intoxications (Philbert et al., 2000). Because of the
unique structural and functional characteristics of the ner-
vous system, neurotoxicity has features distinct from the
toxic effects in other organs. Neurotoxicants show selective
toxicity for cells or areas of the CNS and peripheral nervous
system, but the mechanisms underlying such selectivity are
relatively evasive. The relationship among the biochemical,
anatomical, and physiological parameters within the ner-
vous system are not fully understood. It is therefore difficult
to evaluate certain biochemical modifications observed in
animals or humans following exposure to neurotoxicants.
Establishing a correlation between mercury level in humans
and toxic reaction in the nervous system has been attempted
in various studies (Clarkson, 1991; Stem, 1993; Gilbert and
Grant-Webster, 1995; Marsh et al., 1995; U.S. EPA, 1997;
Rice et al., 1999; Philbert et al., 2000). Most extrapolations
are made from animal studies, and the findings may or may
not reflect a true state in humans.
In humans functional and pathological nervous tissue
alterations induced by exogenous chemicals can also be
caused by several other unrelated factors including stress,
social environment, and lifestyle. The complexity of these
factors makes the search for biological indicators of neuro-
toxicity a huge undertaking. The most common approach, of
searching for a correlation between Hg concentration in
blood or urine and the appearance of symptoms or electro-
neurographic changes, may not be the best one; most results
ENVIRONMENTAL EXPOSURE TO MERCURY 167
have proved negative (Philbert et al., 2000). It is now
believed that a time-integrated assessment of absorption
may be a determining factor for toxic neuropathies resulting
from prolonged low-level exposures. Therefore, the level of
Hg detected in the hair is now believed to be a more
appropriate but unproven alternative for monitoring Hg
toxicity (Cernichiari et al., 1995).
In pregnancy this presents another level of complication.
No data clearly present the effect of mercury on exposed
pregnant women except retrospective studies arising from
disasters (Amin-Zaki et al., 1981). Estimates of reasonably
safe exposure have been based on pharmacological princi-
ples (Clarkson, 1997; Nierenberg et al., 1998; Philbert et al.,
2000); taking into account the amount ingested, duration of
exposure, excretory rate, and sensitivity. A certain mercury
dose delivered acutely may or may not present with toxic
effects, and the same amount distributed over a period of
time may still give no evidence of mercury poisoning. Yet
there is no certainty that the same dose will present the same
signs and symptoms in two different individuals. Methyl-
mercury accumulates in the body at 100 times the daily
intake at equilibrium (WHO, 1990), and individual varia-
tions in sensitivity to mercury compounds have been ob-
served from epidemiological studies. In Iraq, the half-life of
methylmercury elimination was found to vary from 40 to
105 days, with a mean of 65 days (Bakir et al., 1973;
Amin-Zaki et al., 1974). The body burden at which pares-
thesia in adults could be detected in Iraq varied from 25 to
200 mg. The chemical form of mercury also determines its
toxicity. In mice given intraperitoneal injections acute LD50
values for mercuric chloride, phenylmercury, and methyl-
mercury have been reported to be 5, 8, and 14 mg of Hg/kg
of body weight, respectively (Clarkson, 1997; Nierenberg et
al., 1998). Inorganic mercury appeared to be the most toxic
in acute administration; in humans, however, chronic oral
mercury intake resulting in minimal toxic effects has been
estimated to be 28 mg/day for inorganic salt Hg2⫹, 0.75
mg/day for phenylmercury, and 0.3 mg/day for methylmer-
cury (Philbert et al., 2000).
Apparently there is no clear-cut evidence supporting any
of the safe limits set by the regulatory agencies. Besides, it
is becoming quite clear that a low level of exposure to
mercury may be hazardous to the immune system, as dis-
cussed earlier. Based on the currently available scientific
information on the adverse health effects of mercury, it is
probably safe to say that zero tolerance of mercury may be
the objective for most health authorities and policy makers.
Diagnosis of Mercury Intoxication
Mercury intoxication has been diagnosed primarily based
on history of exposure and symptoms of intoxication. Acute
exposure to mercury vapor can cause coughing, dyspnea,
chest pain, cyanosis, excitement, and tremor (Albers et al.,
168 TCHOUNWOU ET AL.
1988). Chronic exposure may lead to subtle symptoms such
as weakness, fatigue, anorexia, weight loss, and gastroin-
testinal disturbances (Amin-Zaki et al., 1974; Dewailly,
1997; Prati et al., 2002). Inorganic mercury ingestion in-
duces symptoms of acute thirst, metallic taste, nausea, and
abdominal pain, followed by tenesmus, bloody diarrhea,
stomatitis, gastritis, colitis, renal tubule degeneration, and
death (Choi et al., 1978; Albers et al., 1988; Dewailly,
1997). Chronic ingestion results in excessive salivation,
loose teeth, and gingivitis. Neurologic signs include irrita-
bility, nervousness, tremors, and slurred speech. Paresthesia
occurs in the distal extremities with methylmercury intoxi-
cation, followed by fatigue, headache, and neurasthenia.
There is a prolonged interval between exposures to meth-
ylmercury, in particular, and the appearance of symptoms
that last up to several weeks in some cases (Bakir et al.,
1973; Amin-Zaki et al., 1974).
Treatment Schedules
A major challenge is the treatment of pregnant women
exposed to mercury. Ideally, prevention from any further
contact with the source is the first step in management.
Supportive care is given when necessary to maintain vital
functions. More definitive treatment is based on knowing
the type and degree of exposure. In treatment of acute
ingestion of inorganic Hg, dosing with egg whites or milk is
recommended to decrease further absorption of mercuric
ions (Albers et al., 1988). A 5% sodium formaldehyde
sulfoxylate solution by mouth decreases mercury absorp-
tion. The use of dimercaprol (BAL), calcium disodium
edetate, and N-acetyl-D, L-penicillamine assists the body’s
ability to eliminate mercury from the tissues. BAL is useful
for severe systemic poisoning; it combines with mercury
and forms a complex excreted by the kidneys (El-Begearmi
et al., 1976; King and Soares, 1981). BAL use is not
recommended for chronic exposure, however, because it
enhances brain uptake of mercury and has local as well as
systemic side effects. Penicillamine also reacts reversibly
with mercury and is able to break mercury/protein com-
plexes (Philbert et al., 2000). Methylmercury poisoning is
treated symptomatically. Chelators are of limited use be-
cause of adverse side effects. Pyridoxine-5-thiol has been
shown to reduce MeHg concentration in the brain and liver
of poisoned rats; thiol resins effectively increase MeHg
excretion, whereas polythiol resin as 1% concentrate with
food increases MeHg excretion in mice (Vijayalakshmi et
al., 1992).
CONCLUSIONS
Mercury is one of the toxic elements that are widely dis-
tributed in nature. Available scientific data show that the
sources of mercury polluting the environment are numerous
and generally can be grouped into natural processes and
sources originating from human activities. Geogenic pollu-
tion by mercury arises from the earth’s crust and oceans,
erosion of mineral deposits, and volcanoes. Human activi-
ties such as metal smelting, coal production, chemical syn-
thesis and use, and waste disposal are means of adding large
quantities of mercury to the environment. Interconversions
of mercurous species by microorganisms lead to bioaccu-
mulation of mercury. Biomethylation and concentration of
mercury in bodies of water play significant roles in the
spread of mercury throughout the environment.
Problems arising from mercury contamination are en-
hanced when mercury gets into the food chain. Throughout
the world exposure to mercury occurs via ingestion, inha-
lation, dental amalgams, and dermal contact; however, the
food chain seems to be the predominant route of human
exposure to methylmercury, which is the most toxic form of
mercury. These avenues of pollution present great chal-
lenges to public health. Mass outbreaks of mercury poison-
ing in many parts of the world including China, Japan, Iraq,
the former Soviet Union (now Russia), the Seychelles, the
Faroe Islands and Ghana have prompted health profession-
als to take a second look at the public health impact of
mercury toxicity. After the largest outbreak, which occurred
in rural Iraq during the winter of 1971–72, as many as
40,000 individuals were found to suffer from mercury poi-
soning resulting from consuming homemade bread prepared
from mercury-contaminated seed grains. In most cases se-
vere brain damage was detected from prenatal exposure.
These children were found to have difficulties in achieving
developmental milestones at the appropriate time.
Amalgam fillings have also been associated with a vari-
ety of problems such as Alzheimer’s disease, infertility,
food allergies, multiple sclerosis, and thyroid and kidney
dysfunction. Organic mercury compounds are generally
more toxic, with their toxicity centered in the CNS, though
the kidneys and the immune system may also be signifi-
cantly affected. Prenatal and postnatal exposure to mercury
adversely affects the CNS, but toxicity is pronounced from
exposure during the prenatal period, when neurogenesis is at
its height. In adults exposure to mercury can result in visual
and hearing impairment, tremor, and muscle spasticity,
leading to coma and death. One of the most serious threats
from mercury toxicity, however, is insidious, involving the
development of an autoimmune state in genetically predis-
posed individuals. Although mercury is capable of inducing
an immunosuppressive state with continuous exposure, it
also has the ability to cause defects in programmed cell
death that eventually end in the generation of lupuslike
symptoms and possibly carcinogenesis. Mercury toxicity
depends on exposure route, frequency, dose level, nutri-
tional status, individual susceptibility, and genetic predis-
position. Many guidelines have been developed to protect
public health; however, the mercury reference dose needs to
be revisited in light of recent findings indicating that low

levels, as little as 0.1– 0.4 ␮M of mercury, induce mutations
in cultured cells. Understanding the general risk involved in
mercury pollution and toxicity is a prerequisite for devel-
oping a useful health advisory document for mercury com-
pounds. Therefore, it is important to know the physical and
chemical properties, sources and pathways of exposure,
systemic and carcinogenic health effects, current regulatory
and health guidelines, and diagnostic and treatment sched-
ules that can assist in developing a comprehensive risk
assessment and in implementing appropriate risk manage-
ment strategies for mercury.
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