Biometals (2015) 28:605614

DOI 10.1007/s10534-015-9857-5

Selenium as an antidote in the treatment of mercury

intoxication
Geir Bjrklund

Received: 12 January 2015 / Accepted: 23 April 2015 / Published online: 7 May 2015
Springer Science+Business Media New York 2015

Abstract Selenium (Se) is an essential trace element

for humans. It is found in the enzyme glutathione
peroxidase. This enzyme protects the organism against
certain types of damage. Some data suggest that Se
plays a role in the bodys metabolism of mercury (Hg).
Selenium has in some studies been found to reduce the
toxicity of Hg salts. Selenium and Hg bind in the body
to each other. It is not totally clear what impact the
amount of Se has in the human body on the
metabolism and toxicity of prolonged Hg exposure.
Keywords
toxicology

Selenium
Mercury
Interaction
Metal

Introduction
Interactions between metals and selenium (Se) have
been known for more than 60 years (Parzek and
Ostadalova 1967). The research was intensified after
Ganther et al. (1972) had shown that Se can protect
against the toxic effects of methylmercury (MeHg).
Most studies have been conducted in experimental
animals where high single doses of Hg and Se or only a
few doses have been used. In the human situation,
G. Bjrklund (&)
Council for Nutritional and Environmental Medicine
(CONEM), Toften 24, 8610 Mo i Rana, Norway
e-mail: bjorklund@conem.org

however, is the exposure characterized by low Hg

doses for a long time. Supplementation of Se is
continuously present through the diet. Selenium has in
most animal studies been supplemented as inorganic
salts (most often selenite), while the Se humans get via
food is mainly organically bound.
Multiple animal experiments have shown a very
good effect of Se at high dosage level as antidote
against a large range of toxic metals, but with some
few exceptions, notably in the case of Pb. The
selectivity of Se as an antidote for toxic rather than
nutritionally essential metals is probably far better
than for any of the chelators now used for treatment of
heavy metal poisoning.
When the dietary Se intake is less than optimal, Seantagonistic toxic metals, such as Hg, cadmium (Cd)
and silver (Ag), will bind Se in a biologically inert
form as heavily soluble selenides. The toxic metals
concerned cannot do any harm after they have been
precipitated as selenides inside the cells, but they will
reduce the amount of selenide ions available for
synthesis of selenophosphate and selenocysteyltRNA, as well as for incorporation in the iron-sulphur
groups of enzymes in the mitochondrial respiratory
chain (Christophersen et al. 2012).
In agreement with this theoretical expectation, it
has been found that workers in an Hg mine had
significantly lower (p \ 0.05) average blood plasma
Se concentration (71.4 lg/L) than in the controls
(77.3 lg/L) (Kobal et al. 2004). However, the miners

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had significantly more (p \ 0.05) Se in their urine

(16.5 lg/g creatinine) than the controls (14.0 lg/g
creatinine) (Kobal et al. 2004), which is puzzling, but
perhaps might reflect enhancement of the diurnal
creatinine excretion because of Hg-induced kidney
damage (Tchounwou et al. 2003; Kern et al. 2012)
rather than enhancement of the diurnal Se excretion.

Selenium
Selenium is an essential trace element for many
animal species, including humans. It is an integral part
of the enzyme glutathione peroxidase (GPx). This
enzyme protects the organism against oxidative damage by reducing lipid peroxides and hydrogen peroxide in the presence of glutathione. Selenium is found in
the enzyme as the amino acid selenocysteine. GPx is
composed of four identical parts with a Se atom in
each. In experimental animals, it has been shown that
Se is also included in a structural protein in sperm and
heme metabolism, which appears to be independent of
the GPx activity. Mammals have also a Se independent GPx (GSH-transferase B) that only converts lipid
peroxides and not hydrogen peroxide.
Most water-soluble Se compounds are rapidly
absorbed from the gastrointestinal tract in animals
regardless of dose. It can be assumed that the proteinbound Se in food are as Se-containing amino acids.
Both organic and inorganic Se compounds appear in
the organism converted to selenide to be incorporated
in selenocysteine and further in the protein. Selenide
can in high doses be methylated and excreted as
dimetylselenid via lungs or trimethylselenium via
urine. Selenide, together with a range of metals
produce very stable metal complexes. In contrast thiol
groups are selenol groups, when present in proteins,
largely dissociated at physiological pH. This make that
selenol groups easier complexbinds metal salts. The
Se intake varies tremendously in different parts of the
world. There are also reports from a Se deficient area
of China, known as Keshan Province, that children
with low Se values are affected by cardiomyopathy
(Keshan disease) and Se alleviate or prevent this
disease. If supplemented for a long time can selenite at
doses of 0.51 mg/day cause toxic effects.
Impaired intracellular antioxidative defense will,
moreover, enhance the liability of cell populations to
undergo mitochondrially induced apoptosis, which

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Biometals (2015) 28:605614

might be especially important as an important part of

the pathogenetic mechanism of oligospermia in
menbeing now the most serious public health
problem in Europe because of the disastrous decline
in average sperm density for the entire male population that has occurred probably in all of Europe over
the last 70 years.
The intake of Se is less than optimal for much of the
world population for a variety of reasons, including
high dietary intake of Se-free foods such as refined
sugar and dietary fats and oils, reduced food consumption because of sedentary lifestyles, topsoil
erosion, anthropogenic fires (e.g. on savannas in
Africa), and massive application of commercial fertilizers with low Se/phosphorus (P) ratio causing
inhibition of Se uptake into plant roots (Haug et al.
2007; Christophersen et al. 2010, 2012). While Se
deficiency in the soil is very widespread in poor
countries, inhibition of Se uptake in plant roots by Sepoor fertilizers is probably the most important cause of
low Se intake in Europewhich cannot be explained
only as a consequence of low Se concentrations in the
soil or natural binding of selenite ions to soil minerals
(Christophersen et al. 2012). The Se intake is most
likely much less than what is needed for optimal
detoxification of Hg and other toxic metals (such as
Cd) for most of the population in Europe (with the
average dietary Se intake being especially low in
Sweden, as well as in some of the countries on the
Balkan Peninsula).
The average Se intake in most parts of Europe is now
far below the optimum for health, as illustrated i.a. by
epidemiological data from the United States regarding
the relationship between individual Se status and
survival of AIDS patients. It will therefore be a
synergistic interaction, unless the patient is taking Se
as a dietary supplement at an adequate dosage level,
between low Se intake and intoxication by strongly Seantagonistic toxic metals such as Hg, Cd and Ag. The
most probable main reason for the low Se intake in most
of Europe is very large consumption of Se-poor
commercial fertilizers. The fertilizers inhibit the uptake
of Se in plant roots by a combination of mechanisms,
including (a) competitive interactions between selenate
and sulphate and between selenite and phosphate for the
same membrane transport proteins in the plant roots
(and presumably in mycorrhiza as well, although this
has not so far been studied experimentally, as far as I
know), and (b) coprecipitation of selenite with

Biometals (2015) 28:605614

phosphate when new phosphate minerals are formed in

the soil following commercial fertilizer application.
The average Se intake must be considerably higher
in North America than in Europe, if differences in
average blood Se concentrations can be taken as
representative of the geographic variations in Se
intake (Shamberger et al. 1979; Christophersen
1983; Chakar et al. 1993; Wang et al. 1995; Bates
et al. 2002; Berthold et al. 2012; Gac et al. 2012). But
studies of toxic effects of Hg suggest that dietary Se
intakes sometimes may be less than what is needed for
optimal antidote protection against Hg in North
America as well. This question, however, has probably
never been well enough studied either epidemiologically (e.g. by comparing the prevalence of
Hg-related problems in the most Se-rich and the most
Se-poor parts of the United States) or through clinical
intervention trials (to establish the Se supplementation
dose needed for optimal antidote protection against Hg
or other toxic metals).

Selenides
Selenide is needed as a precursor to make selenocysteyl-tRNA, which is in turned needed for incorporation of selenocysteyl groups into Se-dependent
enzymes during translation, using UGA as codon in
the mRNA molecule, while TGA is used as codon in
the DNA molecule (Christophersen et al. 2012).
Selenocysteyl-tRNA is produced by reaction between
a specific form of phosphoseryl-tRNA and the energyrich compound selenophosphate, with selenophosphate being formed by an enzyme-catalyzed reaction
between ATP and selenide ions (Xu et al. 2007;
Turanov et al. 2011; Christophersen et al. 2012).
The selenides of all the metals concerned have
much lower solubility products, as found by Buketov
et al. (1964), compared with the solubility products of
the corresponding sulphides as found in ordinary
chemical textbooks. The natural geochemical abundance of Se, on a molar basis, is four orders of
magnitude less than for sulphur (S), being close to the
Se/S elemental abundance ratio in the solar system as a
whole. This is also close to the natural Se/S abundance
ratio in the human body.
However the heavy metal selenides are commonly
from seven to 14 orders of magnitude less soluble than
the corresponding sulphides. If the concentration ratio

607

of selenide to sulphide ions in the cell reflects the total

Se/S abundance ratio in the human body, the selenides
of various toxic metals will therefore precipitate long
before the intracellular fluids will become saturated
with respect to the corresponding sulphides.
It is apparently a consequence of these evolutionary
adaptations that there is strong antagonistic interaction
between Se and several toxic metals that are not
essential, but little antagonistic interaction between Se
and nutritionally essential metals, although it is
possible that copper (Cu) and perhaps more importantly chromium (Cr) may be partial exceptions to this.
However, use of Se as an antidote for heavy metal
intoxication is not free of potential hazards of its own
as there are anecdotal reports especially from Sweden
about paradoxical intolerance to Se supplementation
among patients suffering from Hg intoxication. It is
possible (Alloway 2012) that this may be explained by
an autoinhibition mechanism when selenite ions react
with selenol groups of Se-dependent enzymes, forming SeSe covalent bonds leading to inhibition of
the enzyme, which is perhaps irreversible.
The procedure should therefore be to start very
cautiously with very low daily doses of a Se supplement and enhance the daily doses gradually over a
long period of time, thus making it possible for the
cells to make new selenoprotein molecules before the
daily Se dose is increased. If symptoms of Se
intolerance arise, one must stop for a while enhancing
the daily doses.
Animal experiments have been disappointing,
regarding the use of Se as an antidote for lead (Pb)
poisoning (Christophersen et al. 2012). It is proposed
that PbSe in spite of heaving a low solubility product,
compared for instance to CdSe, is easily oxidized
because of simultaneous oxidation both of the selenide
and Pb?? ions (Christophersen et al. 2012). In CdSe,
on the other hand, it is only the selenide ions that can
be further oxidized. CdSe microcrystals are therefore
from a kinetic point of view far more resistant to
oxidation than PbSe microcrystals, and HgSe microcrystals are also kinetically very resistant to oxidation
(Christophersen et al. 2012).
Mercuric selenide (HgSe) has a solubility product
of about 10-64 (Buketov et al. 1964). This is so low
that if one tries to calculate how much water is needed
for dilution, if the solution shall be at equilibrium with
solid HgSe with just 1 Se ion and 1 Hg?? ion in the
solution, one needs cubic kilometres of water for

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dilution. In practice this means that HgSe is totally

insoluble in living organismsand it is apparently
also totally biologically inert.
This explains why Se has been found to be a very
good antidote against Hg poisoning in animal experiments (Underwood 1977; Christophersen et al.
2012), and it explains why marine animals such as
tuna and sea eagles are well protected against the toxic
effects of Hg, being present at high natural levels in
marine food-chains (with Hg enrichment taking place
upwards in the chain).
Selenium supplementation should always be used
as part of the treatment for heavy metal intoxication,
even in the case of Pb poisoning in spite of the lack of
efficacy of Se as an antidote against Pb. However, Pb
has a strong in vivo prooxidant effect, and it is
important also in the case of Pb poisoning to optimize
the intracellular antioxidant defence (Christophersen
et al. 2012).

Selenoproteins
The cells have probably much larger capacity to make
selenide ions than sulphide ions, compared to total
abundance of the two elements in the cells, causing the
selenide/sulphide concentration rate in the cells to be
much higher than the concentration ratios between
total Se and total S. An important reason for this is
probably that the cells need selenide ions to make
selenophosphate by an enzyme-catalyzed reaction
with ATP, and selenophosphate is needed to make
selenocysteyl-tRNA prior to synthesis of selenoproteins such as GPx and thioredoxin reductase.
Among the selenoproteins, there are at least two that
can form chelates, where the toxic metal is simultaneously coordinated to a Se and an S atom, viz. thioredoxin reductase and selenoprotein P. Selenoprotein P is
important for antiatherogenic production, while inhibition of thioredoxin reductase will have multiple
consequences in a wide range of different disease
because of the important role of thioredoxin both in
antioxidant defense (as cofactor for 2-Cys peroxiredoxins and methionine reductases, as well as participating in the repair of oxidatively damaged proteins
by reduction of abnormal intramolecular disulphide
bonds in the protein concerned) and in DNA synthesis
and repair because it is one of the two reducing
cofactors for thioredoxin reductase.

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The inhibition of the enzyme thioredoxin reductase

by Hg?? ions happens with an inhibition constant Ki
(for 50 % inhibition of the enzyme, and at a relevant
concentration of the substrate thioredoxin) of 7.2 nM,
while for inhibition of thioredoxin reductase by
MeHg, Ki is 19.7 nM (Carvalho et al. 2008). By
contrast, the reduced glutathione (GSH) concentration
in human erythrocytes has been reported to be in the
range 1-3.2 mM (Hempe and Ory-Ascani 2014),
which means 5 orders of magnitude higher concentration of GSH thiol groups, compared with the Hg??
concentration needed for 50 % inhibition of thioredoxin reductase.
Thioredoxin reductase has been shown to be
extremely vulnerable to inhibition by Hg??, as well
as by gold (Au) and platinum (Pt) compounds that are
or have been used therapeutically either for treatment
of rheumatoid arthritis (in the case of Au) or cancer (in
the case of Pt). But it is for obscure reasons not
sensitive to inhibition by Pb??. It might be speculated,
very hypothetically, that this is because Pb?? is
instead bound to thioredoxin as a tetrathiolate complex. There are two different dithiol configurations in
thioredoxin, one at the active site and another in
another part of the molecule, but it has not yet been
experimentally verified that all the four thiol groups
can be simultaneously coordinated to the same metal
atom.
Impaired scavenging of H2O2, peroxynitrite and
organic hydroperoxides will lead to enhancement of
the mutation rates in mitochondrial and nuclear DNA,
with enhancement of the mutation rate in mitochondrial DNA leading to patological enhancement of the
rate of aging processes (which can lead to premature
development of age-related degenerative diseases in
several different organs, including the brain), and also
impaired semen quality in men, while enhancement of
the mutation rate in nuclear DNA will enhance the risk
of cancer as well as of genetic diseases in the offspring
of the patient concerned, if the patient is not beyond
the age of reproduction. Potential consequences of
enhanced mutation burden in human germ cells are
truly disastrous (Christophersen 2012a).
However, inhibition of thioredoxin reductase because of low Se intake or toxic metals may also be
expected to contribute to impairment of DNA synthesis and repair, especially if the patient is also GSHdeficient, because of the role of thioredoxin as one of
the two alternative reducing cofactors for

Biometals (2015) 28:605614

ribonucleotide reductase. The other reducing cofactor

for ribonucleotide reductase is glutaredoxin (also
called thioltransferase when functioning as a protein
repair enzyme in its own right), which in turn depends
on GSH as a reducing cofactor.
Impaired intracellular antioxidative defense will,
however, also affect the function of multiple redoxregulated intracellular signal cascades, including NFkappaB, AP-1 and Sp1. This affects the regulation of
cell growth and apoptosis, which is especially important in cancer patients, and the expression of a large
number of proinflammatory proteins, which is important in all non-infectious inflammatory diseases,
including the allergic diseases and rheumatoid
arthritis.

Chalcophile and siderophile toxic metals

All chalcophile and siderophile toxic metals (Goldschmidts classification), i.e. those found in sulphide
minerals in common rocks or being so noble that they
prefer going into an iron-rich melt rather than in a
coexisting silicate melt, form heavily soluble selenides, and bind strongly to selenol groups in
selenoproteins. They are therefore Se antagonists,
and there will be a synergistic interaction between
suboptimal Se intake and the toxic metals concerned
as causes of depletion of Se-dependent enzymes.
Depletion of the selenoproteins concerned causes
impairment of antioxidant defense at a cellular level
because of impaired scavenging of H2O2, organic
hydroperoxides and peroxynitrite and impaired repaired of oxidatively damaged proteins by thioredoxin
and methione sulfoxide reductases. All the methionine
sulfoxide reductases use thioredoxin as one of their
reducing cofactors and one of them is itself a
selenoprotein also called selenoprotein R, which is
vulnerable to Se depletion because of suboptimal
intake.
All the toxic chalcophile and siderophile metals
lead to enhancement of in vivo oxidant stress by a
combination of mechanisms that includes scavening of selenide ions because of precipitation of
heavily soluble metal selenides, direct inhibition of
Se-dependent enzymes, and pro-oxidant catalytic
effects of metals that can occur in more than one
oxidation number in vivo, such as Pb, vanadium (V),
Cr, Cu (when present at a toxic concentration level in

609

the cells) and probably tin (Sn). Treatment with a good

antioxidant cocktail should therefore be part of the
standard therapy. A combination both of hydrophile
and lipophile natural antioxidants should be used, and
probably also melatonin because of the double function of melatonin both as a good antioxidant in its own
right, and, more importantly, as a hormone enhancing
the expression of several antioxidant enzymes, as well
as ancillary enzymes that participate in chains of
electron transport leading to the actual antioxidant
enzymes (with glutathione reductase as a good example). This antioxidant cocktail therapy should also be
used for treatment of all acute intoxications with
organic substances that exert a prooxidant effect,
including alcohol and the fungal poison orellanine
(Christophersen 2012b).
Chalcophile metals that are essential nutrients, such
as Cu, zinc (Zn) and nickel (Ni) form also selenides
that have much lower solubility products of than the
corresponding sulphides. But there must apparently
have been evolutionary adaptations hindering too
strong antagonistic interaction between Se and nutritionally essential metals, probably mainly because of
strong binding of the essential metals concerned to
those proteins, where they function as essential
enzyme cofactors. CuSe has a solubiity product far
lower than for CdSe, but Cu forms also very stable
complexes with ordinary amino acids and proteins.

Selenides compared with sulphides

It has often been thought that the toxicity of Hg is
mainly a consequence of Hg having high affinity for
the thiols of cysteyl groups in proteins and GSH
(Clarkson 2002; Lorscheider et al. 1995). It is wellknown that thiol (SH) groups are often found at the
active site or other functionally important sites in
protein molecules. Thus, it has been thought that the
Hg2? ion may bind to thiol groups of enzymes,
proteins, ion channels, membranes, etc., alter their
normal function and, in many instances, render them
essentially nonfunctional.
These ideas at best represent a gross oversimplification. It is possible that binding of Hg to thiol groups
may help to explain some of the effects of Hg in the
control of gene expression (for apometallothionein,
various CYPs and heme oxygenase), and it is certainly
correct that strong binding will occur, when the same

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toxic metallic ion can bind to two different thiol

groups or more simultaneously. But the traditional
idea referred to above cannot be entirely true, if we
think about thiol groups in general, because Hg can
exert toxic effects at tissue concentrations, where there
is a vast suberabundance of thiol groups, compared
with the number of Hg atoms, and because Hg? and
Hg?? ions bind much more strongly to selenide ions
(Se) and selenol groups (R-SeH or R-Se) than to
sulphide ions (S-) and thiol groups (R-SH) (Christophersen et al. 2012).
Sulphide is formed from methionine S by two
different enzymes simultaneously as methionine is
degraded to form cysteine (Christophersen et al.
2012), for which reason the concentration ratio
sulphide/selenide in the cells is probably determined
mainly by the ratio of methionine to total Se in the diet
(Christophersen et al. 2012).
A comparison of the solubility products for sulphides and selenides of the same metals (Buketov et al.
1964; Christophersen 1983) gives a measure of the
difference in binding strength for the same metallic
cations to sulphide and selenide ions. Thus measured,
the difference in binding strength (comparing the same
metal atoms binding to S and Se atoms), exceeds the
S/Se abundance ratio in living cells by a large factor
both for Hg?, Hg??, and the cationic forms of several
other toxic metals, including Ag, Au and Pt (Christophersen 1983; Christophersen et al. 2012).
The Se/S atomic abundance ratio is about 104 both
in the igneous rocks of the Earths crust (Krauskopf
1982) and in the solar system as a whole (Suess 1987),
thus demonstrating little Se/S fractionation when the
Earth and its core were formed (Christophersen et al.
2012). But it is considerably higher in average shale
and many natural topsoils, which can partly be
explained by Se coming from volcanoes and partly
by biological transport processes (Christophersen
et al. 2012). The Se/S concentration ratio is low in
seawater (much lower than in the Earths crust)
because of Se removal from seawater by biological
processes, but high in most marine animals because of
active uptake of Se (in form of selenite ions) in
plankton organisms from seawater, while there is no
similar bio-enrichment of S in marine organisms
because of the very high sulphate concentration in
seawater (Krauskopf 1982).
All heavy metal selenides have much lower
solubility products (Buketov et al. 1964) than the

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corresponding sulphides (Christophersen 1983), with

the quotient between the solubility products for
corresponding sulphides and selenides increasing
(when the solubility products of sulphides and selenides of different metals are compared) as the
solubility of the sulphide decreasesreaching more
than 10 orders of magnitude for those metals that are
least soluble in form of sulphides and selenides
(Christophersen 1983). This is much more than the
atomic abundance ratio S/Se in the solar system and
the Earths crust (4 orders of magnitude), while in
living organisms, the S/Se ratio can often be even less
than in common igneous rocks.
The sulphide/selenide concentration ratio in living
cells is less than the total S/Se ratio in the cells because
of various biochemical pathways for selenide production that are specific to Se and dont form sulphide ions
simultaneously (Christophersen 1983; Christophersen
et al. 2012). The ratio between the solubility products
for corresponding toxic metal sulphides and selenides
is therefore much higher than the sulphide/selenide
concentration ratio in the cells, which means that if the
concentration of a metallic cation is gradually increased from zero upwards, while sulphide and
selenide concentrations are kept constant at their
normal intracellular levels, saturation will be reached
for the metal selenide concerned well before the
solution becomes saturated with the corresponding
sulphide. The intracellular fluids are therefore undersaturated with regard to all of the toxic metal sulphides
as well as FeS (while iron-sulphur groups in enzymes
are stabilized by the presence of thiol groups being
part of the protein molecule), while they can be
saturated or slightly oversaturated with regard to
various toxic metal selenides, including CdSe, HgSe
and Ag2Se.
Precipitated PbSe, however, is most likely thermodynamically and kinetically unstable because of simultaneous oxidation both of Pb?? and Se- ions, following
PbSe precipitation (Christophersen et al. 2012). The
same is most likely also the case with stannous selenide
(SnSe), since Sn??, similarly as Pb??, can easily be
oxidized to higher oxidation numbers.

Vapor of metallic mercury: selenium

Mercury vapor (Hg0) accumulates in the nervous
system. There have been very few studies on the

Biometals (2015) 28:605614

interaction between Se and Hg0. Some studies have

been performed in rats and mice with short-term
exposure to Hg0 (from 1 hour to 1 day). These show
that supplementation of Se (0.1 mg/kg for 5 days,
1 mg selenite per liter of drinking water, 10 lmol/kg)
seems to lead to an increased retention of Hg,
particularly in the lungs, kidneys, blood, and to
varying degrees in the liver and the brains of mice.
Retention seems to increase at high Se dosage or when
Se poor animals are used. Retention in the liver has
also been demonstrated in rats. The immediate organ
distribution of Hg0 in the organism does not appear to
be significantly altered by Se (Nygaard and Hansen
1978; Hansen et al. 1981; Khayat and Dencker 1983).
It may be possibilities for some protection in that Hg0
is oxidized to divalent Hg intracellularly. Some of the
protective effect of Se against HgCl2 is probably
intracellular interactions with divalent Hg (Magos and
Webb 1980).
Several studies have shown remarkably high Hg
levels in the brain of individuals previously exposed to
Hg even long time after exposure. In a study by Kosta
et al. (1975) from a district with Hg mines showed one
of the former miners brain levels of Hg up to
13,000 lg/kg. In different parts of the brain of the
person with the highest Hg level was it found retention
of Hg and Se in a molar ratio close to 1:1.
It has also in skin biopsies from Hg exposed workers
been found Hg and Se (Kennedy et al. 1977). There are
at least two studies on interactions between Hg and Se in
workers exposed to Hg0 (Alexander et al. 1983; Suzuki
et al. 1986). Alexander et al. (1983) found an increased
excretion of Se in Hg exposed individuals (mean air-Hg
38 lg/m3, urinary Hg 6260 lg/L) compared to an
unexposed control group (urinary Hg 19 lg/L). However, the study didnt show a direct correlation between
Hg levels in urine and corresponding Se levels in the
exposed group. A possible explanation for increased Se
excretion may be increased Se levels in the kidneys of
Hg exposed individuals. Suzuki et al. (1986) found in a
study of Japanese workers exposed to Hg0 (urinary Hg
for men 78 lg/L, urinary Hg for women 22 lg/L) that
exposure to Hg0 likely affected the endogenous
metabolism of Se. Mercury and Se were in this study
analyzed in plasma, erythrocytes and urine. The study
showed that plasma Hg significantly correlated with Se
in erythrocytes and plasma, but it was not found a direct
relationship between urinary levels of Hg and Se
(Suzuki et al. 1986).

611

The interaction between Hg0 and Se is probably

complex. This is because it can be both complex
formation, accumulation of Hg and Se and effects on
urine, plasma and blood levels of Se. However, the
levels are both dependent on the current ongoing
exposure and to what degree and for how long time
prior exposure to Hg0 has been going on. It is not
reported whether exposure to Hg0 can affect the
enzyme GPx, or if different Se status is relevant to the
toxicity of Hg0.

Inorganic mercury salts: selenium

The critical organ for mercury chloride (HgCl2)
exposure are the kidneys. The best protection against
the toxic effects of HgCl2 (Hg ??) can be seen in
animal experiments with high doses of Hg and at the
same time administration of Se (most often selenite) in
equimolar doses (Parzek and Ostadalova 1967;
Magos and Webb 1980; Hogberg and Alexander
2007). The most acute effects including acute tubular
necrosis can under these conditions be counteracted.
However, the protective effect of Se is poor in
continuous HgCl2 exposure. Usually, it is seen a
greater retention of both Hg and Se in the organism.
There are also changes in organ distribution with
increased retention of Hg in the liver, spleen and
blood. From animal experiments it has been reported
both increased and reduced Hg levels in the kidneys
after simultaneous Se exposure. A redistribution of Hg
in the kidneys from low to higher molecular weight
proteins, which also contain Se seems to take place. It
is probably also created a Hg-selenid-complex with
little biological activity. Mercury compounds usually
reduces the toxicity of high doses of Se, but increases
the toxicity of methylated Se compounds. Inorganic
Hg salts inhibit glutathione metabolizing enzymes and
GPx in the kidneys. This effect can be counteracted by
supplementation of Se (Ridlington and Whanger 1981;
Chung et al. 1982). The activity of GPx is inhibited to
varying degrees in other organs (Chung et al. 1982).
Inorganic Hg occur as elemental Hg (Hg0) and Hg
salts (Hg2?). The critical organ is defined as the organ
where it first develops changes. The critical organ for
Hg0 is the CNS, whereas the critical organ for Hg2? is
the kidney. In the blood is Hg0 after a few minutes
oxidized to Hg2? by the action of the enzyme catalase.
Before the oxidation approximately 10 % of the Hg0

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in the blood passes the bloodbrain barrier and the

placenta. In the brain is Hg0 converted to Hg2? and
accumulated (Bjrklund 1991).
When selenite is given shortly after mercuric Hg, it
protects effectively against damage to the kidneys,
acute tubular necrosis and death. However, selenite
gives only partial protection for kidney damage caused
by Hg if it repeatedly is co-administered with mercuric
chloride (Chmielnicka et al. 1978). The protective
effect of Se declines strongly with increased exposure
time of Hg (Magos and Webb 1980; Watanabe 2002).
The Co-administration of Hg and Se usually increases
whole-body retention of both elements, and especially
of Hg. Both fecal and renal excretion of Hg are
reduced, and changes in the organ distribution are seen
(Hansen et al. 1981; Kristensen and Hansen 1979;
Magos and Webb 1980). Mercury and Se form a highmolecular-weight complex with selenoprotein P,
when they are co-administered, which leads to a
reduction of Hg in target organs such as the kidneys.
High-molecular-weight complexes of Hg and Se are
also common in other organs (Yoneda and Suzuki
1997).
Kosta et al. (1975) investigated retired miners
that previously were exposed to elemental Hg. They
found that the co-accumulation of Hg and Se in a
molar ratio was close to unity in the brain, the
kidneys, the thyroid, and the pituitary. The Hg
levels in the brain were remarkably high, up to
13 lg/g. Analysis of biopsy samples of skin pigmentations from the Hg-exposed workers revealed
deposits containing Hg and Se (Kennedy et al.
1977). Workers, who are exposed to elemental Hg0,
excrete significantly more Se in urine than unexposed controls (Alexander et al. 1983).

Organic mercury compounds: selenium

By giving selenite shortly before, at the same time or
shortly after exposure to MeHg can selenite effectively increase survival and prevent neurological symptoms and biochemical and pathological-anatomical
changes. However, the protective effect of Se is more
uncertain for long-term exposure to MeHg. The
interaction mechanisms are probably very complex.
The combined exposure to MeHg and selenite accomplished a lipophilic Se-dimethyl-Hg complex which

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Biometals (2015) 28:605614

probably is not very biologically active. However, the

complex penetrates the bloodbrain barrier easily.
Thereby bringing drawn both distribution and excretion of MeHg. Prolonged high MeHg exposure
combined with a Se deficient diet decreases glutathione in the brain something in rats (Ganther 1980;
Ridlington and Whanger 1981). Such inhibition of
GPx has also been observed in the brain and muscles in
cats following prolonged MeHg exposure and in the
liver of mouse fetus when female mice are exposed.
The level of glutathione can be maintained with Se
supplementation.
Methylmercury selectively damages the nervous
system in man, resulting in dysarthria, ataxia, constriction of the visual field, and paresthesias. Ganther
et al. (1972) were the first who reported that Se had a
protective effect against MeHg toxicity. The same
effect was later found in quail, chick, mice, rat, and cat
(Ganther 1980; Magos and Webb 1980; Skerfving
1978). When MeHg is given in a single dose or a
limited number of doses, selenite prevents the onset of
neurological disorders effectively. During long-term
dosing with MeHg, selenite offers some protection or
at least delays the onset of symptoms (Chang 1983;
Magos and Webb 1980). Surprisingly small amounts
of selenite are sufficient to provide a protective effect
even in cell cultures (Alexander et al. 1979; Ganther
1980).
The protective effects of Se occur even if the coadministration leads to increased levels of Hg in the
brain (Chen et al. 1975; Alexander and Norseth 1979;
Ganther 1980; Magos and Webb 1980). However,
decreased levels of Hg in the brain have also been
reported (Komsta-Szumska and Miller 1984). The
elimination of Hg after multiple doses of MeHg can be
described by a one-compartment model (half-time,
23.6 days). Co-administration of multiple doses of
selenite and MeHg revealed a two compartment model
for elimination of Hg (halftime, 8.7 and 40.8 days)
(Komsta-Szumska and Miller 1984).
After exposure to MeHg are the levels of GPx
decreased in several organs including the brain. These
are restored when Se in small amounts are added
(Ganther 1980). MeHg exposure can also affect other
selenoproteins, such as the deiodinases (Watanabe
2002). A co-accumalation of Hg and Se in thalamus
and in the occipital pole of the brain has been shown
in macaques exposed to MeHg (Bjorkman et al.
1995).

Biometals (2015) 28:605614

Conclusions
Selenium play a role in the metabolism of Hg. Under
defined conditions in animal studies may Se reduce the
toxicity of Hg compounds. The mechanisms are
complex and only partially understood, and require
systematic dose effect/dose response studies. The
retention of Hg and Se in previously Hg exposed
individuals may possibly be a reflection of the
formation of biologically active Hg-complexes.
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