Selenium as an antidote in the treatment of mercuryintoxication

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 Selenium Mercury Interaction Metaltoxicology

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,

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, Se-

antagonistic 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 selenocysteyl-

tRNA, 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 plasmaSe concentration (71.4 lg/L) than in the controls(77.3 lg/L) (Kobal et al. 2004). However, the miners

G. Bjrklund (&)Council for Nutritional and Environmental Medicine

(CONEM), Toften 24, 8610 Mo i Rana, Norway

e-mail: bjorklund@conem.org

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DOI 10.1007/s10534-015-9857-5

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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/gcreatinine) (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 dam-

age by reducing lipid peroxides and hydrogen perox-

ide 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 indepen-

dent 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 protein-

bound 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

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 popula-

tion 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 con-

sumption because of sedentary lifestyles, topsoil

erosion, anthropogenic fires (e.g. on savannas in

Africa), and massive application of commercial fer-

tilizers 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 Se-

poor 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 Se-

antagonistic 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

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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 epi-

demiologically (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 seleno-

cysteyl-tRNA, which is in turned needed for incorpo-

ration 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 energy-

rich compound selenophosphate, with selenophos-

phate 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 abun-

dance 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

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 impor-

tantly 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, form-

ing 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 supple-

ment 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 micro-

crystals 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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SantiagoNota adhesivaQu tipo de suplemento de selenio?

SantiagoNota adhesivaCunto es este largo perodo de tiempo?

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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 ex-

periments (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 selenopro-

teins such as GPx and thioredoxin reductase.

Among the selenoproteins, there are at least two that

can form chelates, where the toxic metal is simultane-

ously coordinated to a Se and an S atom, viz. thiore-

doxin reductase and selenoprotein P. Selenoprotein P is

important for antiatherogenic production, while inhi-

bition 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 peroxire-

doxins and methionine reductases, as well as par-

ticipating 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.

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 concen-

tration of GSH thiol groups, compared with the Hg??

concentration needed for 50 % inhibition of thiore-

doxin 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 com-

plex. 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 mitochon-

drial 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 be-

cause of low Se intake or toxic metals may also be

expected to contribute to impairment of DNA synthe-

sis and repair, especially if the patient is also GSH-

deficient, because of the role of thioredoxin as one of

the two alternative reducing cofactors for

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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 redox-

regulated intracellular signal cascades, including NF-

kappaB, AP-1 and Sp1. This affects the regulation of

cell growth and apoptosis, which is especially impor-

tant in cancer patients, and the expression of a large

number of proinflammatory proteins, which is impor-

tant in all non-infectious inflammatory diseases,

including the allergic diseases and rheumatoid

arthritis.

Chalcophile and siderophile toxic metals

All chalcophile and siderophile toxic metals (Gold-

schmidts 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 se-

lenides, 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 re-

paired 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 scaven-

ing 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

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 func-

tion 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 exam-

ple). 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 nutri-

tionally 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 well-

known 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 oversimplifi-

cation. 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) (Christo-

phersen 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 sul-

phides 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 (Christo-

phersen 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

corresponding sulphides (Christophersen 1983), with

the quotient between the solubility products for

corresponding sulphides and selenides increasing

(when the solubility products of sulphides and se-

lenides 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 produc-

tion 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 in-

creased 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 under-

saturated 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 thermo-

dynamically and kinetically unstable because of simul-

taneous 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

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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 theperson 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 anunexposed control group (urinary Hg 19 lg/L). How-ever, 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) thatexposure 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).

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

Biometals (2015) 28:605614 611

123

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 high-

molecular-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 pig-mentations 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 unex-

posed 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 effective-

ly increase survival and prevent neurological symp-

toms 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 accom-

plished a lipophilic Se-dimethyl-Hg complex which

probably is not very biologically active. However, the

complex penetrates the bloodbrain barrier easily.

Thereby bringing drawn both distribution and excre-

tion of MeHg. Prolonged high MeHg exposure

combined with a Se deficient diet decreases glu-

tathione 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, con-

striction 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 co-

administration 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).

612 Biometals (2015) 28:605614

123

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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Selenium as an antidote in the treatment of mercury intoxicationAbstractIntroductionSeleniumSelenidesSelenoproteinsChalcophile and siderophile toxic metalsSelenides compared with sulphidesVapor of metallic mercury: seleniumInorganic mercury salts: seleniumOrganic mercury compounds: seleniumConclusionsReferences