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Environmental Mercury and Its Toxic Effects: Review
Environmental Mercury and Its Toxic Effects: Review
1
Center for Diagnostic Nanosystems, Marshall University, Huntington, WV; 2Department of Pharmacology, Physiology, and Toxicology, Joan C.
Edwards School of Medicine, Marshall University, Huntington, WV; 3Department of Pharmacy Practice, Administration, and Research, School of
Pharmacy, Marshall University, Huntington, WV; 4Department of Pharmaceutical Science and Research, School of Pharmacy, Marshall University,
Huntington, WV, USA
Mercury exists naturally and as a man-made contaminant. The release of processed mercury can lead to a progressive increase in the
amount of atmospheric mercury, which enters the atmospheric-soil-water distribution cycles where it can remain in circulation for
years. Mercury poisoning is the result of exposure to mercury or mercury compounds resulting in various toxic effects depend on its
chemical form and route of exposure. The major route of human exposure to methylmercury (MeHg) is largely through eating con-
taminated fish, seafood, and wildlife which have been exposed to mercury through ingestion of contaminated lower organisms. MeHg
toxicity is associated with nervous system damage in adults and impaired neurological development in infants and children. Ingested
mercury may undergo bioaccumulation leading to progressive increases in body burdens. This review addresses the systemic patho-
physiology of individual organ systems associated with mercury poisoning. Mercury has profound cellular, cardiovascular, hematolog-
ical, pulmonary, renal, immunological, neurological, endocrine, reproductive, and embryonic toxicological effects.
Mercury
Mercury-contained Table 1. Mercury content of different seafoods [14]
Human products
vapor Mercury content
(i.e., pigments) Species Safety
(ppm)
Anchovies 0.0431 Eco-good
Food chains Butterfish 0.0581
Eco-good
Catfish 0.049±0.084 Eco-good
Crab (blue, king, and snow) 0.060±0.112 Eco-good
Crawfish 0.033±0.012 Eco-good
Methylmercury (bacteria)
Flatfish (flounder, plaice, and sole) 0.045±0.049 Eco-good
Haddock 0.031±0.021 Eco-good
Herring 0.0441
Eco-good
Inorganic mercury Mackerel, Atlantic 0.0501 Eco-good
Mullet 0.0461 Eco-good
Figure 1. Routes of mercury exposure in humans.
Oysters (farmed) 0.013±0.042 Eco-good
once oxidized the potential exist for bioaccumulation in the re- Pollock 0.041±0.106 Eco-good
nal cortex, liver, and especially the brain. It is estimated that the Salmon, wild (Alaska) 0.014±0.041 Eco-good
half-life of mercury in the brain can be as long as 20 years [9]. Sardines, Pacific (US) 0.016±0.007 Eco-good
Scallops 0.0501 Eco-good
Squid 0.0701 Eco-good
STATES OF MERCURY Tilapia 0.0101
Eco-good
Trout, rainbow (farmed, freshwater) 0.072±0.143 Eco-good
Inorganic mercury exists in either the mercurous and mer- Tuna, albacore (US, Canada) 0.353±0.126 Eco-bad
curic form. Like oxidized elemental mercury, mercuric salts are Atlantic cod (also known as gadus 0.095±0.080 Eco-bad
more water soluble and toxic than elemental mercury. Mercu- morhua, rock cod, codling, scrod cod)
ric salts are also easily absorbed by the gastrointestinal tract Bigeye/yellowfin tuna (imported long- 0.325±0.220 Eco-bad
line)
[10]. The average whole body half-life of inorganic mercury is
Bluefish 0.337±0.127 Eco-bad
about 40 days [11].
Chilean sea bass 0.386±0.384 Eco-bad
The most common form of organic mercury is methylmer- Carp 0.1401 Eco-bad
cury (MeHg), which is the major source of organic mercury Grouper 0.465±0.293 Eco-bad
found in the ecosystems [12]. MeHg is readily transported by Halibut 0.252±0.233 Eco-bad
water into the aquatic ecosystems. Because of its low water Imported swordfish 0.976±0.510 Eco-bad
solubility it is considered to be relatively lipid soluble. MeHg is King mackerel 0.7301 Eco-bad
easily taken up by lower organisms, tends to work its way up Marlin 0.485±0.237 Eco-bad
the food chain and exhibits a proclivity to bioaccumulate in Monkfish 0.1801 Eco-bad
fish [13]. Fish appear to be the primary source of MeHg poi- Orange roughy 0.554±0.148 Eco-bad
Sablefish (Alaska, Canada) 0.220 1
Eco-bad
soning in humans. Through mechanisms which are not yet
Shark (Carcarhinus limbatus) or short- 0.988±0.631 Eco-bad
known, various species of fish tend to have higher rates of fin mako (Isurus oxyrinchus)
MeHg bioaccumulation (Table 1) [14]. The gastrointestinal Snapper 0.189±0.274 Eco-bad
tract absorbs approximately ninety five percent of ingested Tilefish (golden bass, Atlantic) 1.450±0.122 Eco-bad
MeHg where it can then enter the red blood cells and the Values are presented as mean±SD.
brain by binding covalently to glutathione and cysteine pro- Maximum allowable concentration in seafood is 1 ppm according to US Food
and Drug Administration.
tein groups [15,16]. Because urinary excretion of MeHg is neg- Mercury levels in commercial fish and shellfish US Food and Drug Adminis-
ligible, MeHg is primarily eliminated from the body in an inor- tration and US EPA Advisory EPA-823-F-04-009 (March 2004).
1
No SD given.
ganic form through the action of the biliary system at the rate
of 1% of the body burden per day. The biological half-life of emissions, the incineration of medical waste, dental amalgam,
MeHg is 39 to 70 days depending on body burden. Potential and various commercial products including skin creams, ger-
sources of organic mercury included exposure to fossil fuel micidal soaps, various medications, teething powders, analge-
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Kevin M. Rice, et al.
Table 2. Some characteristics methylmercury toxic signs and SYSTEMIC TOXICOLOGICAL EFFECTS OF
symptoms are associated with the following mnemonic: MERCURY
DEADLY METHYLMERCURIALS
Mercury exposure has been associated with the induction of
Letter Definition
over 250 symptoms which can complicate accurate diagnosis.
D Dental problems and amalgam release of mercury
E Endocrine toxicity and dysfunction
Differential diagnosis begins with a patient history and physi-
A Affects adrenal function and hormone production (inhibiting of cal examination consistent with mercury exposure. Laboratory
21α-hydroxylase) testing typically includes 1) blood analysis; 2) urinalysis, with a
D Diabetes may be associated or caused 24-hour urine analysis, and a urine challenge test with a “che-
L Likely inhibits myelin synthesis in developing feti and children lating” agent; 3) hair analysis; and (d) tissue biopsy if warrant-
Y Young’s syndrome (Azoospermia sinopulmonary infections) ed [10,18]. Because mercury can be quickly removed from the
M Methylation of inorganic mercury in body
blood, redistributed and sequestered into different tissues it is
E Environmental accumulation (soil, water, air)
important to note that there may not be a direct correlation
T Toxic to GI, liver, and pancreas
between blood mercury concentration and the severity of
H Hypertension due to epinephrine excess (inhibits catecholamine
metabolism) mercury poisoning. Indeed, it is thought that shortly after en-
Y Young women should avoid some fish tering the body that mercury quickly becomes tightly bound
L Long biological half-life (may be >90 days) in the brain, spinal cord, ganglia, autonomic ganglia, and pe-
M Microorganisms (sulfate processers) synthesize from inorganic ripheral motor neurons. Nonetheless although the nervous
mercury
system is the primary repository for mercury exposure, the
E Enters food chain, bio accumulates, and biomagnifies
R Red blood cell accumulation (competes with iron for hemoglobin
transient and residual systemic distribution of mercury has the
binding) potential to cause symptoms in a number of different organ
C Crosses blood-brain barrier and produces central nervous system systems. In addition reports indicate that individual genetic
toxicity
background may play a role in mercury toxicokinetics [19].
U Uterine fetal toxicity
R Renal toxicity, especially to renal tubules
I Immune, enzyme, and genetic alterations CELLULAR EFFECTS OF MERCURY
A Association with many neurodegenerative diseases
L Long-term toxicity on many organs and systems At the cellular level mercury exposure is associated with al-
S Special senses affected terations in membrane permeability, changes in macromolec-
Developed by Walker EM Jr, 2008. ular structure due to its affinity for sulfhydryl and thiol groups,
and DNA damage [20-22]. Mercury has also been shown to in-
sics, diaper treatments, vaccinations, thermometers, sphyg- duce oxidative stress and mitochondrial dysfunction [23] which
momanometer, barometers, incandescent lights, and batteries can result in alterations in calcium homeostasis and increased
[5,7]. Other sources for organic mercury include phenyl mer- lipid peroxidation [24]. In addition, mercury may also increase
cury compounds and ethyl mercury compounds, which were radical oxygen species levels because of its ability to act as a
components of latex paints that were used before 1990s [12] catalyst for Fenton-type reactions [24].
and thimerosal which has been used as a preservative in vac-
cines [7]. Among the most dangerous mercury compound is CARDIOVASCULAR, HEMATOLOGICAL, AND
dimethylmercury ((CH3)2Hg) which is toxic enough to cause PULMONARY EFFECTS
death if only a few microliters is spilled on the skin, or even la-
tex gloves [17]. Mercury poisoning can result in death, mental Mercury accumulation in the heart is thought to contribute
retardation, dysarthria, blindness, neurological deficits, loss of to cardiomyopathy. Indeed, mercury levels in the heart tissue
hearing, developmental defects, and abnormal muscle tone of individuals who died from idiopathic dilated cardiomyopa-
[7]. Table 2 presents a helpful mnemonic that practitioners can thy were found to be on average 22 000 times higher than in
use when examining possible MeHg toxicity. individuals who died of other forms of heart disease [25,26].
Mercury poisoning may also cause chest pain or angina, espe-
76
Systemic Toxicity of Mercury
cially in individuals under age 45 [26]. In vitro studies have in- EFFECTS ON THE IMMUNE SYSTEM
dicated that MeHg can inhibit the cardioprotective activity of
paraoxonase 1 [27]. There is also good evidence linking mer- Klinghardt’s axiom states that “Most, if not all, chronic infec-
cury with anemia including hemolytic anemia and aplastic tious diseases are not caused by a failure of the immune sys-
anemia as mercury is thought to compete with iron for bind- tem, but are a conscious adaptation of the immune system to
ing to hemoglobin which can result in impaired hemoglobin an otherwise lethal heavy metal environment”. It has been
formation [28]. In addition to anemia, additional data has also known for many years that mercury impairs immune system
suggested that mercury may be a causative factor in mononu- function most likely via its deleterious effects on the polymor-
cleosis and involved in leukemia, and Hodgkin’s disease [29-31]. phonuclear leukocytes (PMNs). Mercury through suppression
Toxic vapors formed from mercury vaporization or the burn- of adrenocorticosteroids production prevents normal stimula-
ing of mercury containing materials can enter the respiratory tion of PMNs production and also affects PMN function by in-
system and pass readily into the circulation. Case control stud- hibiting their ability to destroy foreign substances [43]. Mercu-
ies have demonstrated that the chronic inhalation of even low ry-sensitive individuals are more likely to have allergies, asth-
concentrations of mercury (0.7 to 42 μg/m3) can produce ma, and autoimmune-like symptoms, especially rheumatoid-
tremors, sleep disturbances, and impaired cognitive skills in like ones. Mercury can produce an immune response in the
workers [12,32,33]. Mercury poisoning is associated with sev- central nervous system, induce alterations in immune cell pro-
eral different pulmonary conditions including Young’s syn- duction and function, and modulate the production of inter-
drome [34], bronchitis and pulmonary fibrosis [35,36]. feron gamma and interleukin-2 [44]. With impairment comes
a chronically susceptible to infections, if not chronic sickness.
EFFECTS ON THE DIGESTIVE AND RENAL Interestingly, the ingestion of mercury is oftentimes associ-
SYSTEMS ated with increased levels of yeasts, bacteria, and molds which
are thought to function in a protective manner to absorb ex-
Mercury is absorbed through the epithelial cells when in- cess mercury from the body. Indiscriminant and rapid destruc-
gested. This absorbed mercury can cause various digestive tion of the Candida albicans and other pathogens by antibi-
disturbances as it can inhibit the production of the digestive otics in adults with a significant body burden of toxic metals,
trypsin, chymotrypsin, and pepsin along with the function of including mercury, may cause the sudden release of large
xanthine oxidase and dipeptyl peptidase IV [37]. The effects of amounts of toxic metals contained within them and be poten-
mercury on the gastrointestinal system typically present as tially very dangerous. Mercury body burden has also been as-
abdominal pain, indigestion, inflammatory bowel disease, ul- sociated with or implicated in a number of immune or autoim-
cers and bloody diarrhea. Mercury ingestion has also been as- mune conditions including allergic disease, amyotrophic later-
sociated with the destruction of intestinal flora which can in- al sclerosis, arthritis, autoimmune thyroiditis, autism/attention
crease the amount of undigested food products in the blood deficit hyperactivity disorder, eczema, epilepsy, psoriasis, mul-
stream causing immune mediated reactions and reduced re- tiple sclerosis, rheumatoid arthritis, schizophrenia, scleroder-
sistance to pathogenic infection [38]. ma, and systemic lupus erythematosus [45-51].
Mercury can cause kidney damage and evidence suggests a
linkage between mercury exposure and acute tubular necro- EFFECTS ON THE NERVOUS SYSTEM
sis, glomerulonephritis, chronic renal disease, renal cancer and
nephrotic syndrome [35,39-41]. Various reports have shown It is clear that mercury is accumulated in nervous tissues all
mercury exposure can lead to various kidney injuries includ- through the body [52]. The most devastating effect of mercury
ing: subacute-onset nephrotic syndrome, tubular dysfunction, in the nervous system is interference with the production of
secondary focal segmental glomerulosclerosis, syncreticatic energy which can impair cellular detoxification processes
nephrotic syndrome, nephritic syndrome, nephrotic-range causing the cell to either die or live in a state of chronic malnu-
proteinuria, glomerular disease, and membranous glomerulo- trition. It is thought that mercury causes neuronal problems
nephritis [42]. through blockage of the P-450 enzymatic process [26]. Mercu-
ry is associated with increased tissue oxidative damage, and
77
Kevin M. Rice, et al.
children with autism had significantly higher urinary levels of production causes a compensatory rise in adrenocorticotropic
lipid peroxidation when compared to controls. In the periph- hormone leading to adrenal hyperplasia. Mercury-induced ad-
eral nervous system, circulating inorganic mercury can be tak- renal hyperplasia may eventually stress the adrenal to a point
en up into the nerve terminals where it can impair the synthe- at which there is adrenal atrophy and may be a causative factor
sis of tubulin and actin which are important constituents of in the development of Addison’s disease [43].
neuronal cell structure and detoxification processes [53]. Pri- Autopsy studies in 1975 revealed that the thyroid and pitu-
mary sensory neuropathy is a hallmark of MeHg poisoning. itary retain and accumulate more inorganic mercury than the
In the central nervous system mercury can damage the kidneys [59]. Mercury levels in the pituitary gland ranged from
blood brain barrier and it facilitates penetration of the brain 6.3 to 77 ppb in one study, while another found the mean lev-
by other toxic metals and substances. The effects of mercury els to be 28 ppb, levels found to be neurotoxic and cytotoxic
poisoning effects in the central nervous system include de- [60]. Low levels of pituitary function are associated with de-
pression, paranoia, extreme irritability, hallucinations, an in- pression and suicidal thoughts, and appear to be a major fac-
ability to concentrate, memory loss, tremors of the hands, tor in suicide of teenagers and other vulnerable groups. Be-
head, lips, tongue, jaw and eyelids, weight loss, perpetually cause of its effect on the pituitary, mercury is known to cause
low body temperature, drowsiness, headaches, insomnia, and frequent urination as well as high blood pressure [61].
fatigue. Along with nervous system effects, mercury has also The thyroid is one of the largest endocrine glands in the
shown to have various effects on other special sensory sys- body. The thyroid controls how quickly the body burns energy,
tems including blindness, retinopathy, optic neuropathy, hear- makes proteins, and how sensitive the body should be to oth-
ing loss, a reduced sense of smell, and abnormal touch sensa- er hormones. Like the pituitary, the thyroid displays an affinity
tion [54]. Autism is a syndrome characterized by impairments for accumulating mercury. Mercury blocks thyroid hormone
in social relatedness, language and communication, a need for production by occupying iodine-binding sites and inhibiting
routine and sameness, abnormal movements, and sensory or altering hormone action leading to the impairment of body
dysfunction [55]. Mercury can cause immune, sensory, neuro- temperature control, hypothyroidism, thyroid inflammation
logical, motor, and behavioral dysfunctions similar to traits defin- and depression [43,61].
ing or associated with autism [56] leading some to suggest that Like the thyroid, the pancreas is also susceptible to the toxic
many cases of autism may be a form of mercury poisoning [55]. effects of mercury. Insulin, the molecule involved in diabetes,
has three sulfur-binding sites which can be bound by mercury
EFFECTS ON THE ENDOCRINE SYSTEM causing the interference with normal biological function and a
dysregulation of blood glucose levels [62].
Low exposure levels of mercury may affect the endocrine
system in animals and people by disruption of the pituitary, EFFECTS ON THE REPRODUCTIVE SYSTEM
thyroid, adrenal glands and pancreas [57]. It is thought that
mercury might impair endocrine function through its ability Mercury can precipitate pathophysiological changes along
to reduce hormone-receptor binding or through the inhibition the hypothalamus-pituitary-adrenal and gonadal axis that
of one or more key enzymes or steps in hormone biosynthesis may affect reproductive function by altering the circulating of
as is seen in the case of adrenal steroid biosynthesis and the levels of follicle-stimulating hormone (FSH), luteinizing hor-
inhibition of 21α-hydroxylase [58]. Hormones that appear to mone (LH), inhibin, estrogen, progesterone, and the andro-
be the most affected by mercury are insulin, estrogen, testos- gens [63,64]. Reduced fertility among dental assistants with
terone, and adrenaline. occupational exposure to mercury has been noted [65,66].
Mercury can also inhibit catecholamine degradation through Studies in Hong Kong demonstrated that increased mercury
inactivation of S-adenosyl-methionine which can cause the ac- levels were associated with infertility in both men and women
cumulation of epinephrine and hyperhidrosis, tachycardia, pty- [67]. In males, mercury can have adverse effects on spermato-
alism (hyper salivation) and hypertension [1]. In the adrenal genesis [68], epididymal sperm count, and testicular weight. Ev-
cortex, mercury exposure has been found to be associated with idence also exists linking mercury with erectile dysfunction [64].
lowered plasma levels of corticosterone [58]. Reduced cortisol In females, mercury has been shown to inhibit the release of
78
Systemic Toxicity of Mercury
FSH and LH from the anterior pituitary which in turn can effect form of mercury is detrimental to public health. Evaluation of
estrogen and progesterone levels leading to ovarial dysfunc- the epidemiological consequences of mercury toxicity over
tion, painful or irregular menstruation, premature menopause, the years has added greatly to the understanding of mercury
and tipped uterus [62]. There is good evidence linking mercury toxicity and its human impact. History has left us with a wide
with menstrual disorders including abnormal bleeding, short, array of information regarding the effects of mercury toxicity:
long, irregular cycles, and painful periods [63]. the earliest recorded death by mercury of the Qin Shi Huang
first emperor to unify China [78], the “Mad Hatter disease”
FETOTOXICITY among milliners in the 18th and 19th centuries [79], the mer-
cury spill on board the two British ships the Her Majesty’s ship
In addition to reproductive issues, mercury is also associated (HMS) Triumph and HMS Philpps in 1810 [80,81], the appar-
with the fetotoxicity which can present as miscarriage, spon- ent death of approximately 60 men during the construction of
taneous abortions, stillbirth, and low birth weights [69]. In the Saint Isaac’s Cathedral in Russia between 1818 to 1858 from
neonate, mercury exposure during pregnancy has been linked the gold amalgam used for gilding [82], the mysterious death
to neural tube defects, craniofacial malformations, delayed of actress Olive Thomas in 1920 from ingestion of her hus-
growth, and others [69]. Mercury is known to cross the placen- band’s mercury pill used at the time to treat syphilis [83,84],
ta where it can inhibit fetal brain development resulting in ce- the event at the Norwich England seed packing facility in the
rebral palsy and psychomotor retardation in the latter stages 1930s where the term “Hunter-Russell syndrome” originates
of development [70,71]. In primates maternal MeHg blood [85], the 1950s industrial spill in Minamata and Niigat Japan
levels were moderatelyrelated to increased abortion rates and where it was defined as “Minamata disease” [4], the rural poi-
decreased oregnancy rates [72]. Embryopathic effects of soning in Iraq in 1971 to 1972 from MeHg-based fungicide
MeHg in humans have also been reported. Fetal autopsies in- [86], Karen Wetterhahn’s death at Dartmouth College in 1996
dicated a generalized hypoplasia of the cerebellum, decreased from a drop of dimethymercury of her latex gloves [87], Tony
number of nerve cells in the cerebral cortex, marked decrease Winneet’s accidental death from using liquid mercury to ex-
in total brain weight, abnormal neuron migration, and brain tract gold from old computer parts [88], the current finding of
centers and layer deranged organization [73-76]. MeHg easily mercury in 6.0% of skin-lightening products tested in one
enters through the placenta and damages the brain of the fe- study [89] and 47% of products tested in a Somali community
tus. Many exposed feti go on to develop infantile cerebral pal- contained mercury [90], the long term effects of the California
sy and there may be a relation with the development of Mina- Gold mining impact on mercury redistribution and potential
mata disease. Babies may be born with a variety of birth de- impact on human health [91], and the numerous links to hu-
fects. A study of 64 children exposed in utero to mercury and man consumption of mercury laden fish [92,93]. All of these
showing mercury associated damage included the following events have left us with an indelible account of the detrimen-
signs and symptoms: mental retardation (100%), primitive re- tal effects of mercury on human health. In light of these his-
flexes (100%), strabismus (77%), cerebellar ataxia (100%), dys- toric events and the toxicological evidence presenting in this
arthria (100%), chorea and athetosis (95%), deformed limbs review regarding the systemic effects of mercury on cellular,
(100%), hyper salivation (95%), epileptic attacks (82%), and cardiovascular, hematological, pulmonary, renal, immunologi-
growth disorders (100%) [6]. Mercury inhibits the trans mem- cal, neurological, endocrine, reproductive, and embryonic de-
brane transport of nutrients including selenium in the placen- velopment, efforts should be made to insure adequate steps
ta. In animal experiments it has also been shown that there is are taken in public health and prevention to reduce the occur-
a much higher accumulation of mercury in the fetal brain tis- rence of mercury exposure and raise public awareness.
sue than in the maternal brain tissue [77].
CONFLICT OF INTEREST
CONCLUSION
The authors have no conflicts of interest with the material
It is evident by the number of organ systems and cellular presented in this paper.
functions affected by mercury that exposure to the various
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Kevin M. Rice, et al.
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Systemic Toxicity of Mercury
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