METHYLMERCURY
EXPLANATION
Mercury was previously evaluated at the sixteenth and
twenty-second meetings of the Joint FAO/WHO Experts Committee on
Food Additives (Annex 1, references 30 and 41). The Committee
established a provisional tolerable weekly intake for total mercury
(Hg) of 0.3 mg of Hg/person, equivalent to 0.005 mg/kg bw for
adults, and a provisional tolerable weekly intake for methylmercury
of 0.2 mg of Hg/person, equivalent to 0.0033 mg/kg bw for adults.
Two other WHO publications have dealt with effects of mercury and
methylmercury on human health (WHO, 1976; WHO, 1986). Relevant
information in the IPCS Environmental Health Criteria document on
Methylmercury (WHO, in preparation) and studies published since the
report of the twenty-second meeting are summarized and discussed in
the following monograph.
DIETARY EXPOSURE
In nature, methylmercury (MeHg) is produced from inorganic
mercury as a result of microbial activity. This microbial
methylation of inorganic mercury is likely to occur in upper
sedimentary layers of lake or sea bottoms and the MeHg formed is
rapidly taken up by living organisms in the aquatic environment
(Friberg et al., 1986).
A number of studies have been conducted to investigate mercury
levels and forms in air. Excluding industrial areas, proximity to
volcanoes and mercury ore deposits, levels of total mercury in air
were generally less than 10 ng/m3. Of this total, mono- and
di-methylmercury accounted for approximately 22%. The intake of
MeHg from air for the general population is estimated to be less
than 0.04 µg/day, and therefore, air is not considered a
significant source of this organometallic substance (deTemmermann
et al., 1986; Mitra, 1986; National Research Council, 1978;
Nriagu, 1979).
Mean total mercury levels in rivers, lakes and groundwater
range from 10-50 ng/l. It is recognized that mercury can form
stable complexes with various organic ligands in the water.
However, it appears that such MeHg compounds are rapidly taken up
by biota since less than 1.0 ng/l of mercury in the methylated form
has been found in non-polluted waters. Assuming consumption of 1.5
to 2.0 l water daily, the intake of MeHg from this source would be
less than 0.002 µg/day (National Research Council, 1978; Nriagu,
1979).
Excluding fish, most foods contain very low levels of total
mercury (i.e. less than 0.01 µg/g) which is almost entirely
inorganic mercury. Fish and shellfish contain much higher mercury
levels and although variable, most of this mercury is in the form
of MeHg. This situation arises from fish feeding on aquatic
organisms that contain MeHg. The amount of mercury in fish has been
shown to be correlated with a number of factors including the size
and age of the fish, the species (e.g. predatory species normally
contain higher mercury levels), as well as the mercury content in
water and sediment and the pH of the water. Levels of MeHg in most
fish are generally less than 0.4 µg/g. Some fish species, such as,
swordfish, shark and tuna have been shown to contain much higher
levels (i.e. up to several µg/g). Intakes of MeHg from fish are
dependent on fish consumption habits and the concentration of MeHg
in the fish consumed. Fish consumption for many individuals is of
the order of 20-30 g/day or less. For certain ethnic groups,
however, consumption of 400-500 g fish/day is not atypical. Thus,
daily dietary MeHg intakes can easily range from less than 0.2 or
0.2 µg/kg bw to 3 or 4 µg/kg bw (Ministry of Agriculture, Fisheries
and Food, 1987; Health and Welfare Canada, 1979; Kirkpatrick &
Coffin, 1977; Schelenz & Diehl, 1973; Stijve & Besson, 1976;
Reilly, 1980).
In summary, food and in particular fish, represents the major
route of human exposure to MeHg. Daily dietary MeHg intakes vary
widely and for some segments of the population can reach several
µg/kg bw.
BIOLOGICAL DATA
Biochemical aspects
Based on a number of recent reports (WHO, 1988; Berlin, 1986;
WHO, 1986) Hg exists in 3 oxidation states: Hg° (metallic), Hg2++
(mercurous) and Hg++ (mercuric). The latter 2 states can form
numerous inorganic and organic chemical compounds. Of these, MeHg
is the predominant potential hazard to human health. MeHg is
effectively absorbed (in excess of 90%) in the gastrointestinal
tract of humans and animals, whereas inorganic Hg is poorly
absorbed. Once absorbed, MeHg is distributed in the blood stream to
all organs and tissues rapidly. It can also pass the blood/brain
"barrier" into the central nervous system (CNS) and the placental
"barrier" into the fetus. When the distribution process is
completed, the blood/brain, blood/hair and maternal blood/cord
blood ratios in humans are about 5-10 to 1, 1 to 250 and 1 to 1.2,
respectively. Within the body tissues MeHg may be converted to
inorganic Hg, although the site of demethylation is not clear. This
conversion is also known to occur in the gastrointestinal tract by
action of microflora.
In red blood cells, MeHg is known to complex to glutathione or
other low molecular weight thiols; these compounds are believed to
play a role in blood transport, tissue distribution and biliary
secretion of MeHg. MeHg secreted into the intestinal contents is
largely reabsorbed into the blood stream and subsequently creates
a secretion-reabsorption cycle. The significance of this
enterohepatic circulation in humans is not yet known.
The rate of excretion of Hg in humans dosed with MeHg is
directly proportional to the body burden. Observation on adult
volunteers exposed to MeHg of various sources revealed that the
average half-times are 70 days in whole body, 50 days in blood and
72 days in hair. Lactating females usually have a lower half-time
(42 days) than nonlactating females (79 days). In infants no direct
observations on the excretion of Hg have been reported. But it has
been shown that in infant monkeys and suckling mice, biliary
excretion of Hg is virtually absent.
The accumulation of MeHg in the whole human body is known to
follow a single compartment model and can be described by the
equation:
A = (a/b)(1-exp)(-b × t)
where: A = the accumulated amount
a = the amount taken up by the body daily
b = the elimination constant, and
t = time
This equation, with the half-time of 70 days in adults,
indicates that the body burden in humans will reach a steady state
(intake equal to excretion) in 5 half-times (approx. 1 year).
Accordingly, the maximum body burden of Hg will be about 100 times
the average daily intake/person and approximately 1.0% of the body
burden will be found in one litre of blood or, in other words, the
numerical value of the concentration of Hg in whole blood in
µg/litre is virtually equal to the numerical value of the daily
intake in µg/day/70 kg bw.
Toxicological studies
Special studies on carcinogenicity
Mice
Groups (60/sex/group) of 5 week old ICR mice were fed diets
containing 0, 15 or 30 ppm MeHgCl for 78 weeks. All mice were
examined macroscopically and the kidneys histologically. Most of
the mice in the 30 ppm group died due to neurotoxicity by week 26.
In the 15 ppm group, a renal mass was seen in one male at week 58.
Histological examination of the kidneys from the survivors after 53
weeks revealed renal tumours in 13 (11 adenocarcinoma and 2
adenoma) of 16 males in the 15 ppm group in contrast to 1 (adenoma)
of 37 males in the control. No renal tumours were seen in females
of either the control or MeHgCl-treated groups (Mitsumori et al.,
1981).
In a follow-up study, groups of ICR mice (60/sex/group) were
fed MeHgCl at dietary levels of 0, 0.4, 2 or 10 ppm for 104 weeks.
During the feeding period, 6 males and 6 females from each group
were sacrificed at intervals of 26 weeks for histological
examination. All survivors at termination and those found dead or
killed in extremis were also examined histologically. A compound
related increase of renal tumours were observed in male mice only.
In the 10 ppm group the incidences of adenoma and adenocarcinoma
were 3/59 and 10/59, respectively; the corresponding incidences for
the control were 1/58 and 0/58. No renal rumours were found in
other MeHgCl-treated groups (Hirano et al., 1986).
Special studies on embryotoxicity and/or teratogenicity
Mice
The developing fetus has shown the greatest degree of
sensitivity to the toxicity of MeHg (WHO, 1976). This is borne out
by a recent study in which pregnant mice received a single i.p.
injection of 0.4 or 8 mg/kg MeHg dicyandiamide on day 7, 9 or 12 of
gestation. Fostering and cross-fostering procedures were carried
out at birth to partition the effects of prenatal and postnatal
exposure on two parameters: survival and weight gain. Prenatal
exposure caused twice the level of mortality as postnatal exposure
and the effect was greatest when administered late in the period of
organogenesis. There were no apparent effects on the maternal animals
(Spyker & Spyker, 1977). These data indicate that in utero exposure
to MeHg may be more critical than postnatal exposure via the mother's
milk.
Groups of IVCS female mice (10 or 14/group) were given MeHgCl
or MeHgCl plus selenite from precoital day 30 to gestation day 18
at 4 dose levels: 15.9 nmol MeHgCl/g feed; 15.9 nmol MeHgCl/g feed
plus 11.4 nmol selenite/ml drinking water; 31.9 nmol MeHgCl/g feed;
31.9 nmol MeHgCl/g feed plus 11.4 nmol selenite/ml drinking water.
Following treatment the mice were sacrificed for determination of
Hg in organs and tissues, and the fetuses examined. Gross
abnormalities of fetuses were noted in two mice only. The co-
administration of selenite did not decrease the fetal toxicity of
MeHgCl (Satoh & Suzuki, 1983).
Groups of pregnant ICR Swiss/Webster mice (12/group) were
given MeHgCl by gavage at doses of 5, 15, 20, 25 or 30 mg/kg bw on
day 9 of pregnancy; control mice received a corresponding volume of
saline. On gestation day 18, the mice were laparotomized and the
fetuses were examined. A significant increase in fetal toxicity,
including weight loss, resorption, abortion etc, was observed with
doses of 15 mg/kg bw or higher. At the 5 mg/kg bw level the mean
weight of fetuses was reduced as compared to that of controls, but
no gross or skeletal abnormalities were detected (Curie et al.,
1983).
Groups of pregnant ICR mice (20/group) were gavaged with
MeHgCl at 0, 10, 15, 20 or 25 mg/kg bw on day 10 of gestation. On
gestation day 18 the mice were laparotomized and the fetuses were
examined. The number of resorbed or dead embryos in the 25 mg/kg bw
group was moderately increased, and the weight of fetuses in the
15, 20 and 25 mg/kg bw groups were decreased as compared to the
controls. In the treated groups, dose-related increases in the
incidences of malformations and skeletal variations were also
observed. The lowest level at which cleft palate, hydronephrosis
and incomplete fusion of sternebrae were observed was 15, 20 and 10
mg/kg bw, respectively (Fuyuta et al., 1979).
In a later study, exposure of the pregnant mice on day 12 was
found to give a higher incidence of cleft palate than when treated
on day 10 (Yasuda et al., 1985).
Rats
Injection of MeHgCl (0 or 4 mg Hg/kg bw) into pregnant
Sprague-Dawley rats (4/group) on the eighth day of pregnancy
resulted in degenerative changes in the proximal convoluted tubules
in the kidneys of neo-nates. These changes included accumulation of
lysosomes, enlargement of apical vacuoles, cytoplasmic vacuolation
and extrusion of large cellular casts into the tubular lumen. In
addition, hyperplastic changes were reported in the distal
convoluted tubules including hyperplastic thickening of the tubular
linings. The number of mitotic cells was also increased (Chang &
Sprecher, 1976a; 1976b).
Degenerative changes in the developing nervous system after
in utero exposure to Hg were studied by Chang et al. (1977).
Pregnant Sprague-Dawley rats were injected with MeHgCl on the
eighth day of pregnancy; tissue samples of the cerebral and
cerebellar cortex were taken from selected pups at birth. Although
the pups appeared to be physically normal, ultrastructural
examination revealed various degenerative changes, the most
prominent being disruption and myelin figure formation of the
nuclear membranes together with large areas of focal degradation
and endothelial damage.
Groups of pregnant Wistar rats (21/group) were given MeHgCl
equivalent to 0 or 2.5 mg Hg/kg bw by gavage, from gestation day 6
to 12. On gestation day 21, the females were laparotomized, fetuses
examined and removed. The number of fetuses with delayed
ossification of sternebra vertebrae or os occipital was
significantly higher in the MeHgCl treated group than in the
control group. Apart from this, there were no adverse effects on
the number of implantations, corpora lutea, live fetuses and
resorptions, and on fetal length and fetal weight (Chmielnicka et
al., 1985).
Special studies on mutagenicity
Endpoint (test) Test Object Concentration Results References
Chromosomal Hamster bone 6.4 or 12.8 mg Hg negative Watanabe
abberrations marrow cells /kg bw of MeHgCl et al., 1982
and oocytes (in vivo)
Sister Mouse bone 5 mg MeHgCl negative Curle et al.,
chromatid marrow cells /kg bw (in vivo) 1983
exchanges
Chromosomal Hamster oocytes 10 mg MeHgCl positive* Mailhes, 1983
aberrations /kg bw (in vivo)
Dominant BALB/c mice 2.5 mg MeHgCl positive Verschaeve
lethal assay /kg bw & Leonard, 1984
Chromosomal Human 5-30/µM, MeHgCl; positive Verschaeve
aberrations lymphocytes or 30/µM, HgCl2 et al., 1985
(in vitro)
* Hyperploidy but not structural aberrations.
Special studies on neurotoxicity
Mice
Groups of pregnant C3H/HeN mice (10/group) were given a single
dose of MeHgCl at 20 mg/kg bw on one of days 13 through 17 of
pregnancy. One group served as controls. After birth, the newborns
were examined once a week for behavioural changes. Several
treatment-related behavioural symptoms (reduction of spontaneous
locomotor activity, strong flexion and crossing of the hind limbs when
held by the tail, disturbance of righting movement when dropped from
about 40 cm high) were observed. At 10-12 weeks of age the pups were
sacrificed and the brain was examined histologically. In the treated
groups the lateral ventricles of the brain were dilated. The nucleus
caudatus putamen was reduced in size. Some fissure and sulci of the
cerebellum disappeared or became shallow. The cortical architecture of
the cerebellum was, however, well preserved (Inouye et al., 1985).
Hamsters
Groups of pregnant Golden hamsters (Mesocricetus auratus)
(10/group) were given, orally, a single dose of 10 mg MeHg/kg bw on
gestation day 10 or daily doses of 2 mg MeHg/kg bw on gestation days
1015. Two additional groups of pregnant hamsters received saline in
the same manner to serve as controls. Light and electron microscopic
examinations on the brain of the pups on postnatal days 10-15 showed
that degenerating or pyknotic cells in the external granular layer and
swollen dendrites in the internal granular layer of the cerebellar
cortex were more frequently observed in both of the Hg treated groups
than in the controls. At 275-300 days of age, astrogliosis in the
molecular layer and degenerative changes of myelinated axons in the
internal granular layer of the cerebellum were identified in the
treated animals. This morphological residua of injury was suggested by
the authors to be a potential threat to the neurological integrity of
the exposed animal (Reuhl et al., 1981a; 1981b).
Rats
Six young male Charles River rats were given MeHgCl via
intubation at 2.0 mg/kg bw/day for 8 weeks; another 6 rats were given
equal volumes of saline solution. After the treatment the dorsal root
spinal ganglia and fibers were removed for light and electron-
microscopic examinations. In the treated group, extensive changes
(axonal degeneration and myelin degradation) were observed in
the dorsal root fibers but not in the dorsal root neurons and the
ventral root fibers. These changes were suggested by the authors to be
an important morphological criteria for early detection of MeHgCl
toxicity (Yip & Chang, 1981).
Groups of pregnant Long-Evans rats were intubated with a single
dose (0, 5 or 8 mg Hg/kg bw) of MeHg on day 8 or 15 of gestation.
Administration of MeHg at 5 mg Hg/kg bw showed no apparent effect on
maternal weight gain, pup and litter size. At 8 mg Hg/kg bw, the
weight gain of females (given MeHg on day 8 of gestation) was
significantly reduced, but the pup weight and the litter size were not
affected. There was an increased neonatal motor activity at both
treatment levels. However, when the rats were tested (two operant
tasks) after 9 weeks and 5 months, only the 8 mg/kg bw group rats were
different from controls. The authors suggested that a single prenatal
exposure to MeHg can affect learning and drug sensitivity of the adult
rat (Eccles & Annau, 1982a; 1982b).
Two litters of Sprague-Dawley neonatal rats (8 pups/litter) were
s.c. injected with MeHgCl at 1.5 mg Hg/kg bw every 2 days from
postnatal day 2 to day 50. Control littermates of similar body weight
were injected with an equivalent volume of saline. All animals were
sacrificed and cerebral cortex were properly prepared for
electron-microscopy. No apparent differences in body weight, brain
weight and gross pathological changes in the cerebral cortex between
the treated and control groups were observed. In the treated rats
there were pronounced mitochondrial ultrastructural changes (including
swollen matrix, disrupted inner membrane and accumulation of
electron-dense material) in the dendrites, axons and presynaptic
terminals of cortical neurones (O'Kusky, 1983).
Groups of pregnant rats (Sprague-Dawley) were intubated with 0 or
8 mg/kg bw of MeHgCl on day 8 of gestation. After conducting
neurochemical and behavioural tests on the pups (15-60 days of age),
the authors suggested that prenatal exposure to MeHg at doses that do
not result in overt signs of toxicity may still induce long lasting
behaviour alterations (Cuomo et al., 1984).
Groups of Sprague-Dawley rats were s.c. injected with MeHgOH at
0, 0.5, 1.0 or 2.5 mg Hg/kg bw/day from day 8 to 21 of gestation.
Immediately after birth, each litter was culled to 10-11 pups and the
pups were sacrificed at intervals of 5-9 days throughout postnatal
development (33 days of age). No effects were observed on body weight
gain, litter size and organ weights of the pups in the treated group
up to 1.0 mg Hg/kg bw. However, at about 3 weeks of age, the level and
the turnover rate of brain dopamine but not the brain norepinephrine
in the 1.0 mg Hg/kg bw group were significantly lower whereas the
dopamine syaptosomal uptake and norepinephrine syaptosomal uptake were
elevated as compared to the controls. At this level and at the lower
dose level (0.5 mg Hg/kg bw) the activity of brain ornithine
decarboxylase showed an early elevation (3 days of age) and postnatal
decline (5 to 12 days of age). These biochemical changes indicate that
prenatal exposure to MeHg at subtoxic dose levels produce
transmitter-selective alterations in synaptic dynamics and function
which may contribute to adverse behavioural outcomes (Bartolome
et al., 1984).
In a study to examine the relationship between histological
changes and Hg content in the CNS and some non-neural tissues, two
groups of male Sprague-Dawley rats (number and age not specified) were
dosed orally with MeHgCl at 0 and 8 mg/kg bw/day, respectively for 6
days. About 3 days after the last dose, the characteristic signs of
MeHg intoxication including hindlimb crossover and flailing reflex
were observed in the treated rats. The severity of these symptoms
increased rapidly up to 8 days and reached a plateau between days 17
and 31; the histological lesions in the CNS observed during this
period included axonal loss and demyelination (Wallerian degeneration)
in the lower brain stern and spinal cord, and nuclear pyknosis and
loss of the granular layer neurones of the cortex in the cerebellum.
The CNS, liver and kidneys all showed an affinity for Hg, but within
the CNS the regional distribution of Hg (localized histochemically)
was not closely related to the neuropathological changes (Hargreaves
et al., 1985).
Female Sprague-Dawley rats were given MeHg in the drinking water
at 12.5 ppm from day 2 of pregnancy and continued throughout the
gestation and suckling periods. Control animals received tap water.
The rats were observed daily for gross signs of toxicity such as
tremor or ataxia. At the time of delivery, the litter size was
recorded and reduced to 10 pups per litter. Each pup was weighed prior
to sacrifice (postpartum days 6, 12 and 18). Cerebellar tissue from
fetuses (day 15 of gestation) and from 6-, 12-, 15- and 24-day old
pups were examined histologically. No gross evidence of maternal Hg
intoxication or gross malformations in pups was observed. The pup
death rate in the treated group (33%) was, however, higher than in the
controls (2%). Ultrastructural examination on the external granular
layer of the cerebellar cortex on 6-, 12- and 18-day old pups revealed
that the total cerebellar cell count in the treated rats was reduced
as compared to the control, and the pattern of mitotic figures altered
(Howard & Mottet, 1986).
Two groups of young male Sprague-Dawley rats (8 rats/group) were
intubated with MeHgCl at 0 and 2 mg/kg bw/day, respectively for 5
weeks. Following the treatment, the motor and sensory innervation of
extensor digitorum longus muscles were examined histologically. Light
microscopic examination of silver-stained axons in the intramuscular
nerve bundles of the treated rats showed Wallerian-like degeneration
and a reduction in the number of nerve fibers. Disrupted axons were
predominantly sensory as 22% of spindle afferents and 90% of Golgi
tendon organ sensory fibers and about 14% of motor endings were
degenerated; the corresponding percentages for the controls were 0, 0
and 3.7%. The authors concluded that the abnormal reflexes, ataxia and
muscle weakness following Hg poisoning appear related to reduction of
proprioceptive feedback from muscle and tendons in addition to the
documented lesions in the CNS (Yip & Riley, 1987).
In a study on the effect of MeHg exposure on adrenergic receptors
in the developing brain of rats, three groups of in utero exposed
neonates (s.c. injection of MeHgOH at 0, 0.5 or 1.0 mg Hg/kg bw/day to
dams during gestation days 8 to 21) and another 3 groups which had
been s.c. injected with MeHgOH at 0, 1.0 or 2.5 mg Hg/kg bw/day on
postnatal days 1-21, were examined for their receptor binding
characteristics in three regions (cerebral cortex, cerebellum and
midbrain plus brainstem) of the brain. It was found that 1-, 2-, and
ß-receptor sites were most vulnerable to MeHg in the cerebellum
(develop last) and least in the midbrain plus brainstem (develop
earliest). Within the cerebellum, prenatal exposure to MeHgOH had no
consistent effect on receptor ontogeny, but postnatal exposure at 1.0
mg Hg/kg bw/day produced an acute reaction characterized by an initial
elevation (postnatal days 10 to 15) and followed by a sharp reduction
of receptor binding during postnatal days 15-32 (Bartolome et al.,
1987). In peripheral tissues, prenatal exposure to MeHgOH was also
found to reduce binding capability of alpha1-, alpha2-, and ß-
receptor sites in the liver and of alpha1-, and 2-receptor sites in
the kidney but not in other tissues such as heart and lungs (Slotkin
et al., 1987).
Groups of adult male Wistar rats (6-16/group) were fed diets
containing 0 or 20 ppm MeHgCl for 2 or 4 weeks. No differences in body
weight were noted between the control and MeHgCl treated groups.
Neurobehavioural examinations conducted on rats hung by the tail
showed that the incidence of flexion of hind legs was higher in the
MeHgCl treated group (12/31) than in the control group (0/26). At 24
hours after termination of MeHgCl treatment, there were no differences
in early evoked potential (EEP) among the three groups. The latency of
the peak wave EEP in the MeHgCl treated groups, however, was slightly
longer (3.8-4.2 ms) than in the control group (2.1 ms) (Yamamura
et al., 1986).
In a study to examine the mechanisms of neurotoxicity in terms of
disorder of protein synthesis and transport in the visual system, two
groups of adult female rats (Long-Evans strain) were intubated with
MeHgCl at 0 or 4 mg Hg/kg bw/day for 4-12 days. No clinical neuropathy
(hindlimb cross-over and paralysis) was observed, but the rate of
protein synthesis in the retinal cells and axonal transport in the
optic nerve were increased in the MeHgCl treated group compared to
controls (Aschner, 1986a, 1986b, Aschner et al., 1987a). This effect
was suggested by the authors to be an adaptive compensatory
regenerative response through induction of a small subset of proteins
(Aschner, 1987b).
Monkeys
Small doses of MeHg were administered to rhesus monkeys (Macaca
mulatta) daily for periods of up to 17 months. Blood was
periodically sampled for Hg concentration and routine clinical
diagnostic test. Behavioural tests sensitive to changes in peripheral
visual fields and in accuracy and rapidity of hand movement were
conducted continuously during the course of exposure. The blood Hg
levels increased initially to peak values at 1 to 2 months, then after
3 to 5 months of dosing the blood Hg levels began to decline even
though the dose remained constant. It was postulated that this decline
in blood Hg was due to a stimulation in mechanisms of MeHg excretion.
No deficits were detected in the behavioural parameters tested prior
to the development of neurological signs of toxicity (Luschei et al.
1977). Several studies have demonstrated behavioural effects (WHO,
1976) and observed onset of tunnel vision in monkeys exposed to MeHg
prior to the development of neurological signs of toxicity (Evans
et al., 1975). The question of whether or not behavioural effects
definitely occur prior to neurological signs is unresolved.
Five cynomalgus monkeys (Macaca irus) of either sex weighing
2.1 to 3.5 kg were given orally MeHgCl once a week at calculated doses
of 0.02, 0.03, 0.10, 0.23 and 0.23 mg Hg/kg bw/day for 181, 331, 126,
56 and 63 days, respectively. During the test, neurological
examinations and electrooculargraphy were carried out 1-2 times a
week. No clinical signs of toxicity or histological changes (at
termination) were detected in the first 2 monkeys (received the
minimum doses), but both monkeys exhibited spontaneous nystagmus and
positional nystagmus on post exposure days 371 (monkey 1) or 242
(monkey 2). The MeHgCl concentrations in blood at this time were 1.02
ppm (monkey 1) and 0.51 ppm (monkey 2). In the last 3 monkeys, in
addition to spontaneous nystagmus and positional nystagmus which
occurred at 1-2 weeks after the MeHgCl treatment, neurological
symptoms including neuronal degeneration with astrocytic proliferation
in the cerebral cortex and hyperreflexia of tendon reflexes were
observed. The blood concentrations of MeHgCl in these monkeys were not
sated (Kato et al., 1981).
Five cynomalgus monkeys (Macaca fascicularis) were given,
orally, MeHg at 50 µg/kg bw/day from birth to about 4 years old;
another 2 monkeys receiving no Hg served as controls. The blood Hg
concentration of the Hg treated monkeys peaked at 1.2-1.4 ppm and then
dropped after withdrawal of infant formula at 200 days of age to a
steady level of 0.6-0.9 ppm. The Hg treated monkeys showed no overt
signs of neurotoxicity and their food intake, weight gain and
haematological measurements were normal. But when tested between 3 and
4 years of age under conditions of both high and low luminance, all 5
Hg treated monkeys exhibited impairment of spatial visual function (at
high and/or low frequencies) as compared to the 2 controls. The
authors suggested that impairment of visual acuity may occur
independently of constriction of visual fields in infantile MeHg
poisoning (Rice & Gilbert, 1982).
Ten adult female monkeys (Macaca fascicularis) were given
MeHgOH in apple juice during the mating and pregnancy period at levels
of 50 µg/kg bw/day (8 monkeys) or 70 µg/kg bw/day (2 monkeys). As a
control group another 10 monkeys were given distilled water only.
Immediately after delivery, the infant monkeys were separated from
their mothers and housed and fed individually. There were no
differences between the exposed and control groups in birth weight and
clinical complications. At 30, 41 and 51 days of age the infants were
tested for visual recognition memory (Fagan's method). The Hg exposed
infants directed less visual attention to novel stimuli than did the
controls. The blood Hg level of the treated monkeys prior to the Fagan
test was 0.95-1.31 ppm (Gunderson et al., 1986).
Special studies on reproduction
Mice
Groups of BALB/c female mice (2-9/group) were given, orally, on
postfertilization day 9.5, 12.5 or 15.5 a 0, 3.6, 5.3, 8, 12, 18 or 27
mg Hg/kg bw dose of MeHgCl. MeHgCl treatment at 9.5 days
postfertilization caused no observed effects on dams (F0) and their
pups (F1) at doses up to 12 mg Hg/kg bw. In the 12.5 and 15.5-day
treatment groups however, there were dose related responses on the
fertility (capability of delivering viable pups) of F0 mice and on the
viability of F1 pups at 1 day postpartum. The estimated thresholds for
delivering viable pups for the 12.5- and 15.5-day treatment groups
were 8.0 and 5.3 mg/kg bw, respectively. Among the surviving F1 mice,
sterility (inability to produce offspring) did not occur in males at 4
months and in females up to 14 months of age, but there was a trend
toward a dose related reduction of litter size and survival rate of F2
females at 8.0 mg Hg/kg bw (Gates et al., 1986).
Rats
In a three-generation reproduction study, groups of 20 female and
10 male SPF-Wistar rats were fed diets containing 0 (controls), 0.1,
0.5 or 2.5 ppm MeHgCl. No adverse effects were noted on fertility or
lactation indices or the 21-day body weights of the pups, but the
viability index was impaired at the 2.5 ppm level in the F1 and F2
generations. No treatment-related effects were noted on body weight
gain, food intake, haematology or urinalysis. The relative weights of
kidneys, heart, spleen, brain and thyroid were increased at the 2.5
ppm level of all generations, but no significant histological changes
were observed.
In a special seven-week study involving the F3a generation, 20
female and 10 male weanling rats obtained from the four different
treatment groups were given diets containing 25 ppm MeHgCl. Evidence
of clinical toxicity in the form of signs of paralysis were seen at
the end of the feeding period, although there was no apparent
difference between the treated groups (Verschuuren et al., 1976b).
Monkeys
Groups of mature female monkeys (Macaca fascicularis) (7 or
8/group) were given, orally, 0, 50 or 90 µg/kg bw/day of MeHgOH. After
124 days of treatment, the monkeys were mated to non-treated males.
None of the females receiving MeHgOH exhibited signs of Hg poisoning
during the breeding and pregnancy period. The numbers of females with
reproductive failure (i.e. nonconception, abortion) were 0, 2 and 5,
respectively in the 0, 50 and 90 µg/kg bw/day groups. These females
had a higher blood Hg concentration than the other treated females. In
general, the infants in the treated groups had lower birth weight and
crown-rump length than those in the controls. In the 90 µg/kg bw/day
group, 4 females showed a marked increase in the number of licking
responses, mouth tremors and gross motor incoordinations after 177-392
days of treatment. The blood Hg concentration at the onset of these
clinical signs of toxicity ranged from 2.3 to 2.8 ppm (Burbacher
et al., 1984).
Adult male monkeys (Macaca fascicularis) (3/group) were given,
orally, 0, 50 or 70 µg/kg bw/day of MeHg for 20 weeks. In the treated
groups there were no consistent histological abnormalities in
testicular biopsies, but the mean % motile spermatozoa and the average
scores for sperm speed and forward progression were decreased
considerably as compared to the control (Mohamed et al., 1987).
Short-term studies
Rats
Groups of 4 male and 4 female weanling SPF-Wistar rats (body
weight 40-60 g) were given diets containing 0 (controls), 0.1, 0.5,
2.5, 12.5 or 250 ppm MeHgCl for two weeks. At the 250 ppm level only,
signs of CNS toxicity, weight loss and high mortality were observed.
The relative weights of the liver in females given 2.5 or 12.5 ppm and
of the kidneys in females given 12.5 ppm were significantly increased.
Similar, but not statistically significant, changes were observed in
the males. Hg concentrations in the kidneys increased significantly
with increasing dietary levels of MeHgCl. Hyperaemia and local
haemorrhages of the brain observed in the 250 ppm group could not be
further studied owing to the advanced degree of autolysis of the
tissues (Verschuuren et al., 1976a).
Groups of 15 male and 10 female weanling SPR-Wistar rats (body
weight 40-60 g) were given diets containing 0 (controls), 0.1, 0.5,
2.5 or 25 ppm MeHgCl for 12 weeks. Four males and 3 females died
before the end of the study. Most of the treatment-related effects
noted were reported in the group given 25 ppm and included: retarded
growth, reduced food intake, clinical signs of intoxication from week
nine onwards, increased neutrophil and decreased lymphocyte counts;
significant decreases in haemoglobin concentration, packed cell volume
and erythrocyte count (females only) as well as significant increases
in serum alkaline phosphatase, GPT and urea (males only). Analysis of
urine revealed increased protein and occasional presence of glucose
and blood. Activities of the liver enzymes aniline hydroxylase and
aminopyrine demethylase were increased whereas liver glycogen levels
were decreased; relative weights of kidneys, heart, adrenals and
thyroid in both sexes and of the pituitary, testes, and brain in males
were significantly increased. In addition, histological changes were
observed in many organs (Verschuuren et al., 1976a).
Cats
Groups of adult cats (4-5/group) were fed dosages of 3, 8.4, 20,
46, 74 or 176 µg Hg/kg/day for 39 months either as MeHgCl or as MeHg
contaminated fish. Total whole blood Hg levels were followed monthly.
Complete haematology as well as biochemical and microscopic urinalysis
were performed monthly. Neurological examinations were conducted
monthly and at increasingly frequent intervals as the animals
developed signs of MeHg toxicity. Complete gross and histopathological
examinations were conducted on all animals. No significant differences
on toxicity between groups receiving MeHgCl or MeHg contaminated fish
were observed. The lowest effect dose was 46 µg Hg/kg bw/day where
non-progressive neurological signs developed after 60 weeks of
treatment. Pathological changes, observed at 46, 74 and 176 µg Hg/kg
bw/day, were limited to the CNS and consisted of neural degeneration
with replacement by reactive and fibrillary gliosis. No compound-
related effects were noted in the groups receiving 20, 8.4 or
3 µg Hg/kg bw/day (Charbonneau et al., 1976).
Monkeys
Six male monkeys (Macaca mulatta) were given MeHgOH in apple
juice for up to 15 months and another 2 given equal volume of
untreated juice to serve as controls. In the treated group, the first
three were dosed at 125, 80 and 80 µg Hg/kg bw/day for 3.5, 7 and 12
months, respectively and sacrificed immediately (Group 1), the other 3
were dosed at 100, 80 and 90 µg Hg/kg bw/day for 10, 15 and 10 months,
respectively and sacrificed 2-5 months after cessation of the
treatment (Group 2). The mean blood Hg levels detected prior to
sacrifice were: 1.2-2.1 µg Hg/ml (Group 1) and 0.01-0.12 µg Hg/ml
(Group 2). Throughout the experiment, no obvious neurological or
behavioural effects were noted. Weekly blood chemistry and haematology
data were within normal limits. However, significant ultrastructural
changes in the liver (proliferation of smooth endoplasmic reticulum
and cytoplasmic vacuoles) and in the kidney (cytosomal vacuoles and
intracellular inclusion) were observed in Group 1; some of these
changes were also detected in Group 2. The authors concluded that
continuous exposure to MeHgOH at 50-125 µg Hg/kg bw/day for up to 1
year does not affect the general well being of the monkeys, but may
cause organelle ultrastructural changes although the significance of
these changes are still not known (Shaw et al., 1975; Luschei
et al., 1977; Chen et al., 1983).
Groups of 5 male monkeys (3 Macaca mulatta and 2 Macaca
fascicularis) were fed MeHgCl at 0, 10, 30, 100 or 300 µg Hg/kg
bw/day for 52 months. All animals in the 300 and 100 µg Hg/kg bw
groups exhibited characteristic signs of neurotoxicity including
ataxia, visual disturbance, tremor, loss of reflex and paralysis etc.,
at about 2 and 6 months, respectively. Also, lesions of the cerebral
cortex in the occipital lobe and tubular degeneration in the proximal
tubules of the kidney were observed. In the 30 and 10 µg Hg/kg bw
groups, the animals survived the experimental period without
exhibiting any clinical signs of toxicity and biochemical and
haematological changes, except a slight reduction in body weight gain
and an elevation of urea nitrogen content in the 30 µg Hg/kg bw group.
None of the animals in these 2 groups showed any histopathological
alterations in organs including the nervous system.
The total amounts of MeHgCl ingested during the 52-week period
were 39.6 and 13.2 mg Hg/kg bw in the 30 and 10 µg/kg bw groups,
respectively (Kawasaki et al., 1986).
Long-term studies
Rats
Groups of 25 male and 25 female weanling SPF-Wistar rats (body
weight 40-60 g) were fed diets containing 0 (controls), 0.1, 0.5 or
2.5 ppm MeHgCl for two years. No adverse effects relating to the
administration of MeHgCl were noted for body weight gain, food intake,
urinalysis, serum GPT, alkaline phosphatase and urea, microsomal liver
enzymes, histochemistry of the cerebellum and nature or incidence of
pathological lesions or tumours. Changes of significance included
increased neutrophil and decreased lymphocyte counts in males given
0.5 and 2.5 ppm after six months, as well as increased relative kidney
weight and histochemical changes in the kidney at the 2.5 ppm level
(Verschuuren et al., 1976c).
Groups of Wistar rats (50/sex/group) were fed MeHgCl in the diet
at levels of 0, 2, 10, 50 or 250 µg Hg/kg bw/day for up to 26 weeks.
The rats were observed daily for clinical signs of toxicity. Food
consumption and body weight were measured weekly. Haematology was
conducted at 0, 6, 12, 15 and 17 months of treatment, and histology
performed terminally. At 250 µg Hg/kg bw/day decreased body weight,
reduced food consumption, overt signs of neurotoxicity (hind leg
crossing, paralysis, loss of balance), demyelination of the dorsal
nerve roots (spinal cord) and peripheral nerves were observed. Male
rats in this and the 50 µg Hg/kg bw/day group also had decreased
haematocrit and haemoglobin values and renal damage such as fibrosis
of the glomerulus and dilation of Bowman's capsule. No adverse effects
were observed in the other dose groups. The authors indicated 10 µg
Hg/kg bw/day to be a no toxic effect level (Munro et al., 1980).
Groups of 5 week old Sprague-Dawley SPF rats (56/sex/group) were
maintained on diets containing 0, 0.4, 2 or 10 ppm MeHgCl for 130
weeks. Six to ten rats/sex/group were killed for clinical chemistry
and Hg analysis at weeks 13, 26, 52 and 78, and all survivors at week
130. The rats killed at week 130 were autopsied and examined
histologically. There were no apparent differences in behaviour,
general condition, body weight gain, food consumption, mortality,
haematology and blood chemistry measurements between the control and
Hg treated groups up to the 2 ppm level. In the 10 ppm group, toxic
effects such as ataxic gait and/or crossing reflex of hindlimbs were
noted in males after 22 weeks and in females after 46 weeks. The total
Hg levels in various tissues and organs reached a plateau after about
78 weeks. Histopathological examinations revealed no compound related
increase of tumour incidences, and pathological lesions in the
cerebrum and cerebellum. However, the incidences of peripheral sensory
neuropathy (loss of nerve cells in the spinal ganglion and nerve fiber
degeneration in the spinal dorsal root) in the 10 ppm group and the
incidences of cytoplasmic vacuolation and nuclear swelling in the
renal proximal tubular epithelium in the 2 ppm and 10 ppm groups were
significantly higher than in the controls. The rats with these renal
lesions were frequently accompanied by hyperparathyroidism (Mitsumori
et al., 1983; Mitsumori et al., 1984).
Observations in man
In four cases of MeHg poisoning due to the consumption of a pig
(the feed of which had been contaminated with Hg-dressed grain), the
neurological damage was reported to be severe in all cases but greater
in the young children. The most severe manifestations occurred in a
child who had been exposed in utero. The two younger children
(including the transplacental case) both, six years later, displayed
severe neurological impairment, manifested by blindness, spastic
quadriparesis and increased tendon reflexes (Snyder & Seelinger,
1976).
Associated with the neurological disorders seen in the Minamata
outbreak of Hg poisoning was renal tubular dysfunction; the quantities
of urinary renal tubular epithelial antigen and ß-2-microglobulin and
the ratios of these proteins to albumin were significantly (P > 0.05)
higher than those in healthy control subjects. The values observed
were reported to be almost identical with the values found in patients
with tubular proteinuria (Iesato et al., 1977).
The assessment of signs of MeHg poisoning and blood Hg values was
conducted on 89 inhabitants of two Indian reservations, Grassy Narrows
and White Dog in Ontario, Canada, who were consuming Hg-contaminated
fish. Thirty-seven of the 89 patients examined revealed sensory
disturbances. Other effects such as disturbance of eye movement (19
cases), impaired hearing (40 cases), contraction of visual field (16
cases), tremor (21 cases), hyperreflexia (20 cases), ataxia (8 cases),
dysarthria (5 cases) were also observed. The neurological symptoms
observed are characteristic of Hg poisoning. The symptoms were
considered mild and many of them were thought to be caused by other
factors. Blood Hg values for this population indicated that a
significant number of individuals had blood Hg levels above 100 ppb
with several above 200 ppb (Harada et al. 1976).
Since the previous reviews (WHO, 1976, 1978), more data has been
published and evaluated. Repeated analyses for Hg content in hair,
brain and other tissue samples and follow-up clinical examinations of
some victims in the Japanese outbreaks indicated that the lowest
observed effect level in the patients from Niigata area appeared to be
still valid: 50 ppm in hair or 200 ppb in blood. In the Iraqi
outbreak, the threshold body burden for paresthesia (earliest clinical
signs of Hg poisoning) was found to be 24-40 mg Hg (equivalent to
blood Hg level of 250-400 ppb). Statistical re-analysis of the Iraqi
data and other case reports revealed that in non-pregnant adults
intakes of 50 and 200 µg/person/day of MeHg would give rise to risks
of about 0.3% and 8%, respectively for the symptoms of paresthesia.
Pregnant women may be at a greater risk as paresthesia has also been
reported in pregnant women with hair Hg levels in the range of 10 to
70 ppm (WHO, 1989).
In addition to the dose-response relationship in adults, the
effect of prenatal exposure on psychomotor function in children was
also investigated. In a series of studies, a total of 84 mother-infant
pairs were selected from the Iraqi victims. These infants were
examined for retarded standing, walking and talking and findings were
related to their maternal hair Hg concentration. Five infants were
observed with severe psychomotor retardation and all were born to
mothers who had high hair Hg concentrations during pregnancy, ranging
from 165 to 320 ppm (Marsh et al., 1977, 1980, 1981).
To re-examine the relationship between maternal hair Hg
concentrations and neurological effects of these infants, the same
Iraqi hair samples were analyzed using X-ray fluorescence spectrometry
on single strands of hair instead of conventional atomic absorption
analysis of bundles of 50 to 100 hair strands. It was shown that as
the maternal hair Hg concentration exceeded 50 ppm the presence of
mental retardation and seizure in the infants was observed with
increasing frequency, and the onset of walking and talking delayed
considerably. Neurological scores graded on the basis of these
symptoms also exhibited a dose-dependent increase within the ranges of
maternal hair Hg concentrations of 23 to 674 ppm (Marsh, et al.,
1987). Statistical analysis of these data using both a non-parametric
model and 2 parametric models (Hockey Stick and Logit) indicated
further that the "practical threshold" maternal hair value during
pregnancy to be about 10 ppm for retarded walking (motor retardation)
of their children (Cox et al., 1988).
In an investigation conducted in Canada, 234 Cree Indians between
12 and 30 months of age, born to mothers who consumed MeHg
contaminated fish during pregnancy, were selected for a number of
examinations including: special senses, cranial nerves, sensory
function, muscle tone, stretch reflexes, coordination, Denver
development scale, These children were identified as the highest
Hg-exposed group in 4 communities (Mistassini, Great Whale, Waswanipi
and Fort George) of northern Quebec. Their maternal hair Hg levels
were at 24 ppm or lower and only 6% of them were greater than 20 ppm.
The neurologic findings showed that out of the 234 children, 13 boys
and 14 girls were observed with abnormal muscle tone or reflexes, but
there was no consistent dose-response relationship between the
maternal hair Hg levels and the prevalence of the abnormalities in the
children. No other neurologic disorders were found to be associated
with the exposure to MeHg (McKeown-Eyssen et al., 1983).
During the Iraqi epidemic, some infants born shortly before their
mothers consumed the contaminated bread were selected to assess the
adverse effect of exposure to MeHg through suckling breast milk. A
total of 30 infant/mother pairs were examined and monitored over a
period of 5 years and their blood and milk Hg levels were determined.
The average total blood Hg concentration for both infants and mothers
was higher than 200 ppb within 4 months after the outbreak. Organic Hg
accounted for 86 and 60% in the blood and milk, respectively. No
mental "destruction" and cerebral palsy were observed in the infants
during the study. Instead, hyperreflexia, delayed motor development
and delayed language development were diagnosed. These manifestations
persisted and became more obvious with time even when the blood Hg
level decreased to below 200 ppb (Amin-Zaki et al., 1981).
In Canada, an epidemiological study was conducted on 460 adult
Cree Indians in 2 communities (Mistassini and Great Whale) of Quebec
who were exposed to MeHg through consumption of local fish or
fish-eating animals. Each of these subjects was examined by one of
five neurologists for various abnormalities including: reduction of
visual fields, incoordination, tremor, nystagmus, sensory loss and
astereognosis. Tremor, incoordination and abnormal reflexes were
reported to be the most prevalent neurologic abnormalities among these
Indians, with their prevalence rates ranging from 6.5 to 15.4% in
Mistassini and 20.4 to 44.2% in Great Whale; the severity of these
abnormalities, however, were mostly assessed as being questionable or
mild (McKeown-Eyssen & Ruedy, 1983a). Further studies on 41
individuals with neurologic abnormalities and 179 controls, selected
from these two communities indicated that these neurologic
abnormalities were significantly associated with MeHg exposure in one
community (Mistassini) but not in the other (Great Whale). The mean
hair Hg levels were: 15.9 (males) and 16.7 (females) ppm for
individuals with neurologic abnormalities, and 10.7 (males) and 10.3
(females) ppm for controls in Mistassini; in Great Whale the
corresponding levels were 10.5, 10.1 and 5.6, 9.3 ppm (McKeown-Eyssen
& Ruedy, 1983b).
During 1979-1982, a surveillance program to monitor Hg exposure
in Indian and Inuit residents across Canada was carried out on 16,149
individuals in 243 communities. A total of 61 individuals were found
to have a peak blood Hg level of over 100 ppb, at least once during
the test period. Forty-eight of these "at risk" individuals were
subject to clinical neurological examinations and it was observed that
28 were with no abnormal findings and 20 were with abnormal findings
but not attributable to Hg exposure (Health and Welfare Canada, 1984).
In another study on Indians, a total of 200 male and 200 female
adults in the St. Regis Reserve (the convergence of New York State and
Ontario Province) were subjected to a short battery of performance
tests to determine whether the residents in the area were experiencing
adverse effects associated with undue intake of MeHg. The test scores
of the residents were examined in relation to their blood and hair Hg
levels and fish consumptions. The mean blood Hg levels and their
ranges were 3.16 (0.5-19.5) ppb in males and 1.94 (0.2-11.3) ppb in
females; and the mean hair Hg levels and their ranges were 0.80
(0.2-5.3) ppm in males and 0.53 (0.2-1.6) ppm in females. Of the Hg
found in the blood, about 73% was in organic forms. Both blood and
hair Hg levels were indicated to be correlated with local fish
consumption but not with performance test scores (Valciukas et al.,
1986).
In Greenland, blood samples were collected from 153 Greenlanders
and 25 Danes (served as controls) inhabited in the Angmagssalik
district. Hair was collected from 32 of the study participants. Hair
Hg levels were found to correlate well with blood Hg levels and the
hair/blood ratio was estimated to be 289. The blood Hg levels of the
153 Greenlanders were further divided into 3 groups according to their
consumption habits of seal meat: 1) at least 6 times weekly (Group 1);
2) 5 times weekly (Group 2); once a week or less (Group 3). The
average blood Hg levels found for the 3 groups were 63 ppb (Group 1),
25 ppb (Group 2), and 22 ppb (Group 3), as compared to 6 ppb in the
control (Danes). The authors indicated that the present relatively
high Hg exposure in Greenland does not constitute immediate risk to
the adult population, but more investigation on fetal exposure is
needed (Hansen et al., 1983).
In New Zealand, a study was carried out to investigate the effect
of prenatal exposure to fish Hg. From a cohort consisting of 11,000
mothers and their children, a total of 31 children of 4 years of age
from mothers who ate fish more than 3 times per week and had an
average hair Hg level during pregnancy of about 6 ppm were selected.
These children were matched with 30 control children of the same or
similar age, birthplace and ethnic origin but exposed to less Hg (none
of the mothers consumed fish more than once per week). The 2 groups of
children were "double-blind" tested by a specially trained nurse with
the Denver Development Screening Test (DDST), a vision test and a
sensory test. The DDST results showed that 52% (16/31) of the high Hg
children had abnormal or questionable performance and 48% (15/31) had
normal performance, in the control children 17% (5/30) had abnormal or
questionable performance and 83% (25/30) had normal performance. The
number of children in the high Hg group who could not understand or
failed the sensory test was greater (19/31) than those in the control
group (8/30). The vision test, however, showed no significant
difference between the 2 groups. The average peak maternal hair Hg
levels during pregnancy were 8.8 and 1.9 ppm in the exposed and
control groups, respectively. The corresponding mean hair Hg levels
for the two groups of children at the time of testing were 2.0 (range
0.5-9) and 1.3 (range 0.2-4) ppm. It was concluded that the prevalence
of developmental delay according to the DDST results will be at least
twice the background level for infants born to mothers with hair Hg
levels of 9-10 ppm (Kjellstrom et al., 1986).
COMMENTS
MeHg is readily absorbed (>90%) from the gastrointestinal tract
of man. The estimated whole-body half-time is 70 days. At steady
state, the whole-body burden is approximately 100 times the per capita
daily intake. The ratio of hair Hg to blood Hg is 250. At steady
state, a 1 µg/kg bw/day intake of MeHg would be expected to give,
approximately, total body burden (70 kg person), blood and hair values
of 7 mg, 70 ppb and 17.5 ppm, respectively.
Reproduction/teratology studies revealed that MeHg was fetotoxic
at 2.5 mg Hg/kg bw in rats, 10 mg Hg/kg bw in mice and 50 g Hg/kg bw
in monkeys and teratogenic (cleft palate) in mice at 15 mg/kg bw.
Several recent neurotoxicity studies in rats have demonstrated
behavioural alterations and histological changes following in utero
exposure to MeHg. In some studies this was observed even after a
single dose of 8 mg Hg/kg bw.
No-observed effect levels of 10, 20 and 30 µg Hg/kg bw/day were
indicated in short- and long-term studies with rats, cats and monkeys,
respectively. When the intake level reached 50 µg Hg/kg bw/day renal
damage in rats, neurobehavioural effects in monkeys and neuroal
degeneration in cats were observed. The effects observed in monkeys
were associated with a blood Hg level of 0.5-1 ppm. No increase in
tumour incidence was observed in the rat studies with MeHg. However,
in mice, MeHg increased the incidence of renal adenomas and
adenocarcinomas at a dietary level of 1.5 mg Hg/kg bw/day, but not at
0.06 or 0.3 mg Hg/kg bw/day.
The nervous system is the principal target tissue of MeHg in
humans. The earliest effects are non-specific symptoms, i.e.
complaints of paraesthesia, malaise and blurred vision. Results have
indicated that paresthesia is permanent/transient and thus its
significance on a long-term basis is unclear. The developing nervous
system is the most sensitive and, unlike in adults, the damage is
generalized throughout the brain.
In man, the previously observed lowest-effect blood Hg level of
200 ppb (50 ppm in hair) appeared to be still valid for adults, but
not for women of child bearing age and infants. This blood Hg level
has caused paresthesia in pregnant women and impaired development of
the nervous system in their fetuses and infants. The lowest Hg level
in the hair of mothers which has been related to paresthesia is 10 ppm.
EVALUATION
The Committee confirmed the previously recommended provisional
tolerable weekly intake of 200 µg (3.3 µg/kg bw) methylmercury for the
general population but noted that pregnant women and nursing mothers
are likely to be at greater risk to adverse effects from
methylmercury. The available data were considered insufficient at
present to recommend a methylmercury intake specific for this segment
of the population and further, more detailed studies are recommended.
The Committee was aware of an IPCS Task Group on methylmercury which
was also addressing this situation (WHO, 1989).
The Committee noted the distinction between elevated
methylmercury levels found in certain fish from unpolluted waters and
similar levels that can result from industrial pollution. In this
regard, levels of selenium and other naturally occurring trace
constituents in fish from unpolluted waters may play an important role
in moderating methylmercury effects. Therefore, it recommended that
further investigation of this hypothesis be undertaken.
The Committee was aware of the variation of naturally occurring
methylmercury levels in fish. This variation has been shown to
correlate with a number of factors including the size and age of the
fish, the species (e.g. predatory species normally contain higher
mercury levels), as well as the mercury content in water and sediments
and pH of the water. Thus, while most fish from unpolluted waters
contain methylmercury levels less than 0.4 µg/g, species such as
swordfish, shark and tuna may contain levels up to several µg/g. Fish
from contaminated waters can contain significantly higher
methylmercury levels.
Finally, the Committee is aware that fish is a nutritious food
and efforts are underway in many countries aimed at increasing fish
consumption as an integral part of a well-balanced diet. Furthermore,
the dietary habits of regional and ethnic groups have evolved over
centuries in response to their needs and are entrenched in their
culture. Any recommendations that imply the need to change these
habits should be based on compelling arguments and must not overlook
possible implications. Efforts should continue, however, to minimize
human exposure to methylmercury that results from industrial
pollution.
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See Also:
Toxicological Abbreviations
Methylmercury (EHC 101, 1990)
Methylmercury (WHO Food Additives Series 52)
Methylmercury (WHO Food Additives Series 44)
METHYLMERCURY (JECFA Evaluation)