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    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 g/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 g/day (National Research Council, 1978; Nriagu,
    1979).

         Excluding fish, most foods contain very low levels of total
    mercury (i.e. less than 0.01 g/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 g/g. Some fish species, such as,
    swordfish, shark and tuna have been shown to contain much higher
    levels (i.e. up to several g/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 g/kg bw to 3 or 4 g/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
    g/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
    g/litre is virtually equal to the numerical value of the daily
    intake in g/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/M, MeHgCl;       positive      Verschaeve
    aberrations      lymphocytes         or 30/M, 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
    -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 -
    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 g/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 g/kg bw/day (8 monkeys) or 70 g/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 g/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 g/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 g/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 g/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 g 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 g Hg/kg bw/day where
    non-progressive neurological signs developed after 60 weeks of
    treatment. Pathological changes, observed at 46, 74 and 176 g 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 g 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 g 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 g 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 g Hg/ml (Group 1) and 0.01-0.12 g 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 g 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 g Hg/kg
    bw/day for 52 months. All animals in the 300 and 100 g 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 g 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 g 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 g/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 g 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 g 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 g 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 g
    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 -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 g/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 g/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 g Hg/kg bw/day were
    indicated in short- and long-term studies with rats, cats and monkeys,
    respectively. When the intake level reached 50 g 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 g (3.3 g/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 g/g, species such as
    swordfish, shark and tuna may contain levels up to several g/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.

    REFERENCES

    Amin-Zaki, L., Majeed, M.A., Greenwood, M.R., Elhassani, S.B.,
    Clarkson, T.W. & Doherty, R.A. (1981). Methylmercury poisoning in the
    Iraqi suckling infant: a longitudinal study over five years.
     J. Appl. Toxicol. 1, 210-214.

    Aschner, M. (1987). Changes in axonally transported proteins in the
    mature and developing rat nervous system during early stages of
    methyl-mercury exposure.  Pharmacol. Toxicol., 60, 81-85.

    Bartolome, J., Whitmore, W.L., Seidler, F.J. & Slotkin, T.A. (1984).
    Exposure to methylmercury in utero: effects on biochemical development
    of catecholamine neurotransmitter systems.  Life Sci., 35, 657-670.

    Berlin, M. (1986). Chapter 16: Mercury. In: Friberg, L., Nordberg,
    G.F. & Vouk, V.B. (eds.)  Handbook on the toxicology of metals, 2nd
    edition. Elsevier Science Publishers, Amsterdam, New York, Oxford,
    Vol. II, pp. 387-445.

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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)