Mercury was evaluated for provisional tolerable weekly intake for
    man by the Joint FAO/WHO Expert Committee on Food Additives in 1972
    and in a document entitled "environmental Health Criteria. 1. Mercury"
    (WHO, 1976). Since the publication of the latter document many studies
    have been published, the most relevant of which have been summarized

    Uptake, distribution and half-life of mercury following ingestion

         In a study using a modified whole-body counting technique, nine
    male and six female volunteers were given orally approximately 22 g
    total Hg (as methyl 203Hg) in fish proteinate, and five male and three
    female volunteers were given orally approximately 6 g total Hg (as
    inorganic 203Hg) in calf-liver paste. Approximately 20% of MeHg was
    found in the head and 10-15% in the legs 30 days after administration
    of MeHg. No significant amounts of 203Hg activity were found in the
    head during the first 58 days after the administration of inorganic
    Hg. A limited number of further measurements revealed the half-life of
    MeHg in the head region to be between 60 and 400 days while the
    half-life of inorganic Hg in the liver region was estimated to be of
    the order of 90 days (Hattula and Rahola, 1975).

    Elimination in the urine and faeces

         Methyl mercury salts have been shown to be converted to inorganic
    mercury in vivo and it is thought that intestinal microorganisms are
    an important factor in this conversion. Five germ-free ICR-JCL female
    mice and four conventional ICR-JCL female mice (controls), matched for
    age and body weight, received 1.0 ml drinking-water, containing methyl
    mercury chloride (MeHgCl) (20 g total Hg) for one day. Faeces and
    urine were collected every 24 hours thereafter, with the exception
    of the faeces during the first four hours which were collected
    separately. The mice were killed on day 10 and Hg levels in faeces,
    urine, brain, liver, spleen and kidney measured. The amount of Hg
    excreted in the urine was similar in both groups of mice. Germ-free
    mice excreted 24% of the administered Hg in the faeces, compared with
    46% by conventional mice. In addition, Hg levels in the tissues were
    slightly higher for germ-free mice than for the controls (Nakamura et
    al., 1977).

    Acute studies


         Groups of four male and four female weanling SPF-Wistar rats
    (body weight 40-60 g) were given diets containing 0 (controls), 0.1,
    0.5, 2.5, 12.5 and 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 and
    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).

    Short-term studies


         Groups of 15 male and 10 female weanling SPF-Wistar rats (body
    weight 40-60 g) were given diets containing 0 (controls), 0.1, 0.5,
    2.5 end 25 ppm MeHgCl for 12 weeks. Four males and three 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).

    Long-term studies


         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 and
    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).


         Adult cats were fed dosages of 3, 8.4, 20, 46, 74 and 176 g
    Hg/kg/day for 39 months either as methylmercury chloride or as
    methylmercury contaminated fish. Total mercury blood levels in whole
    blood 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 methyl-mercury
    toxicity. Complete gross and histopathological examinations were
    conducted on all animals. No significant differences on toxicity
    between groups receiving methylmercury chloride or methylmercury
    contaminated fish were observed. The lowest effect dose was 46 g
    mercury/kg body weight/day where non-progressive neurological signs
    developed after 60 weeks of treatment. Pathological changes, observed
    at 46, 74 and 176 g mercury/kg bodyweight/day, were limited to the
    central nervous system 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 mercury/kg
    body weight/day (Charbonneau et al, 1976).

         A recent study (Hollins et al., 1975) has demonstrated a 
    whole-body half-time for clearance of methylmercury in cats of 76 days.
    This is comparable to the value of 78 days reported in humans (WHO, 
    1976). Hollins et al. (1975) also indicated that the dose of 
    methylmercury required to produce a critical brain level of 
    methylmercury in the cat was approximately 10 times that required for 
    humans. This would suggest a minimum effect dose of methyl-mercury in 
    humans of 1/10 that in the cat or approximately 4 g/kg body 

    Reproduction (embryotoxicity)

         The developing foetus has shown the greatest degree of
    sensitivity to the toxicity of methylmercury (WHO, 1976). This is
    borne out by a recent study in which pregnant mice received a single
    intraperitoneal injection of 0.4 or 8 mg/kg methylmercury
    dicyandiamide on day seven, nine 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 and Spyker, 1977). These data indicate
    that in utero exposure to methylmercury may be more critical than
    postnatal exposure via the mother's milk.

         Pregnant Sprague-Dawley rats were given labelled MeHgCl by
    intubation (10 g/kg) on either days 10, 13, or 19 of pregnancy. The
    dams were killed 24-72 hours after administration of the compound and
    Hg levels of brain, kidneys, liver, heart, placenta and whole foetus
    determined. The foetal brain concentration was 3.4 times higher than
    the maternal brain concentration. The foetal brain was shown to
    accumulate 19 times more as a percentage of its whole-body weight
    compared to the maternal brain/body ratio (King et al., 1976).

         Degenerative and hyperplastic changes in the neonatal kidney
    after in utero exposure to Hg were studied by Chang et al., 1976a
    and b. Injection of MeHgCl into pregnant Sprague-Dawley rats on the
    eighth day of pregnancy resulted in degenerative changes in the
    proximal convoluted tubules.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.

         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.

         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 and 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 in 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 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 groups (Verschuuren et al., 1976b).

    Special behavioural studies


         Small doses of methylmercury were administered to rhesus monkeys
    (Macaca mulatta) daily for periods of up to 17 months. Blood was
    sampled for mercury concentration and routine clinical diagnostic test
    at intervals. Behavioural tests sensitive to changes in peripheral
    visual fields and in accuracy and rapidity of hand movements were
    conducted continuously during the course of exposure. The blood
    mercury levels increased initially to peak values at one to two
    months, then after three to five months of dosing the blood mercury
    levels began to decline even though the dose remained constant. It was
    postulated that this decline in blood mercury was due to a stimulation
    in mechanisms of methylmercury 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 Evans et al.
    (1975) observed onset of tunnel vision in monkeys exposed to
    methylmercury prior to the development of neurological signs of
    toxicity. The question of whether or not behavioural effects
    definitely occur prior to neurological signs is unresolved.

    Effects of mercury on 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
    for the younger 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 inpairment, manifested by blindness, spastic
    quadriparesis and increased tendon reflexes (Snyder and Seelinger,


         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 values found in patients
    with tubular proteinuria (Iesato et al., 1977).

    Sub-cellular effects

         Chromosome analyses of cultured lymphocytes from 21 men and seven
    women occupationally exposed to Hg and its phenyl and ethyl compounds
    or amalgams showed statistically significant increases in rate of
    aneuploidy compared with those of seven control subjects. No
    statistically significant differences, with the exception of ethyl-Hg
    exposure, were found in the frequency of cells with chromosomal
    aberrations, although the observed frequencies were higher for exposed
    subjects (Verschaeve et al., 1976).


         The assessment of signs of methylmercury poisonings and blood
    mercury values was conducted on 89 inhabitants of two Indian
    reservations, Grassy Narrows and White Dog in Ontario, Canada, who
    were consuming mercury-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),
    hyporeflexia (20 cases), ataxia (8 cases), dysarthria (5 cases) were
    also observed. The neurological symptoms observed are characteristic
    of mercury poisoning. The symptoms were considered mild and many of
    them were thought to be caused by other factors. Blood mercury values
    for this population indicated that a significant number of individuals
    had blood mercury levels above 100 ppb with several above 200 ppb
    (Harada et al., 1976). These data on the Canadian Indian population
    are in close agreement with those in which parasthesia was observed in
    Iraqi patients exposed to methylmercury with blood mercury levels
    between 200 and 300 ppb (WHO, 1976).


    Chang, L. W. and Sprecher, J. A. (1976) Degenerative changes in the
    neonatal kidney following in-utero exposure to methylmercury,
    Environ. Res., 11, No. 3, 392-406

    Chang, L. W. and Sprecher, A. (1976) Hyperplastic changes in the rat
    distal tubular epithelial cells, following in utero exposure to
    methylmercury, Environ. Res., 12, No. 2, 218-223

    Chang, L. W., Reuhl, K. R. and Lee, G. W. (1977) Degenerative changes
    in the developing nervous system as a result of in utero exposure to
    methyl-mercury, Environ. Res., 14, No. 3, 414-423

    Charbonneau, S. M., Munrow, I. C., Nera, E. A. and Armstrong, F. A. J.
    (1976) Chronic toxicity in methylmercury in the adult cat. In:
    Trace substances in environmental health-X. A symposium, Columbia,
    Mo., United States of America, University of Missouri, pp. 435-439

    Evans, H. L., Leties, V. G. and Weiss, B. (1975) Behavioral effects of
    mercury and methylmercury, Fed. Proc., 34, 1858-1867

    Harada, M., Fujino, T., Akagi, T. and Nishigaki, S. (1976)
    Epidemiological and clinical study and historical background of
    mercury pollution on Indian Reservations in Northwestern Ontario,
    Canada, Bulletin of the Institute of Constitutional Medicine,
    Kumamoto University, Kumamoto, Japan, 26, 169-184

    Hattula, T. and Rahola, T. (1975) The distribution and biological
    half-time of 203Hg in the human body according to a modified
    whole-body counting technique, Environ. Physiol. Biochem., 5.
    No. 4, 252-257

    Hollins, J. G., Willes, R. F., Bryce, F. R., Charbonneau, S. M. and
    Munro, I. C. (1975) The whole body retention and tissue distribution
    of (203Hg) methylmercury in adult cats, Toxicol. appl. Pharmacol.,
    33, 438-449

    Iesato, K., Wakashin, M., Wakashin, Y. and Tojo, S. (1977) Renal
    tubular dysfunction in Minamata disease. Detection of renal tubular
    antigen and beta-2-microglobin in the urine, Ann. intern. Med.
    86, No. 6, 731-737

    King, R. B., Robkin, A. and Shepard, T. H. (1976) Distribution of
    203Hg in pregnant and fetal rats, Teratology, 13, No. 3, 275-280

    Luschei, E., Mottet, N. K. and Shaw, C. M. (1977) Chronic
    methylmercury exposure in the monkey (Macaca mulatta), Arch.
    environm. Hlth, 32, 126-131

    Nakamura, I., Hosokawa, K., Tamura, H. and Miura, T. (1977) Reduced
    mercury excretion with feces in germfree mice after oral
    administration of methyl mercury chloride, Bull. Env. Contam.
    Toxicol., 17, No. 5, 528-533

    Snyder, R. D. and Seelinger, D. F. (1976) Methylmercury poisoning,
    J. Neurol. Neurosurg. Psychiat., 39, 701-704

    Spyker, D. A. and Spyker, J. M. (1977) Response model analysis for
    cross-fostering studies: prenatal versus postnatal effects on
    offspring exposed to methylmercury dicyandiamide, Toxicol. appl.
    Pharmacol., 40, 511-527

    Verschaeve, L., Kirsch-Volders, M., Susanne, C., Groetenbriel, C.,
    Haustermans, R., Lecomte, A. and Roossels, D. (1976) Genetic damage
    induced by occupationally low mercury exposure, Environ. Res., 12,

    Verschuuren, H. G., Kroes, R., Den Tonkelaar, E. M., Berkvens, J. M.,
    Helleman, P. W., Rauws, A. G., Schuller, P. L. and Van Esch, G. J.
    (1976) Toxicity of methylmercury chloride in rats.  I. Short term
    study, Toxicology, 6, 85-96

    Verschuuren, H. G., Kroes, R., Den Tonkelaar, E. M., Berkvens, J. M.,
    Helleman, P. W., Rauws, A. G., Schuller, P. L. and Van Esch, G. J.
    (1976) Toxicity of methylmercury chloride in rats. 2. Reproductive
    study, Toxicology, 6, 97-106

    Verschuuren, H. G., Kroes, R., Den Tonkelaar, E. M., Berkvens, J. M.,
    Helleman, P. W., Rauws, A. G., Schuller, P. L. and Van Esch, G. J.
    (1976) Toxicity of methylmercury chloride in rats. 3. Long-term
    toxicity study, Toxicology, 6, 107-123

    World Health Organization (1972) Evaluation of certain food additives
    and the contaminants mercury, lead and cadmium, sixteenth report of
    the Joint FAO/WHO Expert Committee on Food Additives, WHO Food
    Additive Series, No. 4

    World Health Organization (1976) Environmental health criteria.
    1. Mercury

    See Also:
       Toxicological Abbreviations
       Mercury (EHC 1, 1976)
       Mercury (ICSC)
       Mercury (WHO Food Additives Series 4)
       MERCURY (JECFA Evaluation)
       Mercury (UKPID)