WHO Food Additives Series, 1972, No. 4

    EVALUATION OF MERCURY, LEAD, CADMIUM
    AND THE FOOD ADDITIVES AMARANTH,
    DIETHYLPYROCARBONATE, AND OCTYL GALLATE

    The evaluations contained in this publication were prepared by the
    Joint FAO/WHO Expert Committee on Food Additives which met in Geneva,
    4-12 April 19721

    World Health Organization
    Geneva
    1972

                   

    1 Sixteenth Report of the Joint FAO/WHO Expert Committee on Food
    Additives, Wld Hlth Org. techn. Rep. Ser., 1972, No. 505; FAO
    Nutrition Meetings Report Series, 1972, No. 51.

    MERCURY

    Mercury occurs naturally in the environment and is contributed to by
    human industrial activity.  Because the natural background levels of
    mercury vary it is difficult to distinguish natural from artificial
    levels in any part of the environment.  Annual natural erosion and
    weathering is estimated to contribute some 5000 tons to the sea.
    Another 4000-5000 tons of mined mercury (about half the annual world
    production of 9000 tons) are lost to sea, soil and the atmosphere.
    Following absorption mercury accumulates in most living organisms.  It
    fulfils no known essential function in man or animals.

    There is much concern about the potential for human intoxication due
    to mercury in foodstuffs particularly fish.  The most serious toxic
    hazard arises from methylmercury residues in food (Lu et al., 1972).

    Sources

    (a) Environmental sources

    Air.  Mercury has a relatively high vapour pressure so that the air
    over mercury and its ore deposits generally contains elevated levels
    of mercury (0.2-20 µg Hg/m3).  Small amounts are also found over
    non-mineralized land areas (0.003-0.009 µg Hg/m3), while
    insignificant amounts occur over the oceans (0.001 µg Hg/m3)
    (Fleischer, 1970; Wallace et al., 1971).  If it is assumed that the
    average intake of air is 10m3 per day and that the maximum amount of
    mercury found over non-mineralized land areas is inhaled this would
    amount to 0.1 µg of mercury from this source, probably as elemental or
    inorganic mercury. Only limited information is available regarding
    tobacco; this suggests that for cigarettes most of the trace mercury
    present is retained in the butt and that (on average) not more than
    0.1 µg of mercury per cigarette is inhaled.

    The combustion of fossil fuels will also liberate traces of mercury
    into the atmosphere: these add to the much larger quantities present
    in the atmosphere arising from natural vaporization processes from the
    earth's surface (Weiss et al., 1971) and may be significant locally.

    Water.  Although there is considerable evidence that the manmade
    pollution of rivers, lakes and estuaries has often increased the
    mercury levels in fish, such pollution has not contributed
    significantly to the mercury levels found in wide-ranging ocean fish.
    Since the mercury content of the ocean has been estimated to be of the
    order of 108 tons and the annual industrial output of mercury is
    only of the order of 104 tons, the pollution due to man can have had
    only local effects, e.g. in lakes, rivers, estuaries and coastal areas
    (Miettinen, 1971).  On the other hand, the present degassing of
    mercury from the earth's crust is estimated to range between 2.5 x
    105 and 1.5 X 105 tons per year.  Increased flux over the last few
    decades may be due to alteration of terrestrial surfaces through the

    variety of activities of man.  The mercury content in ocean surface
    waters may have been augmented by a factor of 0.75 (Weiss et al,
    1971).

    There is also natural geological contamination of individual lakes or
    watercourses due to underlying mineral deposits containing mercury,
    which leach into the water under natural circumstances.

    The mercury content of streams, lakes and rivers does not normally
    exceed 0.1 µg per litre although some water sources located near
    mercury ore deposits may contain amounts up to 80 µg/litre (Wershaw,
    1970).  WHO has recommended that the tentative upper limit for mercury
    in drinking water should be 1 µg per litre, this figure being related
    to levels found in natural waters used for drinking purposes (WHO,
    1971).  At the ingestion rate of 2.5 litres of water per day used in
    the calculations for the International standards, the upper limit of
    mercury intake would be 2.5 µg per person per day, mainly in the
    inorganic form.

    The levels of mercury found in treated water are lower than those
    found in food.  Moreover, mercury in water is found in inorganic form.
    In terms of methylmercury, therefore, the contribution to the body
    load in man from water and air is unlikely to be significant.

    (b) Industrial sources

    The direct pollution of water by industrial sources is likely to
    affect fish more than other foods.  Similar pollution will be caused
    by dumps of industrial wastes which will transfer mercury into the
    soil and, eventually, into water.  The transfer into the atmosphere
    may form a significant addition locally due to the large amounts
    evolved by natural outgassing of surface materials.

    Mercury or mercury salts entering water may eventually result
    (primarily through microbial but also through other biological and
    chemical processes) in the formation of methylmercury compounds which
    can be absorbed and accumulated by aquatic organisms.  The industrial
    sources that cause the transfer of mercury-containing wastes to water
    or mud in fishery areas constitute sources of most direct concern.
    Furthermore, once mercury has been deposited in watercourses and
    estuaries it may remain and give rise to the formation of
    methylmercury compounds by bacterial action over a period of many
    years (Wood et al., 1968).  Thus, both past and present sources of
    contamination must be considered.  Measures to control industrial
    sources can bring about a considerable reduction of new pollution.
    However, the problem presented by levels of mercury in fish taken from
    already polluted watercourses and estuaries will continue for a long
    time.  The industrial processes which are likely to introduce
    significant quantities of mercury into the environment have been
    examined in a number of countries and control measures have been
    suggested (Env. Res. 1971).  The principal sources are the
    chlor-alkali industry using the mercury process, the pulp and paper
    industry and other industries using mercury.  Effluent from these

    industries in watercourses and estuaries has been the cause of much
    local pollution in fish.  Indeterminate but significant quantities of
    mercury originate from mining, smelting and refining of ores, but the
    effects are usually localized.  Industrial control equipment, hospital
    and laboratory instrumentation containing elemental mercury, such as
    relays, mercury arc rectifiers and thermometers represent minor
    sources when there are losses due to breakages. Laboratory and
    hospital wastes, discarded electrical apparatus, fluorescent lamps,
    paints, catalysts and other sources of mercury in dumps and sewage
    water, through seepage into watercourses, may also cause contamination
    of fish.

    (c) Agricultural sources

    Alkyl, alkoxyalkyl, aryl, and inorganic mercurial fungicides have been
    used for seed dressing, as turf fungicides, and in orchards.  The
    amount of mercury entering the food supply from normal agricultural
    use has been usually small compared with that from other sources.  On
    occasions, the use of alkyl mercury has resulted in the fortuitous
    accumulation of mercury by game birds feeding on mercury-treated seeds
    in the fields.  Although the use of alkyl and aryl mercurial
    fungicides has been restricted or prohibited in a number of countries
    in recent years, accidents have occurred from the misuse of seeds
    treated with alkyl mercury compounds.

    (d) Other sources

    Additional intake sources are pharmaceuticals containing either
    inorganic or organic mercury compounds, and mercurials used as
    preservatives in cosmetics and toiletries.  Care should therefore be
    taken in epidemiological surveys to consider these sources of
    exposure, as well.

    Transformation of mercury from inorganic to organic

    The geochemistry of metallic and inorganic mercury involves numerous
    interconversions and transformations.  Mercury is present in both
    humic complexes and in the relatively unionized and stabilized form of
    mercuric sulfide (Wallace et al., 1971).  Under oxidizing conditions,
    mercuric sulfide is gradually converted to mercuric sulfate, which is
    more readily dissociated, releasing ionic mercury in solution. 
    Conditions of oxidation also promote the conversion of metallic
    mercury to ionic mercury.  Mercuric compounds located on the earth's
    surface will usually degrade to metallic mercury and subsequently
    volatilize due to the action of sunlight.  On the other hand, most of
    the mercury compounds which are carried down into river beds and lake
    bottoms will, in the presence of hydrogen sulfide, ultimately be
    converted to insoluble mercuric sulfide, which may be, in turn,
    converted into methylmercury compounds.

    The principal forms of mercury commercially discharged into the
    environment are metallic mercury, inorganic mercury, aryl-mercury,
    alkyl-mercury and alkoxyalkyl-mercury compounds.  The transformation
    of inorganic mercury into the organic methylmercury form is promoted
    by micro-organisms or other biologically derived alkylating systems
    present in the sediments of lakes, rivers and estuaries.  These
    systems are capable of forming methylmercury and dimethylmercury from
    inorganic mercury, both under aerobic and anaerobic conditions (Jensen
    & Jernelöv, 1969; Wood et al., 1968).

    Both methyl and dimethylmercury compounds appear as initial products
    of methylation.  High mercury concentrations favour the monomethyl
    form while alkaline pH favours the highly volatile dimethyl form,
    which decomposes to monomethylmercury at acidic pH.

    The formation of methylmercury in bottom sediment under aerobic and
    anaerobic conditions was studied using 203Hg labelled mercury.  The
    reaction proceeds under both conditions, but the rate of reaction
    depends upon the number of micro-organisms.  No methylation occurs
    when the bottom mud is sterilized.  The possibility of spontaneous
    chemical transformation to methylmercury has also been reported.  The
    mechanisms of the methylation reaction are not yet fully understood,
    although several hypotheses have been advanced.

    Methods of analysis

    In the estimation of trace quantities of mercury a method is generally
    employed which determines the total mercury content.  If necessary,
    separate analysis for alkyl-mercury compounds should follow.  Total
    mercury and any mercury compounds are calculated as mercury, and may
    be expressed as µg Hg/kg, µg Hg/litre, mg Hg/kg, etc., according to
    the substrate examined.

    In the basic method for total mercury estimation, the sample is
    oxidized with a mixture of sulfuric and nitric acids, converting all
    the mercury present into inorganic form.  Care is necessary to avoid
    losses of mercury by volatilization in this process, and specially
    designed apparatus should be utilized.  After oxidation, the mercury
    is reduced to metallic state and the amount present estimated in the
    form of vapour released from the solution in a stream of nitrogen by
    flameless atomic absorption spectrophotometry, using the 253.7 nm
    line.  Due regard should be given to the proportion of mercury
    recovered in control experiments.

    Similarly, in the determination of methylmercury compounds, these are
    extracted with organic solvents (usually benzene), re-extracted into
    aqueous cysteine solution and extracted back into solvent after
    acidification.  Mercury in this solvent is then estimated by gas
    chromatography.  Thin layer chromatography of the extract may also be
    useful as a confirmatory test for establishing the identity of unknown
    compounds.  Due regard should be given to the proportion of
    methylmercury compounds recovered in control experiments.

    Neutron activation analysis requiring expensive and highly specialized
    equipment has been employed successfully as an alternative technique.
    Low temperature combustion has also been used in place of wet
    oxidation.  When using either of these methods, particular attention
    should be exerted to possible losses of mercury, to contamination from
    outside sources and to recovery percentages.

    The method of the International Union of Pure and Applied Chemistry
    for the analysis of traces of mercury in food (IUPAC, 1965) is under
    revision and a further study of the Official Method of Analysis (AOAC,
    1972) is currently in progress.  A basic technique for estimating
    methylmercury compounds is described in the method of the Nordic
    Committee on Food Analysis (Nordic Committee, 1972).

    Levels in food

    The amount of mercury compounds found in plant produce is very small
    or zero.

    Although the use of alkyl mercury fungicides (particularly as seed
    dressings) is being discouraged, there may still be possibilities, in
    the absence of appropriate regulatory measures, that traces of such
    fungicides will get into cereals by accident.

    Low levels of total mercury can also occur in meat and dairy produce
    and may include some methylmercury compounds, derived presumably from
    residues in feeds containing fish-meal or treated cereal grains.

    Fish constitute a special problem.  Since the tragic accidents at
    Minamata and Niigata in Japan, aquatic pollution with mercury and its
    resulting uptake and accumulation by edible fish has been given
    special attention in many parts of the world.  In recent years
    thousands of analyses have been performed and comprehensive studies
    have been reported.  The results show that increased levels are
    consistently found in places where the water is contaminated with
    mercury from industrial and mining processes.  In fish from unpolluted
    water, comprising most of the world's total catch of food fish, low
    values are generally found.  Some of the larger specimens of predatory
    species may contain high levels, apparently derived from natural
    sources since the same levels are found in museum specimens caught
    50-100 years ago.

    There is evidence that the level of methylmercury in fish increases
    with the age of the fish, e.g., data on swordfish show levels of
    mercury clearly increasing with size (age) of the fish.  The ratio of
    methylmercury to total mercury in edible fish muscle is usually high
    (approaching 100%). In shellfish, the proportion is only 50% or less
    when mercury is high.  However, the high level of inorganic mercury
    may be due to the inclusion of viscera in the material analysed.

    Information available shows that 99% of the world's commercial catch
    has a total mercury content not exceeding 0.5 mg/kg, and 95% probably
    contains less than 0.3 mg/kg.  In 1971 the United States Food and Drug
    Administration conducted a nationwide survey and found less than 3% of
    1400 random samples of market fish (mainly deep ocean species) to
    contain mercury in excess of 0.5 mg/kg.

    Tuna species make up only about 2% of the total world catch of fish,
    and almost all of this goes for human consumption.  The average
    mercury concentrations are below 0.5 mg/kg but old and large specimens
    may contain levels above 1 mg/kg.  A United States study showed that
    95% of the canned tuna contained less than 0.5 mg/kg (U.S., FDA,
    1971).  Larger specimens of halibut and shark may contain increased
    levels of total mercury, up to and exceeding 1 mg/kg (Bligh, 1971;
    Faile, 1971; Westöö & Rydälv, 1971).

    In some communities in countries where total diet surveys based on
    fish consumption of the edible portion of 20 g or less per day have
    shown an average daily intake of total mercury of 10 µg per person,
    the average amount of methylmercury present has been estimated to be
    not greater than 2 µg, depending on the amount and type of fish
    consumed (United Kingdom Report).

    Freshwater fish in unpolluted waters seem to have total mercury
    contents less than 0.2 mg/kg.  In some cases, however, fish have been
    found to contain values up to 0.5-1 mg/kg in apparently uncontaminated
    lakes (Hasanen a Sjöblom; Westöö & Rydälv, 1969; 1971).  Unusually
    elevated natural mercury concentrations in underlying geological
    structures may be responsible for the high levels of methylmercury in
    fish from these lakes.

    Freshwater fish in mercury-polluted environments has been extensively
    studied in some countries. Some larger species, such as pike, perch,
    pickerell, bass and burbot have in many lakes been found to contain
    1-5 mg/kg of mercury; and in some cases even more.

    Freshwater fish in unpolluted waters seem to have total mercury
    contents less than 0.2 mg/kg.  In some cases, however, fish have been
    found to contain values up to 0.5-1 mg/kg in apparently uncontaminated
    lakes (Hasanen & Sjöblom, 1969; Westöö & Rydälv, 1969; 1971).  In some
    cases, sources of pollution have been revealed later on (Westöö, 1972)
    e.g. hospital sewage or mercury airborne by prevailing winds from
    industrial sources.  However, in a large number of cases of bodies of
    water in isolated areas, there can be no man-made source of mercury
    pollution and in perhaps one half or more of these areas, there is
    reason to believe there may be natural occurrences of mercury often
    associated with methyl sulfide ore deposits (Tam & Armstrong, 1972).
    Other significant factors influencing the mercury content found in
    fish are shallow lakes, oligotrophic conditions (organisms other than
    fish "competing" for the mercury), pH of the water (low pH favours
    formation of methylmercury).

    Fish, as well as shellfish and crustacean and eels (anguila species),
    that constitute the local population in polluted estuaries may contain
    high values of mercury and as they may represent a valuable local fish
    supply, they should be more extensively surveyed.

    Levels in oysters and shellfish can be controlled by antipollution
    measures. Mercury levels in fish from certain lakes in Sweden and
    certain rivers in Japan have also fallen after the elimination of
    contamination sources.

    Fish caught elsewhere have not shown such a response with respect to
    mercury levels, but the period of observation was relatively short.

    BIOLOGICAL DATA

    Effects of mercury

    The chemical form of mercury determines the biological effects which
    occur.  Mercurials fall into a number of well defined classes,
    distinguished by differences in absorption, biotransformation,
    deposition, retention and excretion.  These metabolic features largely
    determine the toxic effects produced.  Mercurials can be divided into
    the following groups: (a) elemental mercury, (b) inorganic mercury
    compounds, (c) aryl and alkoxyalkyl mercury compounds, (d) alkyl
    mercury compounds.

    (a) Elemental mercury

    The major route of human exposure is by inhalation of mercury vapour.
    The vapour diffuses rapidly (75-85%) across the alveolar membrane as
    shown by studies on four volunteers exposed to 50-350 µg/m3 metallic
    mercury.  This absorption is reduced by the ingestion of alcohol
    (Kudsk, 1965).

    Occasional instances of acute poisoning from vapours have been
    reported.  Major symptoms are acute pneumenitis ("metal fume fever"),
    gastrointestinal disturbances, bloody diarrhoea and severe kidney
    injury with uraemia and anuria.  Chronic exposure produced tremor and
    psychological disturbances, (erethismus mercurialis) and occasional
    proteinuria which may progress to nephrotic syndrome (Kazantzis et
    al., 1962; Joselow & Goldwater, 1967).  Gingivitis, stomatitis,
    excessive salivation, occasional dermatitis, mercurialentis,
    non-specific fatigue, weight-loss and pallor have been reported
    (Bidstrup, 1964).

    (b) Inorganic mercury compounds

    Following the absorption of a soluble inorganic mercury salt the
    mercuric ion is transported in approximately equal proportions bound
    to plasma proteins and haemoglobin in the red cell.  The biological
    half-life in man has been determined at 42 ± 3 days for the whole body
    and 16 days for the RBC.  Only 0.2-0.4% of the initial dose appeared
    in the whole blood.  The RBC/plasma activity ratio was 0.4.  Ionic (in

    water) or protein bound mercury (calf liver) was handled metabolically
    the same way (Rahola et al., 1971).  The immediate effects of acute
    poisoning are due to irritation, coagulation and superficial corrosion
    of exposed tissues.  Chronic effects include kidney damage and
    intestinal ulceration with haemorrhage (Bidstrup, 1964).

    (c) Organomercurials

    The biological effects of organomercurials are much influenced by the
    particular organic group present.  They enter the body by inhalation,
    by skin absorption though only slowly, or by oral ingestion.  They are
    volatile to a variable degree.  Aerosol inhalation leads quickly to
    solution of the unchanged compound in body fluids and distribution to
    the blood.  The compounds at present in use have the general formula
    R-Hg+-X(-) and biotransformation follows two general pathways: (a)
    splitting of the C-Hg bond to liberate Hg++ or (b) modification to
    R'-Hg+.

    (i) Aryl mercury compounds

    Man rapidly metabolises phenylmercury compounds to inorganic mercuric
    ions which are excreted in the urine.  The RBC/Plasma ratio is about
    1.  Urine levels of mercury could be used to indicate the degree of
    exposure.  Human chronic exposure by inhalation at air levels of up to
    5.1 mg Hg/m3 had not produced clinical manifestations: blood levels
    reached 0.52 µg/ml and urinary excretion 2.8 µg/ml (Ladd et al., 1964;
    Goldwater et al., 1964).  No systemic injury was noted by exposure
    from 0.2-3.2 mg/m3 With urinary excretion of 0-6 µg/ml.  However,
    chronic exposure increases urinary protein level (Joselow & Goldwater,
    1967).  In exposed groups of seed dressers mercury levels in urine
    were 0.035 µg/ml, blood levels O-0.21 µg/ml and urinary protein was
    166 mg/24 hours compared with 70 mg/24 hours in matched controls.  No
    correlation was established between exposure and urinary mercury
    excretion.  Serum glutathione reductase was unaffected but serum
    phosphoglucoseisomerase was low in the exposed group.

    The biological half-life of diphenylmercury in an individual
    accidentally exposed to this compound was found to be 14 days (Morsy &
    El-Assaly, 1970).  There is some evidence that phenylmercury compounds
    produce chromosomal abnormalities in Drosophila melanogaster and
    possibly teratogenic effects in mice.  However, studies with 203Hg
    phenyl acetate in pregnant mice showed that although the placenta
    takes up large amounts of mercury, only traces were present in the
    foetus (Berlin & Ullberg, 1963; Suzuki at al., 1967).

    (ii) Alkoxyalkyl mercury compounds

    Methoxyethyl mercury compounds are rapidly metabolized to inorganic
    mercuric ions and excreted in the urine.  The RBC/Plasma ratio is
    about 1.  In acute poisoning the organs most affected are the kidneys.
    There may be intestinal symptoms, headache and weight loss. Exposure
    may result in mercury blood levels of 0.3-1.1 µg/ml and mercury levels
    in urine of 0.2-1.2 µg/ml without clinical injury (Berlin, 1970).

    (d) Alkyl mercury compounds

    The distribution of alkyl mercury in the body tissues is very
    different from aryl and inorganic mercury.  However, absorption,
    distribution and excretion are closely similar for the hydroxide,
    cyanide, dicyandiamide and propanediol mercaptide.  Distribution and
    elimination after subcutaneous injection are similar for the hydroxide
    and dicyandiamide (Ulfvarson, 1962).  MethyImercury compounds are
    absorbed via the skin, the respiratory tract in rat, mouse and monkey
    (Hunter et al., 1940; Swensson, 1952) and there is almost complete
    absorption from the digestive tract (Berglund, 1969; Ekman et al.,
    1968a; Clarkson, 1971).  Elimination is very slow especially in
    primates, with consequent risk of considerable accumulation.  It seems
    likely that the compounds dissociate in the body: the methylmercury
    group attaches to the functional groups of other substrates, e.g.
    proteins, being then similarly metabolized.  The methylmercury group
    distributes rather evenly in the body but it accumulates in the
    erythrocytes; the distribution between plasma and erythrocytes varies
    with species.  In man, 90% of the total blood mercury appears in the
    cellular elements.  Blood/brain ratios differ from species to species.
    Methylmercury easily penetrates the placenta in animals.  It also
    accumulates in hair.  The most part is excreted in the faeces and some
    in the urine.  Forty to fifty per cent. of the faecal excretion is in
    the inorganic form.  The stability of alkyl mercury compounds favours
    their accumulation in the CNS.

    Observations in man

    Orally administered CH3203HgNO3 in three male volunteers was almost
    completely absorbed (over 90%).  Erythrocytes took up the 203Hg within
    15 minutes, the RBC/plasma ratio being 10.  Maximum blood levels
    occurred three to six hours after ingestion.  Fifty-five per cent. of
    the total 203Hg-activity was found localized in the liver, 12% in the
    head.  Less than 1% of mercury passed through the gut unabsorbed.
    Faecal excretion totalled 34% in 49 days (initial 3% of body burden
    falling to 1% of body burden/day).  Urinary excretion amounted to 3.3%
    in 49 days.  No mercury was found in sperm, but some appeared in hair
    (0.12% of the dose at 50 days).  The epidermis was not considered a
    significant route of excretion.  The biological half-life was 70-74
    days.  At steady state equilibrium one unit dose CH3203HgNO3 per
    week was calculated to give a total body burden of 15.2 unit doses
    (Ekman et al., 1968a; 1968b; Åberg et al., 1969; Falk et al., 1971).

    Nine male and six female volunteers were given orally about 2 µg of
    methyl-203Hg which had been incorporated into fish muscle protein by
    feeding the fish 10 days earlier with labelled methylmercury
    proteinate.  Most of the activity was excreted in the faeces (6% of
    body burden in three to four days, then 1.9% of body burden/day); very
    little was excreted in the urine (no activity until the one hundredth
    day).  Activity in RBC's decreased rapidly, the RBC/plasma ratio being
    10.  The biological half-life was 50 ± 7 days for RBC and 76 ± 3 days
    for whole body activity (Miettinen et al., 1971). When a
    methylmercury-free diet followed a high methylmercury-fish diet the

    biological half-life for RBC activity was 70 days and for plasma
    activity 80 days (Birke et al., 1972).  Urinary excretion of mercury
    cannot be used to evaluate exposure to alkyl mercury compounds
    (Lundgren et al., 1967).

    Alkyl mercury poisoning causes sensory nerve damage (paraesthesia of
    face and extremities), cerebellar damage (ataxia, incoordination,
    dysarthria), calcarine cortical damage (concentric visual field
    constriction), temporal lobe damage (hearing defects).  All are
    associated with raised mercury levels in certain brain areas, liver
    and kidney.  Patient response is very variable, the Hunter-Russel
    syndrome having been defined after industrial exposure (Hunter et al.,
    1940; Edwards, 1865; Hill, 1943).  Diffuse encephalopathy in 168 cases
    with 52 deaths with concentric visual field loss, ataxia and
    peripheral neuropathy secondary to ingestion of mercury contaminated
    fish and shellfish has now been reported in Minamata and Niigata.

    The works of Irukayama (1968), Takeuchi (1968, 1970) and others (Study
    Group of Minamata disease) have established the etiologic role of
    methylmercury in Minamata disease.  The mercury content of organs of
    human autopsy cases of Minamata disease (12 victims, age five to 62
    years), in which the course of the disease was 100 days or less was
    liver 22-70 µg/g, kidney 22-144 µg/g, brain 2.6-25 µg/g.  The
    brain/iiver ratio was 12:50, and brain/kidney 7:37 (Takeuchi, 1970).
    Similar symptoms have been reported in numerous instances following
    accidental ingestion of food treated with alkyl mercuric compounds
    (ethylmercury and methylmercury derivatives), e.g. ingestion of
    treated seeds or of meat from animals fed treated grain (Engleson &
    Herner, 1952; Haq, 1963; Ordoñez et al., 1966; Jalili & Abbasi, 1961;
    Dahhan & Orfaly, 1964; Mukhtarova, 1970; Gis'IU & Pozner, 1970;
    Snyder, 1971; Storrs et al., 1970; Curley et al., 1971; Mnatsakonov et
    al., 1968; Slatov & Zimnikova, 1968; Sandi, 1970; Okinaka et al.,
    1964).

    In the Minamata accident 23 infants with cerebral involvement (palsy
    and retardation) were born to mothers who had ingested mercury
    contaminated fish and shellfish indicating transplacental foetal
    damage.  The mothers of these patients had shown no manifestations of
    the disease or had only slight complaints such as numbness of fingers
    and fatigue.  In both adult and foetal cases there were degenerative
    and regressive alterations of the cerebral cortical nerve cells.  In
    addition, hypoplasia was observed in the foetal cases.  Cerebral
    cortical cell involvement was more diffuse in foetuses than in adults
    (Matsumoto et al., 1965).

    Methylmercury crosses the placental barrier and achieves a higher
    concentration in foetal RBC than in maternal RBC.  The foetal plasma,
    however, has a lower concentration than does maternal plasma.  The
    difference may be due to differences in the binding of methylmercury
    by maternal and foetal haemoglobin.  The mercury content of blood of
    mothers and newborn infants in Sweden was reported as (average values
    ng/g):

    Infants            RBC 11.5      Plasma 1.9
    Mothers            RBC 8.6       Plasma 2.5 (Tejning, 1970)

    Mercury levels in maternal blood, umbilical cord blood and placental
    tissue in Tokyo were reported as: (ng/ml)

    Umbilical cord     RBC 30.8      Plasma 11.2
    Maternal blood     RBC 22.9      Plasma 12.4
    Placenta                         71.5 ng/g (Suzuki et al., 1971)

    It has been reported that accidental exposure of women to
    ethylmercuric chloride resulted in the accumulation of mercury in
    newborn infants because of the presence of mercury in the mother's
    milk but the analytical method was not stated (Bakulina, 1968).

    Chromosome analysis of cultured lymphocytes from normal controls
    (0.004-0.011 µg/g RBC) and individuals with high RBC mercury levels
    0.03-0.23 µg/g (from contaminated fish containing 1.7 mg Hg/kg
    indicated increased chromosome breakage, dose related to mercury
    levels.  The significance for man is unknown (Skerfving et al., 1970;
    Sumari et al., 1971).

    Animal studies

    Biotransformation of methylmercury in the rat was studied using
    detection of cleavage of the C-Hg bond as indicator.  After exposure
    to single intravenous dose of 1 mg/kg methylmercury chloride, 80% of
    the total mercury excretion was in the faeces.  Forty per cent. of the
    total mercury excreted was found to be inorganic mercury.  Fifty per
    cent. of the faecal excretion and 5.20% of the urinary excretion was
    inorganic mercury.  Most of the faecal inorganic mercury was derived
    from faecal bacterial processes.  Ten per cent. of the methylmercury
    chloride was excreted in the bile within 24 hours, falling to 5% on
    day 10.  Only 3% was excreted daily in the faeces.  Methylmercury
    cysteine, or more probably a complex with a sulfydryl-containing
    dipeptide molecule, was the major biliary metabolite together with
    protein-bound mercury.  Methylmercury cysteine was rapidly and nearly
    completely absorbed in the small gut, the methylmercury protein
    representing 15% of the total faecal mercury and the mercury protein
    complex representing another 15%.  Seventy per cent. of the total
    mercury was in the intestinal cell, 95% as methylmercury.
    Methylmercury cysteine accumulated in the kidneys more than
    methylmercury chloride; and this could be inhibited by bile duct
    ligation despite rising blood and plasma levels (Norseth. 1969, 1971;
    Norseth & Clarkson, 1971).

    When polystyrene with thiol ligands was fed at 1% of the diet to
    groups of five mice, given intraperitoneally CH3203Hg, the mercury
    faecal excretion was three times that of controls, whole body count
    was reduced, tissue levels after 22 days treatment were lower, brain
    levels were 1/5 of controls, kidney levels 1/10 and the blood was free
    from methylmercury (Clarkson et al., 1972).

    Methylmercury chloride was mixed with soluble swine brain protein to
    form methylmercury proteinate.  On dialysis against a variety of
    thiocompounds much mercury was removed. Similarly,
    thioclycollate-treated hair powder reduced mercury content.  If mice
    were given intramuscularly 200 or 400 µg methylmercury chloride and
    fed either normal diet or diet with 3% treated hair powder for 10 or
    20 days then the total body mercury of treated mice was lower than
    untreated controls (Hirayama & Takahashi, 1971a; 1971b).

    CH3203Hg was injected intraperitoneally into a guinea-pig two days
    before and three days after parturition.  Milk levels were 5-10% of
    blood concentration.  The blood levels of young mothers (given two
    days before parturition) were the same.  Rapid transplacental transfer
    but difficult transfer to milk was the conclusion (Trenholm et al.,
    1971).

    Rats were maintained on diets containing 2 mg/kg methylmercury for 12
    weeks.  Examination of kidney tissue by electron microscopy indicated
    extrusion of numerous cytoplasmic masses from the proximal tubular
    cells of the pars recta segment in the kidney.  Effects were more
    prominent in females than in males (Fowler, 1972).

    Rats were administered per os 1 mg methylmercuric sulfide per day
    for 20 days.  Peripheral nerves were examined on the seventh and two
    hundred and fiftieth day after withdrawal of the test compound.  On
    day 7 mitosis of Schwann cells were observed and on day 250 myelinated
    fibres were noticeably decreased in numbers, with regeneration of
    nerve fibres and an increase in collagen in the intercellular spaces.
    Posterior nerve root ganglion cells were, however, intact.
    Regeneration of peripheral nerve cells was not a very marked feature
    (Miyakawa et al., 1970).

    In another study, rats were administered per os 1 mg methylmercuric
    sulfide per day for 20 days.  Examination of heart muscle by light
    microscopy, indicated a few degenerated muscle fibres.  Electron
    microscopy indicated that Z-band and every other band were indistinct,
    and that the myofilaments and the sarcoplasmic reticulum were
    disorganized, degenerated or disappeared (Miyakawa or al., 1970).

    Japanese quail given 20 mg/kg of mercury as methylmercury in diets
    containing 17% (by weight) tuna, survived longer than quail given this
    concentration of methylmercury in a corn-soya diet.  When rats were
    maintained on a purified basal diet containing 20% casein or the same
    diet supplemented with 0.5 mg/kg selenium, with various concentrations
    of methylmercury in the drinking water all rats fed 10 mg/kg mercury
    without selenium died, but those fed diet with selenium were still
    alive at the end of week 6 (Ganther et al., 1972).

    Squirrel monkeys were given 0.5-1 mg/CH3203Hg/kg body-weight via the
    diet.  Pairs of monkeys were fed for 21 days (followed by 85 days
    withdrawal), 28 days (one having a 37 day withdrawal period prior to
    sacrifice) and 36 days (one having a 6 day withdrawal period prior to
    sacrifice).  After 121 days feeding, the total body burden of mercury

    was 2.8 and 3.6 mg Hg/kg.  Neither animal showed symptoms, but at
    sacrifice the animal with the greater body burden showed slight
    changes in the calcarine cortex.  After 28 days feeding, body burdens
    were 4.3 and 5.5 mg Hg/kg.  The animal with the lower body burden of
    mercury showed slowly progressing visual disturbance, and possibly
    ataxia.  At sacrifice, severe damage to the entire occipital cortex
    was observed.  The animal with the higher body burden was blind, and
    possibly ataxic at termination of dosing when it was sacrificed.
    Severe calcarine cortex damage was noted.  After 36 days feeding,
    monkeys showed 5.0 and 5.5 mg Hg/kg body burden.  Both animals were
    blind, and, at autopsy, damage to the calcarine cortex was noted.  The
    severity was greatest in the animal permitted a six day withdrawal
    period.  Blood brain ratio was 0.2 (Nordberg et al., 1969).

    Groups each of five male monkeys (3 Macaca mulatta, 2 Macacus
    irus) were administered dietary methylmercury chloride, which had
    previously been mixed with egg and the freeze dried product added to
    the normal diet.  Dose levels were 0, 0.01, 0.03, 0.1 and 0.3 mg Hg/kg
    body-weight/day. At the highest dose level, onset of neurologic
    symptoms were observed at days 50-73 of test, i.e. after a total
    intake of mercury of approximately 60-145 mg.  Other groups appear
    normal after 140 days of test although a light depression in
    body-weight has been observed.  Mercury content of hair of test groups
    after two months averaged 0.3, 4.8, 19, 44 and 202 µg/g, for control
    and respective test groups in order of dose level.  The animals
    continue on study (Ikeda & Tobe, 1972).

    Reproduction studies

    Oral administration of 0.1, 1, 2.5 or 5 mg/kg methylmercury chloride
    from pregnancy day 6-17 to mice, reduced litter size at the highest
    level.  All pups died at 2.5 mg/kg with retarded cerebellar
    development on seventh to fourteenth day post-partum.  0.1 mg/kg was
    the no effect level (Clegg, 1971).

    Methylmercuric sulfide labelled at the mercury and the sulfur atoms
    was given to pregnant rats in daily oral doses of 0.1 mg/kg
    body-weight.  Autoradiographs demonstrated that the sulfur and the
    mercury were present inside the placenta and in the maternal milk.
    Neurological symptoms in the young gave evidence of the transfer to
    the foetus.  Evidence is presented to show that the mercury-sulfur
    bond is dissociated in the animal's body soon after oral ingestion and
    that a mercury compound without sulfur is transferred to the young
    (Fujita, 1969).

    Mutagenic studies

    In a dominant lethal test performed in mice there was no effect 24
    hours after exposure but this may have been too late as regards 
    mating.  When 0.1 mg Hg/kg was injected intraperitoneally prior to
    mating reduced pregnancy incidence was noted but no litter size
    reduction.  In another experiment, male rats received by injection for
    seven days, 1, 2.5 or 5 mg Hg/kg and were then mated with untreated

    females over a period of four weeks.  In matings 10-15 days after
    injection there was reduced litter size at all dose levels, the
    severity being dose related.  Thus a positive response at all levels
    was noted (Clegg, 1971).

    ASSESSMENT OF HAZARD TO MAN

    In view of the large differences in metabolism of methylmercury
    compounds in various species of animals, toxicological evaluation
    based on animal data was not attempted and only human data were used.
    Data were of three types: (1) levels of mercury in hair and whole
    blood of patients with methylmercury poisoning in Niigata; (2) levels
    of mercury in hair, whole blood and blood cells in subjects without
    any symptoms of methylmercury poisoning in Japan, Sweden and Finland;
    (3) calculated relationships between intake of methylmercury from the
    diet and levels of mercury in hair, whole blood and bLood cells in
    subjects in Japan and Sweden.

    From these data a minimum toxic dose of methylmercury compounds in
    fish was calculated, and a proposal was made for a provisional
    tolerable weekly intake of mercury from food.  Theoretically, a more
    direct approach to the establishment of the minimum toxic dose would
    have involved the precise estimation of the dietary intake of fish by
    the cases of poisoning in Niigata or Minamata coupled with accurate
    analyses of the mercury levels in the fish of Niigata or Minamata
    consumed at the time of poisoning, but available data did not permit
    this approach.  It should be realised therefore that with the
    alternative procedure used, each of the above steps embodied factors
    of uncertainty, one common factor being the accuracy of the analysis
    of the mercury.  For these reasons, the proposed tolerable weekly
    intake must be considered as provisional for the time being.

    Indices in man of exposure to methylmercury compounds. 
    Methylmercury and other short chain alkylmercury compounds exert their
    main toxicological effects on the nervous system and the most relevant
    index of exposure would therefore be the concentration of mercury in
    relevant areas of the central nervous system.  In man, methylmercury
    levels in blood cells and in hair provide the best indices of exposure
    of the nervous system to methylmercury compounds.  If exposure to
    other mercury compounds is minor compared with exposure to
    methylmercury, analysis of total mercury may be used instead.  A
    strict correlation between levels in the nervous system, blood and
    hair can only be expected when a steady state has been reached, i.e.
    during long-term exposure to constant levels of methylmercury
    compounds. Blood levels of mercury reflect more accurately the intake
    from recent exposure to methylmercury, while hair levels of mercury
    reflect the average intake over a more prolonged period.  Since
    mercury combines with protein components in hair over the period of
    its formation, the mercury content in successive segments of hair
    gives an indication of the levels of past absorption of mercury
    compounds. The estimation of mercury in hair, provided external
    contamination can be excluded, may therefore be of value in
    epidemiological investigations.

    Levels of mercury in whole blood, blood cells and hair.  The
    relation between mercury levels in blood and hair has been studied in
    Sweden, Finland and Japan in persons exposed to different amounts of
    mercury through the consumption of contaminated fish.  The results are
    summarized in the following table:

    No. of      Blood (x)    Hair (y)    Linear              References
    subjects    Hg )19/9     Hg µg/g     regression

    12          .004-.65     1-180       y = 280X - 1.3      Birke et al.,
                                                             1967 (Sweden)

    51          .004-.11     1- 30       y = 230X + 0.6      Tejning, 1967
                                                             (Sweden)

    30          .005-.27     0 - 56      y = 140X + 1.5      Sumari et al.,
                                                             (1969 (Finland)

    45          .002-.80     20-325      y = 260 x + 0       Tsubeky, 1972
                                                             (Japan)

    The data presented by Tsubaki included 45 persons from the Niigata
    area with more subjects in the very high range (seven subjects above
    180 µg/g hair).  Hair levels at a steady state were approximately 250
    times as high as levels in whole blood.

    Levels of mercury in hair and whole blood of patients with
    methylmercury poisoning in Niigata were determined in a follow-up
    investigation extending over many months after the onset of clinically
    overt poisoning (Tsubaki, 1972).  The decrease of mercury levels in
    hair of eight patients studied corresponded to a biological half-life
    of 50-108 days (median 66 days), and in the blood of seven patients
    studied of 35-137 days (median 55 days).  These figures are of the
    same order of magnitude as those reported from experiments with
    CH3Hg203 in man in healthy subjects Ekman et al., 1968a, 1968b;
    Miettinen et al., 1971; Birke et al., 1967; Tejning, 1969a, 1969b,
    1969c) and from data on persons in Sweden who stopped eating
    methylmercury-contaminated fish (Berglund et al., 1971).

    Extrapolation of the mercury levels in the Niigata patients to the
    time of onset of symptoms indicated that poisoning occurred at mercury
    levels in the hair between 200 and 1000 µg/g but in one case the hair
    level was as low as 50 µg/g.  Similar extrapolation of the blood data
    indicated that poisoning occurred at mercury levels in whole blood
    between 0.2-2.0 µg/g.

    More than 100 persons with hair levels of 50 µg/g have been found in
    Japan, in areas where fish was contaminated by methylmercury.  Of
    these persons, six in Minamata and 17 in Niigata had blood levels
    above 0.2 µg/g.  In Sweden and Finland mercury levels in blood above
    0.2 µg/g were found in five persons, two of which had O.6-0.7 µg/g.
    None of these persons had any detectable evidence of methyl-mercury
    poisoning.

    Relationship to intake of mercury from fish

    The intake of mercury through the consumption of fish and levels of
    mercury in blood cells or hair has been studied in subjects without
    clinical evidence of poisoning and the following relationships
    established.

    No. of      Hg intake    Hg in blood    Hg in hair     Reference
    subjects    mg/day (x)   Cells          µg/g (y2)
                             µg/g (y1)

    6 + 26*       0-0.8      Y1 = 1.4X +    -              Birke et al.,
                                  0.003                    1967

    139 + 26*     0-0.4      y1 = 0.6x +    -              Tejning, 1967;
                                  0.011                    1969a, b, c

    735           0-0.8      -              Y2 = 150X +    Kojima & Araki,
                                            1.66           1972

    * 26 cases from Tejning's non-fish consumers (1969a, b, c; 1970).
    
    Since mercury in fish is largely in the form of methylmercury, the
    proportion of the total body burden of mercury present as
    methylmercury also increases with the degree of exposure.

    Conclusions

    The most reliable data for the toxicological evaluation of mercury in
    fish derive from adults with neurological involvement.  The lowest
    mercury levels associated with the onset of clinical disease have been
    reported to be 50 µg/g in hair and 0.2 µg/g in whole blood,
    corresponding to 0.4 µg/g in blood cells.  These levels would seem to
    represent individuals on the lower end of a distribution curve of
    methylmercury levels in blood and hair in the population exposed in
    Niigata.  These individuals were considered to be more sensitive to
    the action of methylmercury and this assumption is supported by the
    observation of a number of persons in Japan and other countries with
    higher mercury levels in hair or blood but without clinical features

    of intoxication.  On the other hand, the presence of methylmercury
    poisoning can only be diagnosed clinically because there are no
    specific laboratory tests for its early detection.  The occurrence of
    prenatal intoxication also calls for caution.  Clinical data from
    Japan indicate that the foetus is more sensitive than the mother.  The
    significance of the morphological changes seen in chromosomes of
    circulating lymphocytes in a few individuals with a high methylmercury
    blood level is not known at present.

    Due to the uncertainty and indirect nature of relationships calculated
    between intake of mercury through fish, levels of mercury in
    "indicator organs" and mercury levels when poisoning develops, any
    evaluation must be provisional at present.

    EVALUATION

    Lowest Hg levels at onset of poisoning in adults with neurological
    involvement: 50 µg/g hair and 0.4 µg/g blood cells.

    Estimated intake of mercury, mainly as methylmercury compounds,
    causing poisoning; 0.3 mg/day over prolonged periods.

    PROVISIONAL TOLERABLE WEEKLY INTAKE: 0.3 mg total mercury, of which no
    more than 0.2 mg should be present as methylmercury, CH3Hg+,
    (expressed as mercury).

    This corresponds to a provisional tolerable weekly intake of 5 µg/kg
    body-weight of total mercury, of which no more than 3.3 µg/kg
    body-weight should be methylmercury compounds (expressed as Hg).

    This evaluation is based on a high total mercury intake in the diet,
    due to the consumption of fish containing high levels of methylmercury
    compounds.  Where high total mercury intakes occur for other reasons,
    (for example due to inorganic mercury as a consequence of local
    natural conditions) the evaluation does not necessarily apply and the
    whole situation has to be reconsidered on its merits.  When the total
    mercury intake in the diet is found to exceed 0.3 mg per week it would
    be advisable to undertake analyses for methylmercury.  Other suitable
    investigations should be instituted and all possible steps taken to
    keep the levels of methylmercury as low as possible.

    The provisional tolerable weekly in-take, as given above, is probably
    not exceeded at present by the population in general in any country,
    but it is exceeded by fish-eating minorities of some countries.  In
    view of the international importance of fish and fishery products in
    the diet every effort should be made to prevent further pollution by
    mercury.

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    Westöö, G. (1972) Personal comunication

    Westöö, G. & Rydälv, M. (1969) Vår foda, 3, 19

    Westöö, G. & Rydälv, M. (1971) Vär foda, 7-8, 179

    Wood, J. M., Scott Kennedy, F. & Rosen, C. G. (1968) Nature (Lond.),
    220, 173

    WHO (1971) International Standards for Drinking Water (Third Ed.)
    
    See Also:
       Toxicological Abbreviations
       Mercury (EHC 1, 1976)
       Mercury (ICSC)
       Mercury (WHO Food Additives Series 13)
       MERCURY (JECFA Evaluation)