This report contains the collective views of an international group of
    experts and does not necessarily represent the decisions or the stated
    policy of the United Nations Environment Programme, the International
    Labour Organisation, or the World Health Organization.

    Published under the joint sponsorship of
    the United Nations Environment Programme,
    the International Labour Organisation,
    and the World Health Organization

    World Health Organization
    Geneva, 1990

         The International Programme on Chemical Safety (IPCS) is a
    joint venture of the United Nations Environment Programme, the
    International Labour Organisation, and the World Health
    Organization. The main objective of the IPCS is to carry out and
    disseminate evaluations of the effects of chemicals on human health
    and the quality of the environment. Supporting activities include
    the development of epidemiological, experimental laboratory, and
    risk-assessment methods that could produce internationally
    comparable results, and the development of manpower in the field of
    toxicology. Other activities carried out by the IPCS include the
    development of know-how for coping with chemical accidents,
    coordination of laboratory testing and epidemiological studies, and
    promotion of research on the mechanisms of the biological action of

    WHO Library Cataloguing in Publication Data


        (Environmental health criteria ; 101)

        1.Methylmercury compounds 2. Mercury poisoning

        ISBN 92 4 157101 2        (NLM Classification: QV 293)
        ISSN 0250-863X

         The World Health Organization welcomes requests for permission
    to reproduce or translate its publications, in part or in full.
    Applications and enquiries should be addressed to the Office of
    Publications, World Health Organization, Geneva, Switzerland, which
    will be glad to provide the latest information on any changes made
    to the text, plans for new editions, and reprints and translations
    already available.

    (c) World Health Organization 1990

         Publications of the World Health Organization enjoy copyright
    protection in accordance with the provisions of Protocol 2 of the
    Universal Copyright Convention. All rights reserved.

         The designations employed and the presentation of the material
    in this publication do not imply the expression of any opinion
    whatsoever on the part of the Secretariat of the World Health
    Organization concerning the legal status of any country, territory,
    city or area or of its authorities, or concerning the delimitation
    of its frontiers or boundaries.

         The mention of specific companies or of certain manufacturers'
    products does not imply that they are endorsed or recommended by the
    World Health Organization in preference to others of a similar
    nature that are not mentioned. Errors and omissions excepted, the
    names of proprietary products are distinguished by initial capital




        1.1. Identity, physical and chemical properties, analytical 
        1.2. Sources of human and environmental exposure
        1.3. Environmental transport, distribution, and transformation
        1.4. Environmental levels and human exposure
        1.5. Kinetics and metabolism 
        1.6. Effects on experimental animals and  in vitro systems 
        1.7. Effects on man - mechanism of action
        1.8. Conclusions


        2.1. Identity
        2.2. Physical and chemical properties
        2.3. Conversion factors
        2.4. Analytical methods
                2.4.1. Sampling
                2.4.2. Analytical procedures
                2.4.3. Quality control and quality assurance


        3.1. Natural occurrence
        3.2. Man-made sources
        3.3. Uses


        4.1. Transport and distribution between media
        4.2. Biotransformation
        4.3. Interaction with other physical, chemical, or biological 


        5.1. Environmental levels
                5.1.1. Air         
                5.1.2. Water       
                5.1.3. Food        
        5.2. General population exposure    
                5.2.1. Estimated daily intakes


        6.1. Absorption
        6.2. Distribution
        6.3. Metabolic transformation       
        6.4. Elimination and excretion      

        6.5. Retention and turnover
        6.6. Reference or normal levels in indicator media
        6.7. Reaction with body components  



        8.1. Neurotoxicity and nephrotoxicity
        8.2. Reproduction, embryotoxicity, and teratogenicity
        8.3. Mutagenicity and related end-points
        8.4. Carcinogenicity
        8.5. Special studies
        8.6. Factors modifying toxicity; toxicity of metabolites


        9.1. General population exposure
                9.1.1. Effects on adults
               Effects on the nervous system
               Effects on non-nervous tissue
                9.1.2. Effects on developing tissues
               Effects on the nervous system
        9.2. Occupational exposure
        9.3. Mechanisms of toxicity
                9.3.1. The mature organism
               Mechanism of selective damage
               The latent period
               Cellular and molecular mechanisms
                9.3.2. Developing tissues
                9.3.3. Summary
        9.4. Dose-effect and dose-response relationships in human beings
                9.4.1. Adult exposure
               The Minamata and Niigata outbreaks
               The Iraqi outbreak
               Exposed populations in Canada
               Other fish-eating populations
               Special groups
                9.4.2. Prenatal exposure
               New Zealand


        10.1. Exposure levels and routes
        10.2. Toxic effects
                10.2.1. Adults
                10.2.2. Prenatal exposure
        10.3. Conclusions


        11.1. Gaps in knowledge
        11.2. Preventive measures





Dr L.  Albert, Centro de Ecodesarrollo, Xalapa, Vera Cruz,

Dr L.  Amin-Zaki,  Al-Damluji Clinic,  Al-Nasr Street, Abu
   Dhabi, United Arab Emirates

Professor  S.  Araki, Kumamoto  University Medical School,
   First Department of Internal Medicine, Kumamoto, Japan

Professor M. Berlin, Department of Environmental Medicine,
   University of Lund, Lund, Sweden ( Chairman )

Dr P.M.  Bolger,  Food  and  Drug  Administration,  Public
   Health  Service,  Center  for Food  Safety  and Applied
   Nutrition,    Division    of   Toxicological    Review,
   Washington, DC, USA

Dr T. Clarkson, The University of Rochester, Environmental
   Health Sciences Center, Rochester, New Yorka

Dr D.  Dimitroff, Health and Welfare Canada, Environmental
   Health  Services,  Medical  Services  Branch,   Ottawa,
   Ontario, Canada

Dr L.  Magos,  Medical  Research Council,  MRC  Toxicology
   Unit, Carshalton, Surrey, United Kingdom ( Rapporteur )

Dr D.  Marsh, The University  of Rochester, Department  of
   Neurology, Rochester, New York, USA

Dr J.  Piotrowski, Medical Academy  in Lodz, Institute  of
   Environmental Research and Bioanalysis, Lodz, Poland

Professor A. Renzoni, Department of Environmental Biology,
   University of Siena, Siena, Italy

Dr C.  Shamlaye,  Ministry  of Health  &  Social Services,
   Botanical Gardens, Republic of Seychellesa

Dr P.  Stegnar, "Josef Stefan" Institute,  Department of
   Nuclear Chemistry, Ljubljana, Yugoslavia

Professor  S. Yamaguchi, Institute of  Community Medicine,
   University  of  Tsukuba,  Tsukuba City,  Japan   ( Vice- 
    Chairman )


Dr M.  Ancora,  Centro  Italiano Studi  e Indagini, Piazza
   Capranica, Rome, Italy

Professor  M.  Fujiki,  Institute of  Community  Medicine,
   University of Tsukuba, Tsukuba City, Japan

Miss  M. Horvat, "Josef Stefan" Institute, Department of
   Nuclear Chemistry, Ljubljana, Yugoslavia

Professor  A. Igata, Kagoshima University, Kagoshima City,

Professor  C.  Maltoni,  Institute of  Oncology,  Bologna,

Professor  A.A.G. Tomlinson, IBE-Rome Research Area, Rome,


Dr G.C.  Becking,  International  Programme  on   Chemical
   Safety,  Interregional  Research  Unit,  World   Health
   Organization,  Research Triangle Park,  North Carolina,
   USA ( Secretary )

Dr L.J.  Saliba,  WHO/EURO  Project Office,  Mediterranean
   Action Plan, Athens, Greece

a  Invited but unable to attend.


     Every  effort has been made to present information in
the  criteria documents as accurately  as possible without
unduly delaying their publication.  In the interest of all
users  of  the  environmental health  criteria  documents,
readers  are  kindly  requested to  communicate any errors
that may have occurred to the Manager of the International
Programme  on Chemical Safety, World  Health Organization,
Geneva, Switzerland, in order that they may be included in
corrigenda, which will appear in subsequent volumes.

                       *     *     *

     A  detailed data  profile and  a legal  file  can  be
obtained  from  the International  Register of Potentially
Toxic  Chemicals,  Palais  des Nations,  1211  Geneva  10,
Switzerland (Telephone No. 7988400 - 7985850).


     A WHO Task Group on Environmental Health Criteria for
Methylmercury met in Bologna, Italy, at the Provincia from
5 to 9 June 1989. The meeting was sponsored by the Italian
Ministry of the Environment and organized locally  by  the
Institute  of Oncology and Environmental Sciences with the
assistance  of the Provincial Government.  Dr C.  Maltoni,
Director  of the Institute,  welcomed the participants  on
behalf  of the host institution and the local governments,
and  Dr M. Ancora, C.I.S.I., spoke on behalf of the Minis-
try  of the Environment.   Dr M. Mercier,  Manager,  IPCS,
addressed the meeting on behalf of the  three  cooperating
organizations  of  the IPCS  (ILO/UNEP/WHO), reviewing the
accomplishments of the Programme over the last few years.

     The  Task  Group made  minor  revisions to  the draft
document  and made an evaluation of the human health risks
from exposure to methylmercury.

     The   efforts  of  DR  T.   CLARKSON,  University  of
Rochester,  Rochester,  New  York, USA,  who  prepared the
first  two drafts  of this  document, and  all others  who
helped  in its preparation and finalization are gratefully
acknowledged.  Dr  G. Becking  and  Dr P.G.  Jenkins, both
members of the IPCS Central Unit, were responsible for the
overall   scientific   content   and  technical   editing,

                        *    *     *

     Financial support for the meeting was provided by the
Ministry  of  the Environment  of  Italy, and  the  Centro
Italiano Studi e Indagini and the Institute  of  Oncology,
Bologna,  contributed to the organization and provision of
meeting facilities.


    This  monograph focuses on  the risks to  human health
from  compounds of monomethylmercury and examines the data
that  have become available  since the publication  of En-
vironmental  Health Criteria 1: Mercury (WHO, 1976b).  The
environmental effects of mercury are discussed in Environ-
mental Health Criteria 86: Mercury - Environmental Aspects
(WHO, 1989a).

1.1 Identity, Physical and Chemical Properties, Analytical Methods

    The  solubility  of  methylmercury compounds  in water
varies  greatly and depends  on the nature  of the  anion.
Most  are soluble in water  but much less soluble  in non-
polar  solvents.   They generally  have appreciable vapour
pressures  at  room  temperature.   Mercurials,  including
alkylmercurials,  exhibit  high affinities  for sulfhydryl

    Blood  samples for analysis  should be taken  by veni-
puncture,  avoiding devices using  mercury-containing pre-
servatives.  Current methods are capable of measuring mer-
cury  in 1- to  5-ml samples of  whole blood, even  in the
case  of  non-exposed  individuals.   Hair  is  useful  in
assessing exposure to methylmercury in the diet and may be
sampled  as single or bunched  strands.  The single-strand
procedure  requires both sensitive analytical  methods and
the determination of the growth phase of the hair.

    The  method of choice for determining total mercury in
environmental  and biological samples is  flameless atomic
absorption  spectroscopy (detection limits, 0.5-4.0 ng/g).
Neutron  activation analysis serves as  a sensitive refer-
ence method. Gas chromatography is used to determine meth-
ylmercury directly (detection limit, 1.0 ng/g sample).

1.2 Sources of Human and Environmental Exposure

    Environmental  methylmercury  arises  largely, if  not
solely,  from the methylation  of inorganic mercury.   The
major  source  of  atmospheric  mercury  is  the   natural
degassing  of  the  earth's crust,  amounting to 2700-6000
tonnes   per  year.  Deposition  of  atmospheric  mercury,
leaching  from rocks, and anthropogenic sources all add to
the  mercury burden  in bodies  of water,  but  the  exact
contribution of each source is indeterminable.

    About  10 000 tonnes  of  mercury per  year are mined,
subject  to considerable year-to-year variation. Other im-
portant  man-made  sources  are fossil  fuels  combustion,
smelting of sulfide ores, production of cement, and refuse
incineration. The total man-made global release of mercury
to  the  atmosphere is  approximately 2000-3000 tonnes per

year,  i.e.,  less  than the  natural emissions.  Man-made
emissions pose the greatest risk when they are released in
confined areas.

    Mercury  continues  to be  used  in the  production of
caustic  soda and chlorine, and  it is widely used  in the
electrical  industry for lamps, controls, rectifiers, bat-
teries  and switches, as well as in the dental profession.
Environmental losses can also occur from its continued use
in  antifouling and mildew-proofing paints, in seed dress-
ings, and in the extraction of gold.

1.3 Environmental Transport, Distribution, and Transformation

    There is a well recognized global cycle  for  mercury,
whereby  emitted  mercury  vapour is  converted to soluble
forms (e.g., Hg++)   and deposited by rain onto  soil  and
water. Mercury vapour has an atmospheric residence time of
between  0.4 and 3 years, whereas soluble forms have resi-
dence times of a few weeks. Transport in soil and water is
thus  limited, and it is likely that deposition will occur
within a short distance.

    The  change in speciation of mercury from inorganic to
methylated forms is the first step in the  aquatic  bioac-
cumulation  process. Methylation can occur non-enzymically
or   through  microbial  action.   Once  methylmercury  is
released,  it enters the food chain by rapid diffusion and
tight binding to proteins.  As a result of food-chain bio-
magnification,  highest levels are found in the tissues of
such predatory species as freshwater trout, pike, walleye,
bass  and ocean tuna, swordfish, and shark. The bioconcen-
tration  factor, i.e., the  ratio of the  concentration of
methylmercury  in fish tissue to that in water, is usually
between  10 000  and 100 000.  Levels  of selenium  in the
water  may affect the  availability of mercury  for uptake
into aquatic biota. Reports from Sweden and Canada suggest
that  methylmercury  concentrations  in fish  may increase
following  the  construction  of artificial  water  reser-

1.4 Environmental Levels and Human Exposure

    The general population is primarily exposed to methyl-
mercury  through  the diet.  However,  air and  water, de-
pending  upon the level  of contamination, can  contribute
significantly  to the daily  intake of total  mercury.  In
most  foodstuffs, mercury is largely in the inorganic form
and below the limit of detection (20 g mercury/kg   fresh
weight).  However, fish and fish products are the dominant
source  of methylmercury in  the diet, and  levels greater
than 1200 g/kg   have been found in the  edible  portions
of  shark,  swordfish,  and Mediterranean  tuna.   Similar
levels  have been found in  pike, walleye, and bass  taken
from polluted fresh waters.

    It  has been estimated that humans have a daily intake
of  about 2.4 g methylmercury   from  all sources, and  a
daily  uptake of approximately  2.3 g.   The total  daily
intake of  all forms of mercury from all sources  has  been
estimated to be 6.7 g,   with an added burden of  3.8  to
21 g  of mercury vapour from dental amalgams, if present.
The  level of mercury in  fish, even for humans  consuming
only  small  amounts  (10-20 g of  fish/day), can markedly
affect  the intake of  methylmercury.  The consumption  of
200 g  of fish containing 500 g mercury/kg    will result
in  the intake of 100 g mercury    (predominantly methyl-
mercury).  This amount is one-half of the recommended pro-
visional tolerable weekly intake (WHO 1989b).

1.5 Kinetics and Metabolism

    Methylmercury  in the human diet  is almost completely
absorbed  into the bloodstream and distributed to all tis-
sues within about 4 days. However, maximum levels  in  the
brain are only reached after 5-6 days. In humans, blood to
hair  ratios are about 1:250,  with appreciable individual
variation.   Similarly,  large individual  differences are
seen  in cord to maternal blood mercury ratios, the levels
generally being higher in cord blood.  Species differences
exist  in  the  distribution of  methylmercury between red
blood cells and plasma (about 20:1 in humans, monkeys, and
guinea-pigs, 7:1 in mice, and >100:1 in rats).

    Methylmercury  is  converted  to inorganic  mercury in
experimental  animals and humans.  The duration of the ex-
posure and the interval after its cessation, determine the
fraction  of  total  mercury  present  in  tissues  in the
Hg++ form.   In humans, after high oral intakes of methyl-
mercury  for 2 months, the following  values were reported
(percentage  of total mercury in tissues as inorganic mer-
cury):  whole blood, 7%;  plasma, 22%; breast  milk,  39%;
urine, 73%; liver, 16-40%.

    The  rate of excretion  of mercury in  both laboratory
animals  and humans is directly proportional to the simul-
taneous  body burden  and can  be described  by a  single-
compartment  model with a  biological half-time, in  fish-
eating  humans,  of  39-70 days (average  approximately 50
days).  Lactating females have significantly shorter half-
times for mercury excretion than non-lactating ones.

    Mercury  half-times  in  hair closely  follow those in
blood  but with wider  variation (35-100 days, average  65
days). Suckling mice are incapable of excreting methylmer-
cury,  but they abruptly change  to the adult rate  of ex-
cretion at the end of the suckling period.

    In  the case of continuous exposure, a single-compart-
ment  model  with a  70-day  half-time predicts  that  the
whole-body  steady  state (where  intake equals excretion)

will  be attained within  approximately one year  and that
the maximum amount accumulated will be 100 times the aver-
age  daily intake.  The validity of the single-compartment
model  is  supported  by the  reasonable agreement between
predicted  and observed blood concentrations of methylmer-
cury  in  single-dose  tracer  studies,  single-dose  fish
intake  experiments,  and  studies involving  the extended
controlled  intake of methylmercury from fish.  It is also
supported  by results from the  longitudinal hair analysis
of individuals with very high intakes of methylmercury.

    Mean  reference values for  total mercury in  commonly
used indicator media are: whole blood, 8 g/litre;   hair,
2 g/g;  urine, 4 g/litre,   and placenta, 10 g/kg   wet
weight.  Long-term fish consumption is  the major determi-
nant  of methylmercury and, usually,  total mercury levels
in blood.  For example, in communities in which there is a
long-term  daily consumption of  200 g mercury/day   from
fish,  blood mercury levels are approximately 200  g/litre
and  corresponding  hair  levels  about  250 times  higher
(50 g/g hair).

1.6 Effects on Experimental Animals and  In Vitro Systems

    In every animal species studied, the nervous system is
a  target  of methylmercury,  fetuses  appearing to  be at
higher risk than adults. Concerning effects on the nervous
system, animal studies reported since 1976 provide further
support  to the mechanistic  models used to  evaluate  the
available data in humans (summarized in section 1.7).

    Methylmercury   is   fetoxic  in mice  (single dose of
2.5-7.5 mg/kg);   teratogenic   in  rats,   and  adversely
affects  the behaviour of monkey  offspring (mercury doses
of 50-70 g/kg   per day before and during pregnancy).  It
also  affects spermatogenesis in mice  (1 mg mercury/kg as

1.7 Effects on Man - Mechanism of Action

    The  effects  of  methylmercury on  adults differ both
qualitatively  and  quantitatively  from the  effects seen
after  prenatal  or, possibly,  early postnatal exposures.
Thus, effects on the mature human being will be considered
separately from the effects on developing tissues.

    The  clinical  and epidemiological  evidence indicates
that  prenatal life is more sensitive to the toxic effects
of  methylmercury than is  adult life. The  inhibition  of
protein synthesis is one of the earliest  detectable  bio-
chemical effects in the adult brain, though  the  sequence
of events leading to overt damage is not  yet  understood.
Methylmercury  can  also  react  directly  with  important
receptors in the nervous system, as shown by its effect on
acetylcholine  receptors in the peripheral nerves.  In the
case  of prenatal exposure,  the effects of  methylmercury

seem  to  be quite  different and of  a much more  general
basic  nature.   It  affects normal  neuronal development,
leading  to altered brain architecture, heterotopic cells,
and  decreased  brain  size.  Methylmercury  may  also  be
exerting  an  effect,  perhaps through  inhibition  of the
microtubular  system,  on  cell division  during  critical
stages in the formation of the central nervous system.

    Since  1976, a  wealth of  data has  been reported  on
dose-effect and dose-response relationships in humans.  It
has  been  derived  from in-depth  studies  on populations
exposed   to  methylmercury  through  mass  poisonings  or
through  the consumption of fish containing varying levels
of  methylmercury.  Again, prenatal and adult data will be
considered  separately  in  view of  the differences, both
qualitative and quantitative, in effects and dose-response

    In   adults,   the   reported  relationships   between
response  and body burden  (hair or blood  mercury concen-
trations)  are essentially the  same as those  reported in
Environmental   Health  Criteria 1: Mercury (WHO,  1976b).
No adverse effects have been detected with long-term daily
methylmercury  intakes  of  3-7 g/kg   body  weight (hair
mercury   concentrations  of  approximately    50-125 g/g).
Pregnant  women may suffer effects  at lower methylmercury
exposure  levels  than  non-pregnant adults,  suggesting a
greater risk for pregnant women.

    Severe  derangement of the developing  central nervous
system  can be caused  by prenatal exposure  to methylmer-
cury.  The  lowest  level (maximum  maternal  hair mercury
concentration  during  pregnancy) at  which severe effects
were observed was 404 g/g   in the Iraqi outbreak and the
highest  no-observed-effect  level for  severe effects was
399 g/g.     Fish-eating  populations  in Canada  and New
Zealand have also been studied for prenatal  effects,  but
exposure levels were far below those that  caused  effects
in Iraq and no severe cases were seen.

    Evidence  of psychomotor retardation (delayed achieve-
ment  of developmental milestones, a  history of seizures,
abnormal  reflexes)  was seen  in  the Iraqi  outbreak  at
maternal  hair levels below  those associated with  severe
effects.   The extrapolation of data suggested that one of
these  effects  (motor  retardation) rose  above the back-
ground  frequency at maternal  hair levels of    10-20 g/g.
The Canadian study reported that abnormal muscle  tone  or
reflexes  were  positively  associated with  maternal hair
levels in boys but not in girls (the highest maternal hair
level  during pregnancy was 23.9 g/g).    The New Zealand
study  reported  evidence  of  developmental   retardation
(according to the Denver Test) in 4-year-old  children  at
average  maternal  hair  mercury levels  during  pregnancy
within the range of 6-86 g/g  (the second  highest  value

was 19.6 g/g).   The New Zealand mercury values should be
multiplied  by  1.5 to  convert  to maximum  maternal hair
levels in pregnancy.

1.8 Conclusions

    The  general  population  does not  face a significant
health risk from methylmercury. Certain groups with a high
fish  consumption may attain  a blood methylmercury  level
(about 200 g/litre,   corresponding to 50 g/g   of hair)
associated  with a low (5%) risk of neurological damage to

    The fetus is at particular risk. Recent evidence shows
that  at peak maternal  hair mercury levels  above   70 g/g
there  is a high risk (more than 30%) of neurological dis-
order in the offspring.  A prudent interpretation  of  the
Iraqi data implies that a 5% risk may be associated with a
peak mercury level of 10-20 g/g in maternal hair.

    There is a need for epidemiological studies  on  chil-
dren  exposed  in utero to levels of methylmercury that re-
sult in peak maternal hair mercury levels  below    20 g/g,
in  order to screen for  those effects only detectable  by
available psychological and behavioural tests.


2.1 Identity

    The  primary constituent is  the element mercury  (CAS
registry  number 7439-97-6), which  has a relative  atomic
mass  of 200.59.  In the inorganic form, mercury exists in
three  oxidation states: Hg (metallic);   Hg2++   (mercu-
rous);  and Hg++ (mercuric).   The mercurous  and mercuric
states  can form numerous  inorganic and organic  chemical
compounds.  The organic forms are those in  which  mercury
is attached covalently to at least one carbon atom.

    This  monograph focuses on the risk to human health of
the  compounds  of  monomethylmercury.  The  generic  term
"methylmercury"  is  used  throughout this  text to rep-
resent  monomethylmercury  compounds.   In many  cases the
exact identity of these compounds is not known except that
the methylmercury cation, CH3Hg+,     is associated either
with  a simple anion, like  chloride, or a large  molecule
(e.g., a protein) with negative and positive charges.

    Other  physical and chemical forms of mercury are dis-
cussed  in this monograph where  they are relevant to  the
full evaluation of the risks to human health of methylmer-
cury:  for example, the atmospheric transport of elemental
mercury  vapour (Hg),   its  deposition and oxidation  in
natural  waters, and the  subsequent methylation of  inor-
ganic mercury (Hg++).

2.2 Physical and Chemical Properties

    In  its elemental form, mercury at room temperature is
a  heavy silvery liquid.  At 20 C the specific gravity of
the  metal is 13.456  and the vapour  pressure is  0.16 Pa
(0.0012 mmHg). Thus the saturated atmosphere at 20 C con-
tains  mercury vapour at a  concentration of approximately
15 mg/m3.    This  concentration is  over 200 fold greater
than  the  currently  accepted  concentrations  for  occu-
pational exposure.

    It  is of interest that certain forms of mercury, such
as  the  methyl  and ethyl  derivatives,  have appreciable
vapour  pressure  at  room temperature.   Thus, the vapour
pressure  of  methylmercuric  chloride is  1.13 Pa (0.0085
mmHg) and the vapour pressure of dimethylmercury  is  sev-
eral  times greater.  Mercurials  differ greatly in  their
solubilities.  Solubility in water increases in the order:
mercurous   chloride;  elemental  mercury;  methylmercuric
chloride;  mercuric chloride.  Certain species  of mercury
are  soluble in non-polar solvents.  These include elemen-
tal mercury and the halide compounds of alkylmercurials.

    From  the biochemical point of view the most important
chemical  property of mercuric mercury and alkylmercurials
is their high affinity for sulfhydryl groups.

2.3 Conversion Factors

        1 ppm = 1 mg/kg = 1 g/g = 1 ng/mg
        1 ppb = 1 g/kg = 1 ng/g
        1 mol mercury  1 mol methylmercury  200 g

2.4 Analytical Methods

2.4.1 Sampling

    Many  different  sampling  procedures are  used in the
measurement  of  mercury.  Procedures  for   environmental
sampling  in  air, water,  soil,  and aquatic  and animals
species  are beyond the scope of this monograph. Since its
purpose is to evaluate the risks to human health, only the
sampling of human indicator media and tissues will be con-

    Blood  samples  should  be taken  by venipuncture, the
most  convenient  method  being  the  use  of  heparinized
"Vacutainers"a.   Some commercial containers may contain
a  mercury compound added as a preservative. It is wise to
analyse each commercial batch for mercury before use.  The
sample  should be refrigerated  but not frozen,  as it  is
sometimes  useful  to measure  mercury  in plasma  and red
cells separately.  The analysis should be carried  out  as
soon  as possible to avoid  haemolysis of the sample.   If
the  sample  has clotted  or  if extensive  haemolysis has
occurred, the sample should be homogenized before aliquots
are  taken for analysis.  Current methods are  capable  of
measuring  mercury in 1-  to 5-ml samples  of whole  blood
even in the case of non-exposed individuals.

    Urine  sampling is not useful  for individuals exposed
to  methylmercury,  because  little is  excreted  by  this
route.   Hair samples are important  in assessing exposure
to  methylmercury in the diet.  Methylmercury in non-occu-
pationally  exposed individuals is incorporated  into hair
at  the time the hair is formed, the methylmercury concen-
tration  in newly formed  hair being proportional  to  its
simultaneous  concentration  in blood.   Once incorporated
into the hair strand, its concentration remains unchanged.
Thus,  longitudinal analysis along  a strand of  hair pro-
vides  a  recapitulation  of previous  blood levels. Since
hair  grows  at about  1 cm  per month,  recapitulation is
possible  over several months  or years, depending  on the
length of the hair sample.

a Trade name of heparinized test-tube manufactured by
  Becton & Dickinson, USA, and used for blood sample

    There  are  two  sampling methods,  single strands and
bunched  strands.   The  former requires  a more sensitive
method and the determination of the growth phase (anaphase
and telophase) of each strand by the  microscopic  examin-
ation  of the hair root.  However, most methods require at
least 1 mg hair and, preferably, about 10 mg. Thus, if the
hair  is measured in 1-cm lengths, it is necessary to have
about 50 strands. The best sampling procedure is to locate
50 strands of the longest hair on the head, hold  them  in
place with a haemostat, and cut them as close to the scalp
as  possible with surgical scissors.  The strands are tied
with a cotton thread before the haemostat is  released  to
ensure  that  the individual  strands  remain in  the same
alignment. The tied bunch of hair may be stored in a plas-
tic  bag or envelope until it is analysed.  Bunch analysis
tends  to  underestimate  peak concentrations  due  to the
different  growth rates of individual hairs and to mechan-
ical  displacement of individual strands during collection
and subsequent handling (Giovanoli-Jakubczak & Berg, 1974;
Cox et al., in press). Single-strand analysis can  give  a
more  precise  temporal recapitulation  and avoids certain
artifacts  found  in  bunched-strand analysis.   Agreement
between  concentrations  of  mercury  in  individual  hair
strands collected from the same person at the same time is
within  10%.  Nevertheless it is wise to collect more than
one  strand to guard  against accidental contamination  or

2.4.2 Analytical procedures

    The  methods summarized in Table 1  have been selected
from  a large number of publications.  They are typical of
the various methods available for analysis of  total  mer-
cury and its inorganic or organic species.

    All  represent a considerable improvement on the orig-
inal "dithizone" method.  This method was widely used up
to  the  introduction of  atomic  absorption in  the  late
1960s.   Basically it involved the formation of a coloured
complex with dithizone after all the mercury in the sample
had  been  converted  to Hg++ compounds   by  oxidation in
strong acids.  After neutralization of excess oxidant with
a reducing agent, usually hydroxylamine, the coloured com-
plex was extracted into a non-polar solvent. After washing
the  extract, the colour intensity was measured on a spec-
trophotometer and the amount of mercury estimated  from  a
standard curve.  The limit of detection was of  the  order
of  1-10 g   mercury so  that large quantities  of sample
were required for such media as blood and hair.

    The  neutron activation procedure  is regarded as  the
most  accurate and sensitive procedure and is usually used
as the reference method (WHO, 1976b). The "Magos" selec-
tive  atomic-absorption  method  (Magos, 1971;  Magos  and

Clarkson,  1972) has found wide application. It can deter-
mine  both total and inorganic mercury and, by difference,
organic  mercury.  The apparatus is inexpensive, portable,
and does not require sophisticated facilities.

    The  gas  chromatography  method is  usually used when
there  is a need  to selectively measure  methylmercury or
other  organic species.  It has  been widely used for  the
measurement  of methylmercury in fish tissues. An alterna-
tive  approach is the separation of methylmercury from in-
organic mercury by volatilization (Zelenko & Kosta, 1973),
ion exchange (May et al., 1987), or  distillation  (Horvat
et  al.,  1988a),  and  the  estimation  of  the separated
methylmercury  by non-selective methods (e.g.,  atomic ab-

Table 1.  Analytical methods for the determination of total inorganic
and methylmercury
Media             Speciation          Analytical Method    Detection  Comments           References
                                                           (ng mercury/

Food, tissues     total mercury       atomic absorption    2.0        method has many    Hatch & Ott
                                                                      adaptations        (1969)
                                                                      (see Peter &
                                                                      Strunc, 1984)

Blood, urine,     total mercury       atomic absorption    0.5        also estimates     Magos &
hair, tissues     inorganic mercury                                   organic mercury    Clarkson (1972)
                                                                      as difference
                                                                      between total
                                                                      and inorganic

Blood, urine,     total mercury       atomic absorption    2.5        automated form of  Farant et al.
hair, tissues     inorganic mercury                                   the Magos Method   (1981)

Blood, urine,     total mercury       atomic absorption    4.0        automated form of  Coyle & Hartley
hair, tissues     inorganic mercury                                   the Magos Method   (1981)

Food, tissues,    methylmercury       gas chromatography   1.0        based on the       Von Burg et al.
biological fluids                     electron-capture                original method    (1974)
                                                                      of Westoo (1968)   Cappon & Smith

All media         total mercury       neutron activation   0.1        reference method   Kosta & Byrne
                                                                                         Byrne & Kosta
    The  estimation of total mercury in a single strand of
hair  by X-ray fluorescence has been described by Jaklevic
et al. (1978).

    Emulsion  autoradiography has been widely  used in ex-
perimental  studies of tissue deposition  of the radioiso-
topes  of mercury.  However it should be noted that photo-
graphic  emulsions  are also  sensitive to non-radioactive
inorganic forms of mercury (Rodier & Kates, 1988).

    It is necessary to note that, since  methylmercury  is
not  a sample contaminant, external contamination does not
interfere  with  methylmercury-specific  methods.  Greater
care is required when the method is sensitive to inorganic
mercury contamination (Mushak, 1987).

2.4.3 Quality control and quality assurance

    The analysis of most samples of hair or blood involves
very small quantities of mercury (in the ng or even sub-ng
ranges).  Therefore, considerable attention should be paid
to  procedures that will ensure  accurate analytical data.
The  general considerations of quality control and quality
assurance  have been discussed  at a recent  WHO-sponsored
conference   on  Biological  Monitoring  of  Toxic  Metals
(Friberg,  1988). A Global Environmental Monitoring System
(GEMS)  programme has been  described in which  a new  ap-
proach  to  interlaboratory comparisons  has been success-
fully  introduced  on  an international  basis.   Specific
quality-control  programmes  for  mercury using  the  GEMS
approach have been described by Friberg (1983) and Lind et
al. (1988a).


3.1 Natural Occurrence

    As  the predominant, if  not only, source  of environ-
mental  methylmercury is the methylation of inorganic mer-
cury, we need to examine the environmental movement of the
inorganic species if we are to understand the  origins  of
human  exposure to methylmercury. Thus, this section deals
largely  with the environmental aspects  of elemental mer-
cury vapour and inorganic compounds of mercury.

    The  major  natural  sources of  mercury  (Fig. 1) are
degassing  of the earth's crust, emissions from volcanoes,
and  evaporation  from  natural bodies  of water (National
Academy of Sciences, 1978; Nriagu, 1979; Lindqvist et al.,
1984).   The most recent  estimates indicate that  natural
emissions amount to 2700-6000 tonnes per year (Lindberg et
al., 1987).

    The  earth's crust is also an important source of mer-
cury for bodies of natural water.  Some of this mercury is
undoubtedly  of  natural origin,  but  some may  have been
deposited  from the atmosphere  and may, ultimately,  have
been  generated  by  human activities  (Lindqvist  et al.,
1984).   Thus it is difficult to assess quantitatively the
relative  contributions of natural and  anthropogenic mer-
cury to run-off from land to natural bodies of water.

3.2 Man-Made Sources

    The world-wide mining of mercury is estimated to yield
about 10 000 tonnes/year, but this figure varies consider-
ably  from year to year, depending on the commercial value
of  the metal.  Mining activities also result in losses of
mercury  through the dumping  of mine tailings  and direct
discharges to the atmosphere.  The Almaden mercury mine in
Spain, which accounts for 90% of the total output  of  the
European Community, was expected to produce 1380 tonnes in
1987  (Seco, 1987).  Other important  man-made sources are
the  combustion  of fossil  fuels,  the smelting  of metal
sulfide  ores, the production of cement, and refuse incin-
eration.   Using  Sweden  as a  specific  example (Swedish
Environmental   Protection   Board,  1986),   the  mercury
emissions  to the atmosphere  in 1984 were  (in  kg/year):
incineration  of  household waste  (3300); smelting (900);
chloralkali  industry  (400);  crematories  (300);  mining
(200);  combustion of coal  and peat (200);  other sources


    The  total man-made global  release to the  atmosphere
has  been estimated to be  2000-3000 tonnes/year (Lindberg
et  al., 1987; Pacyna, 1987).  It should be stressed  that
there  are  considerable  uncertainties in  the  estimated
fluxes   of  mercury  in   the  environment  and   in  its
speciation.   Concentrations in the  unpolluted atmosphere
and  in  natural  bodies of water are so low as to be near
the limit of detection of current analytical methods, even
for the determination of total mercury.

    Anthropogenic  releases of mercury into confined areas
can  be the source of high toxicity risk even though these
releases may be small relative to global  emissions.   The
point is relevant to the contamination of Minamata Bay and
the  Agano River in Niigata, Japan, as well as to inadver-
tent   poisoning   via   contaminated   bread   in   Iraq.

3.3 Uses

    A  major use of mercury  is as a cathode  in the elec-
trolysis  of sodium chloride  solution to produce  caustic
soda  and chlorine  gas. Quantities  of the  order  of  10
tonnes  of  liquid metal  are  used in  each manufacturing
plant.  In  most  industrialized nations,  stringent  pro-
cedures  have been taken to reduce losses of mercury. Mer-
cury is widely used in the electrical industry (lamps, arc

rectifiers, and mercury battery cells), in control instru-
ments  in  the  home and  industry (switches, thermostats,
barometers),  and in other laboratory  and medical instru-
ments.   It is also widely  used in the dental  profession
for  tooth amalgam fillings.  In certain countries, liquid
metallic mercury is still used in gold extraction. Mercury
compounds  continue to be used in anti-fouling and mildew-
proofing paints and to control fungal infections of seeds,
bulb plants, and vegetation.  WHO has warned  against  the
use  of  alkylmercury  compounds in  seed  dressing  (WHO,
1976a).  Methylmercury compounds are still used in labora-
tory-based  research,  and  so the  possibility  of  occu-
pational exposures remains (Junghans, 1983).


4.1 Transport and Distribution Between Media

    Human  exposure to mercury  should first be  viewed in
the context of the world-wide circulation of  this  highly
mobile  metal (Fig. 1).  The  vapour of metallic  mercury,
hereinafter  referred to as  mercury vapour or  Hg,    is
released  into  the atmosphere  from  a number  of natural
sources (section 3.1). Man-made emissions, mainly from the
combustion  of fossil fuels, form  about 25% of the  total
emissions  to the atmosphere.  However,  the anthropogenic
contribution  is  greater  in  the  northern  than  in the
southern hemisphere and becomes the major form of emission
in  heavily industrialized areas, such  as western Europe.
The  distribution  constants of  various mercury compounds
between  air  and water  are  given in  Table 2.  Clearly,
Hg and   dimethylmercury  ((CH3)2Hg),     as  a result of
their air/water distribution coefficients, are most likely
to be found in the atmosphere.

Table 2.  Experimentally determined distribution constants
for some compounds of relevance for the mercury cyclea
Compound      HgX (air)/    Temperature    Cl-
              HgX (water)   (C)           ionic strength
              (v/v)                        (mol)

Hg           0.29          20             0
(CH3)2Hg      0.31          25             0
(CH3)2Hg      0.15          0              0
CH3HgCl       1.9 x 10-5    25             0.7
CH3HgCl       1.6 x 10-5    15             1
CH3HgCl       0.9 x 10-5    10             0.2 x 10-3
Hg(OH)2       3.2 x 10-6    25             0.2 x 10-3
Hg(OH)2       1.6 x 10-6    10             0.2 x 10-3
HgCl2         2.9 x 10-8    25             0.2 x 10-3
HgCl2         1.2 x 10-8    10             0.2 x 10-3

a Adapted from: Lindqvist et al. (1984).

    The  solubility of mercury vapour in water is not high
enough  to account for the concentrations of mercury found
in  rain water. Thus,  Lindqvist et al.  (1984)  suggested
that  a small fraction of mercury vapour is converted to a
water-soluble species, probably Hg++,   which is deposited
on land and water in rain.  However, the  putative  water-
soluble  forms have yet to be positively identified.  Par-
ticulate forms account for less than 1% of  total  mercury
in the atmosphere but may make an  important  contribution
to mercury in rain water.  The residence time  of  mercury
vapour  is estimated to be between 0.4 and 3 years, and as
a consequence, mercury vapour is globally distributed. The
soluble  form is assumed to  have a residence time  of the
order of weeks, and therefore the distance over  which  it
may  be transported is limited.  The extremely low concen-
trations  in the atmosphere (section 5.1.1) present formi-
dable difficulties both in the analysis of  total  mercury
and  in the identification and measurement of chemical and
physical  species.   For example,  methylmercury compounds
have  been reported in the air above polluted areas in the
USA  (WHO, 1976b), but  their presence in  unpolluted  air
still  needs to be confirmed.  Shimojo et al. (1976) found
methyl  donors in car exhaust gases, but not methylmercury
in the ambient air.

    Mercury  deposited on land and open water is, in part,
re-emitted  to  the  atmosphere as  Hg.    This emission,
deposition, and re-emission ("ping-pong" effect) creates
difficulties  in tracing the  movement of mercury  to  its
source.  The bottom sediment of the oceans is  thought  to
be  the ultimate sink  where mercury is  deposited in  the
form of the highly insoluble mercuric sulfide.

    Recently,  an expert group suggested  that atmospheric
mercury vapour could be taken up directly by plant foliage
and  that this might be an important pathway to watersheds
in highly forested areas (Lindberg et al., 1987).

4.2 Biotransformation

    Despite  the uncertainties concerning  speciation, the
global  cycle  of mercury  is  believed to  involve almost
exclusively the inorganic forms.  These forms do  not  ac-
cumulate  in human food  chains except in  uncommon items,
such  as mushrooms (Minagawa et al., 1980).  The change in
speciation from inorganic to methylated forms is the first
crucial  step  in  the  aquatic  bioaccumulation  process.
Methylation takes place mostly on sediments in  fresh  and
ocean waters but also in columns of fresh and  sea  waters
(Lindberg et al., 1987). Fish intestinal contents (Rudd et
al.,  1980)  and the  outer slime of  fish have also  been
found to methylate inorganic mercury (McKone et al., 1971;
Jernelov, 1972; Rudd et al., 1980).

    The  mechanism of synthesis of methylmercury compounds
(both  CH3Hg+ and    (CH3)2Hg)     is now  well understood
(Wood  &  Wang,  1983).  Methylation  of inorganic mercury
involves  the non-enzymic methylation of  Hg++   by methyl
cobalamine compounds (analogues of vitamin B12)   that are
produced  as  a  result of  bacterial  synthesis. However,
other pathways, both enzymic and non-enzymic, may  play  a
role  (Beijer  &  Jernelov, 1979).   Factors affecting the
aquatic  methylation  of  mercury have  been  described by
Fujiki & Tajuma (1975).

    Microorganisms  have also been isolated that carry out
the reverse reactions:

           CH3Hg+  ->  Hg++  ->  Hg

    The  enzymology of CH3Hg+     hydrolysis  and mercuric
ion  reduction is now  understood in some  detail (Silver,
1984; Begley et al., 1986), as is the oxidation of mercury
vapour  to Hg++ by  an enzyme that is critical to the oxy-
gen  cycle  (catalase).   These  oxidation-reduction   and
methylation-demethylation  reactions  are  assumed  to  be
widespread  in the environment, and each ecosystem attains
its  own  steady  state  with  respect  to  the individual
species of mercury.  However, owing to the bioaccumulation
of  methylmercury,  methylation  is more  prevalent in the
aquatic environment than demethylation.

    Once methylmercury is released from microorganisms, it
enters the food chain by rapid diffusion and tight binding
to proteins in aquatic biota. The results of a field study
on  the entry of methylmercury  to the tuna food  chain in
the  Mediterranean Sea fits the  diffusion model (Bernhard
et al., 1982).

    Methylmercury  is rapidly accumulated by  most aquatic
biota and attains its highest concentration in the tissues
of  fish at the top of the aquatic food chain (Bernhard et
al., 1982).  Thus, large predatory species, such as trout,
pike,  walleye, and bass in  fresh water and tuna,  sword-
fish,  and  shark  in ocean  water,  contain  considerably
higher  levels than non-predatory species  (Table 3).  The
ratio of the concentration of methylmercury in fish tissue
to  that in water can  be extremely large, usually  of the
order  of 10 000 to 100 000  (US EPA, 1980).  However,  it
should be noted that these bioconcentration ratios are not
the  result of partition between  water and tissue but  of
biomagnification  through the food chain.   In addition to
the influence of trophic level or species, factors such as
the  age of the  fish, microbial activity  and mercury  in
sediment  (upper layer), dissolved organic  content (humic
content), salinity, pH, and redox potential all affect the
levels  of methylmercury in fish  (WHO, 1989a). Methylmer-
cury  in freshwater fish is also affected by the catchment
area  of the lake and  by recent flooding or  diversion of
rivers (see section 4.3).

4.3 Interaction with Other Physical, Chemical, or Biological Factors

    Following  the identification of point sources of mer-
cury  pollution in the 1960s (Swedish Expert Group, 1971),
it was discovered in the early 1970s that  numerous  lakes
in  Sweden had increased levels of methylmercury in  pike,
even  though these  lakes had  not been  subjected to  any
direct  discharge of mercury. It was suggested by Hultberg
&  Hasselrot  (1981)  that three  explanations  should  be

-   mercury  discharged into the atmosphere is washed down
    by  precipitation or is deposited (in the dry form) in
    the lake;

-   acid  precipitation causes the release of natural mer-
    cury or mercury deposited earlier by air that had been

-   acidity  in lakes induces a change in  the  biological
    dynamics of the lakes, which results in  a  re-distri-
    bution of mercury in the ecologic system.

    The  long-distance transport of mercury and the poten-
tial  role of acidification have become major factors con-
cerning  future human exposure  to methylmercury.  Low  pH
favours  both the direct  uptake of methylmercury  through
the  gills of  fish and  dietary uptake  due to  increased
mercury  accumulation by organisms in lower trophic levels
(Wiener,  1987;  Xun  &  Campbell,  1987).   According  to
Hultberg and Hasselrot (1981), an increase in  acidity  of
one  pH unit in  a lake increases  the mercury content  in
pike by approximately 0.14 mg/kg wet weight. Wiener (1987)

reported that a change of pH from 6.1 to 5.6 increased the
mercury   concentration  in  1-year-old yellow  perch from
0.11  0.002  (SEM) mg/g to 0.138  0.003 mg/kg within one
calendar  year.  The causal relationship between reduction
in  pH and elevated  mercury levels in  edible tissues  of
fish   has  not  been  established.   Possible  mechanisms

-   changes  in population dynamics (a switch by pike from
    consumption of roach to consumption of perch);

-   a   reduction in the total  biomass where most of  the
    methylmercury  is  found (the  growth  of fish  may be
    retarded  and, for a  given size, the  mercury concen-
    tration will be higher);

-   a   low pH favours monomethyl versus dimethyl mercury;
    the latter is less avidly accumulated by fish;

-   a   low pH may  elute more mercury  from sediments  or

-   as   pH falls, the  ratio of methylation  to demethyl-
    ation  reactions increases, thus favouring an increase
    in the net production of methylmercury (Ramlal et al.,

-   Bjornberg   et  al.  (1988) proposed  that the concen-
    tration  of the sulfide  ion in water  determines  the
    bioavailability  of  inorganic  mercury (Hg++)    and,
    therefore,  the  extent  of methylation  and uptake by
    aquatic  organisms.  A reduction in pH will reduce the
    concentration  of  the  sulfide ion  making  more   Hg++
    available for methylation.

Table 3.  The range of published average values of methylmercury (mg mercury/kg
wet weight) in the muscle tissue of various species of fisha,b
Species                   Atlantic      Pacific      Indian       Mediterranean
                          Ocean         Ocean        Ocean        Sea


  Mackerel                0.07 - 0.2    0.16 - 0.25  0.005        0.24
  Sardine                 0.03 - 0.06   0.03         0.006        0.15
  Unspecified number of
  edible species          0.08 - 0.27   0.07 - 0.09  0.02 - 0.16  0.1 - 0.3


  Tuna                    0.3 - 0.8     0.3          0.064 - 0.4  1.2
  Swordfish               0.8 - 1.3     1.6          -            1.8
  Shark, dogfish, ray     1.0           0.7 - 1.1    0.004 - 1.5  1.8

a       Data from: US Department of Commerce (1978).
b       Where an analysis of methylmercury was not available, the data on total mercury has been used instead.

    Extensive  investigations have been made  in Canada in
recent  years to explain why methylmercury levels increase
in  fish  when  bodies of  fresh  water  are relocated  or
redirected  (Ramlal et al., 1985; Stokes & Wren, 1987). It
is  proposed that the redirecting of rivers and the forma-
tion of reservoirs for hydroelectric production results in
large quantities of organic material in the  water,  which
serves as a food source for microorganisms.  The resulting
increase in microbial activity leads to an increase in the
production  of  methylmercury from  inorganic mercury nat-
urally  present in the  sediment (Furutani &  Rudd,  1980;
Ramlal  et al., 1986).  This  process is sustained by  the
repeated  raising and lowering of water levels to maintain
hydroelectric  production, because the shorelines continue
to be eroded and more vegetation enters the water.  It  is
likely  that  future environmental  impact statements will
have  to take into account this newly discovered source of
methylmercury when hydroelectric schemes are planned.

    As noted by Bjornberg et al. (1988),  "many  biologi-
cal,  chemical  and physical  factors  are linked  to each
other  in  the  limnic  ecosystem"  and  "many  of these
factors  seem to be  of importance for  the Hg content  of
fish".  Thus "it is not  difficult to understand why  it
has  been  considered  hard  to  find  simple   mechanisms
explaining why certain lakes have a high  mercury  content
in  fish and  others have  not".  They  propose that  the
"central  piece in the puzzle" is the critical influence
of  the sulfide ion, which forms the highly insoluble mer-
curic sulfide with Hg++ (Ks = l0-52).

    The  solubility product of mercury  selenide, HgSe, is
even  lower  (Ks = 10-58).       Thus, studies  made  on a
Canadian lake that had received a large discharge of inor-
ganic mercury from a paper pulp factory suggest  that  the
addition of selenite can reduce the availability  of  mer-
cury  for uptake into aquatic biota (Turner & Rudd, 1983).
Studies on Swedish lakes confirm these findings (Bjrnberg
et  al., 1988).  In these  studies the selenium level  was
raised artificially from 0.4 to 2.4 g/litre  over a 1- to
2-year  period, and the mean  levels of mercury fell  from
1.5 to 0.70 mg/kg in pike and from 0.56 to  0.16 mg/kg  in
perch.   Such levels of selenium  are below drinking-water


5.1 Environmental Levels

    There  is considerable variation in  mercury levels in
those  media that are  the source of  human exposure  and,
consequently,  in their contribution to the toxicity risk.
Non-occupational  groups are primarily exposed through the
diet. Although intake of the methylated form is of primary
interest,  levels of other species are summarized so as to
provide a measure of total mercury intake.

5.1.1 Air

    Concentrations  of total mercury in  the atmosphere of
the  northern hemisphere have recently been estimated at 2
ng/m3,    those in the southern hemisphere being half this
value.  Values in urban  areas are usually  higher  (e.g.,
10 ng/m3)   (Lindqvist et al., 1984).  Schroeder & Jackson
(1987)  found values in  the range 3-27 ng/m3    (mean,  9
ng/m3)    in rural areas of Canada and 5-15 ng/m3   (mean,
11 ng/m3)   in urban areas. In Sweden, urban levels appear
to  be  slightly  lower  (range,  0.8-13.2 ng/m3;    mean,
4 ng/m3).

    Dental  mercury fillings are reported  to release mer-
cury  vapour into the oral cavity (Clarkson et al., 1988).
The  resulting concentrations in  intra-oral air can  sub-
stantially  exceed those found in  the ambient atmosphere,
especially after of period of chewing. Estimates  of  pul-
monary  absorption indicate that approximately 3000-17 000
ng mercury  vapour  enter  the systemic  circulation daily
from  this exposure.  As  tobacco leaves contain  mercury,
smoking may also contribute to inhalation exposure (Suzuki
et al., 1976).

    As discussed in section 4.1, the major form of mercury
in  air is believed to  be elemental mercury vapour.  How-
ever, the presence of methylmercury compounds in the ambi-
ent atmosphere has been reported (Johnson & Braman, 1974).
Recent  data from the  vicinity of Toronto,  Canada, indi-
cated  the following average composition (as percentage of
total  mercury):  Hg,  75%;  Hg++,  5%;  and CH3Hg+, 20%
(Schroeder  & Jackson, 1987).  The particulate fraction of
mercury  in air  (as a  percentage of  total  mercury)  is
usually 4% or less (Lindqvist et al., 1984).  The  way  in
which  the "soluble fraction" of mercury in air (section
4.1) relates to these recent findings on individual chemi-
cal species is still unclear.

5.1.2 Water

    Concentrations  of total mercury in  natural water are
so  low that accurate analysis  is still a major  problem.
Values for rain water are usually within the  range  5-100

ng/litre, but mean values as low as 1 ng/litre  have  been
reported.   The most recent  data (Fig. 1) indicate  lower
values   than  those  previously  recorded  (WHO,  1976b).
Representative  values  for  dissolved total  mercury are:
open   ocean,  0.5-3 ng/litre;  coastal  sea  water,  2-15
ng/litre;  freshwater rivers and lakes,  1-3 ng/litre. The
concentration  range for mercury in  drinking-water is the
same  as in  rain, with  an average  of about  25 ng/litre
(Lindqvist et al., 1984).

    The chemical speciation of mercury in water  is  still
not  completely  defined.  Mercury in  ocean waters exists
mainly  in the form of Hg++ complexed  with chloride ions.
Speciation  in fresh water is poorly understood. In a con-
taminated  lake system in Canada,  methylmercury was found
to  constitute  a  varying proportion  of  total  mercury,
depending on the lake that was being tested, but, overall,
accounted  for  approximately  1-6% of  the  total mercury
(Canada-Ontario Steering Committee, 1983).

5.1.3 Food

    Concentrations  of  mercury  in most  foodstuffs (WHO,
1976b;  US EPA, 1984; Piotrowski & Inskip, 1981) are often
below  the reported limit  of detection (usually  20 g/kg
fresh  weight). Fish and  fish products are  the  dominant
source  of  methylmercury  in food.  The  highest  concen-
trations are found in both freshwater and marine  fish  at
the  highest trophic levels (Table 4).  For example, shark
and  swordfish  have average  values  of total  mercury in
edible  tissues above 1200 g/kg,   whereas  anchovies and
smelt  have average values  below 85 g/kg.    Most  other
foodstuffs  have  average  values below  20 g/kg,    with
mercury  mainly  in  the  inorganic  form  (Cappon,  1981;
Gartrell  et al., 1985a,b,  1986). Cappon (1987)  reported
mercury levels in vegetables.

5.2 General Population Exposure

5.2.1 Estimated daily intakes

    The human intake of the three major forms  of  mercury
present in the environment is summarized in  Table 4.  The
intake  of mercury from  the ambient atmosphere  has  been
estimated  by  assuming  that the  concentration  of total
mercury  is 2 ng/m3   and that 75% is present as elemental
mercury vapour, 5% as inorganic mercury compounds, and 20%
as methylmercury. The daily intake of each form of mercury
was  estimated by assuming  a daily ventilation  of 20 m3,
and the amount absorbed was estimated by assuming that 80%
of the inhaled elemental vapour, 50% of the inorganic mer-
cury  compounds, and 80% of the methylmercury was absorbed
across the pulmonary membranes (WHO, 1976b).

    Mercury  intake  from drinking-water  was estimated by
assuming  a  daily water  intake  of 2 litres,  an average
concentration  of 25 ng/litre, and that all the mercury is
in  the inorganic form.  Methylmercury has been found in a
few  samples taken from bodies of natural water, but there
have been no reports of methylmercury in drinking-water.

    The intake of species of mercury in the diet  was  the
most difficult to estimate.  Total mercury intake from all
foodstuffs  in Belgium was  13 g/day,   compared with  an
intake  from fish alone of 2.9 g/day   (Fouassin & Fondu,
1978).  Also in Belgium, Buchet et al. (1983)  measured  a
daily intake from all foodstuffs of 6.5 g mercury.

    The intake of total dietary mercury (g/day)  measured
during  a market basket survey (1984-1986) of the Food and
Drug  Administration  (FDA)  in the  USA  (Shibko,  1988),
according  to age group  was: 0.31 (6-11 months);  0.90 (2
years);  1.76  (16 years,  females);  1.84   (14-16 years,
males);  2.32  (25-30 years, females);  3.01 (25-30 years,
males); 2.29 (60-65 years, females) and 2.52 (60-65 years,
males). It is of interest that when these intake rates are
converted  to g/day   per kg body weight, the values fall
in  a much more narrow  range from 0.04 to  0.09.  In fact
values  for all the  age groups except  the  two-year-olds
fall between 0.044 and 0.054 g/day per kg.

Table 4.  Estimated average daily intake and retention (ug/day) of total
mercury and mercury compounds in the general population not occupationally
exposed to mercurya
Exposure             Elemental         Inorganic mercury   Methylmercury
                     mercury vapour    compounds
Air                  0.030 (0.024)     0.002 (0.001)       0.008 (0.0064)


   Fish              0                 0.600 (0.042)       2.4 (2.3)
   Non-fish          0                 3.6 (0.25)          0

Drinking-water       0                 0.050 (0.0035)      0

Dental amalgams      3.8-21 (3 - 17)   0                   0

Total                3.9-21 (3.1 - 17) 4.3 (0.3)           2.41 (2.31)
a  See text for assumptions underlying the calculations of average daily
   intake and retention. Values given are the estimated average daily
   intake; the figures in parentheses represent the estimated amount
   retained in the body of an adult. Values are quoted to 2 significant

    In Poland, the average daily dietary intake of mercury
(estimated in 2134 duplicate portions) was 5.08 g/day  in
the  age group l-6 years,  5.43 g/day  in the  age  group
6-18 years,   and 15.8 g/day    in  adults   (Szprengier-
Juszkiewicz,  1988).  Owing  to the  low  fish consumption
(6.76 kg/year)  and  low  mercury concentration  in market
fish (65 g/kg),   only 7% of the dietary  intake  derived
from  fish  (Nabrzyski  and Gajewska,  1984).   Bernhard &
Andreae  (1984)  estimated  the world-wide  mercury intake
from  seafood to be 2 g/day,    which is equivalent to  a
daily  intake of 20 g seafood with a mercury concentration
of  0.1 mg/kg.   This agrees  with  estimates by  a United
Nations expert group (GESAMP, 1986).  It should be pointed
out that the individual variation in intake is  large  and
that  significant proportions of national populations have
a  mercury intake via seafood  many times higher than  the
average (GESAMP, 1986).

    For the purpose of estimating the average daily intake
of  total mercury and various mercury compounds (Table 4),
it was assumed that the daily intake of total mercury from
fish and fish products is 3 g  and that 20% of this is in
the form of inorganic mercury compounds (i.e., 0.6 g/day)
and 80% is methylmercury (i.e., 2.4 g/day).    The intake
of total mercury from non-fish sources was  calculated  as
the  difference between the  average total dietary  intake
and the intake from fish. The average total dietary intake
in  the  Belgium  studies was  (6.5 + 13)/2 = 9.75 g/day,
whereas the corresponding value for a 70-kg adult  in  the
USA  can be estimated from the FDA market basket survey as
3.5 g.    Taking  the  average  of  the  Belgian  and USA
figures,  the dietary intake of total mercury is estimated
as (9.75 + 3.5)/2 = 6.6 g/day.   By subtracting from this
figure the intake of methylmercury from fish (2.4 g/day),
the estimated total dietary intake of inorganic mercury is
4.2 g/day.     All the mercury from  non-fish sources was
assumed to be in the inorganic form.  The amounts absorbed
across  the gastrointestinal tract  were estimated on  the
assumption  that 7% of the inorganic and 95% of the methyl
species were absorbed (section 6).

    The  estimated dietary intake of  inorganic mercury of
4.3 g/day    is the least  reliable of the  estimates  in
Table 4.  Data are not available on the species of mercury
in most foodstuffs. In addition, the figures  for  dietary
intake  of total mercury  come from only  two  countries -
Belgium and the USA.

    Table 4 portrays the relative magnitude of the contri-
butions from various media. It is clear that fish and fish
products  are  the dominant  source  of human  exposure to
methylmercury,  even when low fish  consumption is assumed
(as  in Table 4). Daily methylmercury intake can vary over
a wide range, depending on the amount of fish consumed and
the  methylmercury concentration in the fish (Table 5).  A

number of communities have been identified where individu-
al  intakes  exceeded  200 g   mercury/day  (WHO,  1976b,
1980; Turner et al., 1980; GESAMP, 1986). As it is assumed
that  80% of this mercury is methylmercury and that 95% of
the  methylmercury  is  absorbed, the  absorbed  amount of
methylmercury  (>153 g/day)   will, in these cases, domi-
nate the daily mercury exposure (Table 4). On the basis of
general  population  surveys  of fish  consumption, it was
estimated  that in Australia  0.9% of the  population  eat
more than 1000 g fish/week and that this  corresponded  to
about  20 g    mercury/day  (WGMF,  1980).  In  the  USA,
surveys  of  fish  consumption (US  Dept.  Commerce, 1978)
were  used to estimate that, with no regulatory control of
the  mercury  content  of  marketed  fish,  99.81%  of all
respondents  had an upper limit  mercury intake lower than
their  personal  allowable  daily intake  (based  on 30 g
mercury/day for a 70-kg person) at a 95% level.  An action
level  of 1 mg mercury/kg  in fish for  regulatory control
would  increase this percentage  to 99.87% and  an  action
level  of 0.5 mg mercury/kg  would increase it  to 99.89%.

    Dental  mercury amalgams account  for the major  back-
ground intake of mercury vapour (Clarkson et  al.,  1988).
It is possible that mercury liberated from the amalgam can
dissolve in the saliva as inorganic mercury, but there are
no  published reports on this possibility. A detailed dis-
cussion  of the release  of mercury from  dental  amalgams
will be found in the Environmental Health  Criteria  mono-
graph on Inorganic Mercury, which is due to  be  published
in 1990.

Table 5.  Intake of methylmercury (ug/day) from
fish with various methylmercury levels
and at various rates of fish consumptiona
Consumption     Level of methylmercury in fish
of fish         (ug/kg fresh weight)b
(g/day)         200   500   1000   2000   5000

5               1     2.5   5      10     25
20              4     10    20     40     100
100             20    50    100    200    500
300             60    150   300    600    1000
1000c           200   500   1000   2000   5000
a  Adapted from: WHO (1980).
b  For methylmercury concentration in fish see
   Table 3.
c  Data from GESAMP (1986) indicate that maximum
   intakes may equal 1000 g/day.


    A  considerable amount of information was available on
the  metabolism of methylmercury at the time when Environ-
mental  Health  Criteria  1: Mercury was  published  (WHO,
1976b).   This section will briefly review the information
in that document and quote more recent data  where  appro-

6.1 Absorption

    Methylmercury  in  the  diet is  almost completely ab-
sorbed  into the bloodstream (WHO, 1976b). Animals studies
(Walsh, 1982) indicate that age, including neonatal stage,
has  no effect on  the efficiency of  gastrointestinal ab-
sorption,  which is usually in  excess of 90% of  the oral
intake. Data on rats indicate rapid and virtually complete
absorption of inhaled methylmercury vapour into the blood-
stream (Fang, 1980).

6.2 Distribution

    Methylmercury is distributed in the bloodstream to all
tissues.  Distribution is completed within about 4 days in
human  beings (Kershaw et al., 1980), but the time after a
single  dose for maximum levels to be reached in the brain
is  one or two days longer than for other tissues (Berlin,
1986).  At this time,  the total brain  contains  approxi-
mately  6% of the  dose (Kershaw et  al., 1980), which  is
very near to 10% of the body burden (WHO,  1976b).   These
blood  and brain values correspond  to a six times  higher
concentration in the brain than in blood  (Berlin,  1986).
There  are  significant  species differences  in brain-to-
blood  ratios.   After  the  prolonged  administration  of
methylmercury,  brain-to-blood ratios are between  3 and 6
in squirrel monkeys (Berlin, 1986) but somewhat  lower  in
macaque monkeys (Evans et al., 1977).  The ratio is gener-
ally  low in non-primate animals, except in pigs (where it
is 3.3); it is 1.5 in guinea-pigs, 1.2 in mice,  and  0.06
in rats (Magos, 1987). Sex differences in distribution and
retention have been reported in rats dosed with methylmer-
cury (Magos et al., 1981; Thomas et al., 1986) and in both
adult  (Hirayama & Yasutake, 1986)  and prenatally exposed
mice (Inouye et al., 1986).

    There are also species differences in the distribution
of  methylmercury  between erythrocytes  and plasma. After
the  ingestion  by  human volunteers  of  fish  containing
methylmercury,  the  background-corrected  erythrocyte-to-
plasma  methylmercury  concentration  ratio was  about  20
(Kershaw  et al., 1980).   The ratio is  approximately the
same  in monkeys and guinea-pigs, 7 in mice, and more than
100 in rats (Magos, 1987).

    The blood-to-hair ratio in humans is about 1  to  250,
but  appreciable  individual  differences have  been found
(Table 6).   Similarly, large individual differences exist
in  the ratio  of cord  blood to  maternal  blood  concen-
tration. Cord blood usually has somewhat higher methylmer-
cury concentration than maternal blood (WHO, 1976b). Thus,
in  a group of  Japanese women the  average ratio of  cord
blood to maternal blood methylmercury concentration ranged
from  0.8 to  2.8, with  a mean  of 1.65  (Suzuki et  al.,
1984b).   The results of studies  on rats (Ohsawa et  al.,
1981) and pigs (Kelman et al., 1980, 1982)  indicate  that
placental   transport  of  methylmercury  into  the  fetus
increases dramatically towards the end of pregnancy.

6.3 Metabolic Transformation

    Methylmercury  is converted to inorganic  mercury, as-
sumed to be Hg++,   in mammals (WHO, 1976b).  The fraction
of  total mercury present in the tissues as Hg++   depends
on  the duration of exposure to methylmercury and the time
after cessation of exposure.

    The percentage of total mercury present as  Hg++    in
the tissues and body fluids of people exposed to high oral
daily intakes of methylmercury for about 2 months  in  the
Iraqi  outbreak were: whole blood, 7%; plasma, 22%; breast
milk, 39%; and urine, 73% (Amin-Zaki et al.,  1976;  Magos
et  al., 1976; WHO, 1976b).  Measurements of liver tissues
from fatalities in Iraq revealed that 16-40%  was  present
as inorganic mercury. Unfortunately, no other tissues were
available  for  analysis.   There is  a  possibility  that
exposure to other mercury compounds may have  occurred  in
some members of the Iraqi population.
Table 6.  Relationship between mercury concentrations in the blood and
hair of people with long-term exposure to methylmercury from fish
Country           Number of   Whole blood   Hair       Linear            Reference
                  subjects    (x)           (y)        regression
                              (g/litre)    (mg/kg)
Canada            339         1 - 60        1 - 150    y = 0.30x + 0.5   Phelps et al. (1980)

Japan             45          2 - 800       20 - 325   y = 0.25x + 0     WHO (1976b)

Netherlands       47          1 - 40        0 - 13     y = 0.26x + 0     Den Tonkelaar et al.
Sweden            12          4 - 650       1 - 180    y = 0.28x - 1.3   WHO (1976b)
                  51          4 - 110       1 - 30     y = 0.23x + 0.6   WHO (1976b)
                  50          5 - 270       1 - 56     y = 0.14x + 1.5   WHO (1976b)
                  60          44 - 550      1 - 142    y = 0.23x - 3.6   WHO (1976b)

United Kingdom    173         0.4 - 26      0.1 - 11   y = 0.25x + 0.6   Haxton et al. (1979)
                  98          1.1 - 42      0.2 - 21   y = 0.37x + 0.7   Sherlock et al. (1982)

Yugoslavia        38          1.2 - 9.6     0.4 - 3.0  y = 0.34x - 22    Horvat et al. (1986b)
    In  Canadian Indians repeatedly exposed  to methylmer-
cury  in fish during the  summer season every year,  inor-
ganic mercury accounted for about 5% of total  mercury  in
whole  blood and about 20% in samples of head hair (Phelps
et  al., 1980).  Brain mercury levels were measured in one
Indian who had died of natural causes 2 years after having
a high blood level (approximately 600 g/litre).   Most of
the mercury in the brain tissue was in the inorganic form,
but,  at the time of  his death, the total  mercury in the
brain  had fallen to  near background levels  (Wheatley et
al., 1979).

    Following  the outbreak in  Minamata, Japan, in  1956,
tissues  from a number  of early fatalities  were analysed
(Tsubaki  & Takahashi, 1986).   Death occurred between  19
and  100 days after the  onset of symptoms.   Tissues were
also  analysed from  people who  died from  1 to  17 years
after  the  onset  of  symptoms.   Samples  were  analysed
initially  by  the  dithizone  colorimetric  procedure  in
1956-1960  and again in 1973-1983 by atomic absorption for
total mercury and by gas chromatography for methylmercury.
In  this  study,  atomic absorption  generally gave higher
values  for total mercury  than the dithizone  method. The
methylmercury  concentration was always less  than that of
total mercury, usually less than 50%, and in a  few  cases
less  than 10%.  The  chemical nature of  the mercury  not
accounted for as methylmercury was not determined. It may,
in  whole or in part,  have been methylmercury that  could
not  be extracted in the gas chromatographic procedure, or
it may have been inorganic mercury.

    Speciation  of mercury in human brain has been studied
by Friberg et al. (1986) and Nylander et al.  (1987).   An
average of 80% of the mercury in the occipital lobe cortex
of  autopsy cases  in Sweden  was found  to  be  inorganic
mercury  (3-22 ng/g wet weight).  Exposure to mercury from
dental  fillings  could  explain the  high  proportion  of
inorganic mercury in some cases but not in all.

    There is considerable evidence indicating the presence
of  inorganic mercury in the tissues of animals dosed with
methylmercury  (WHO, 1976b).  Magos & Butler (1972) showed
that  during long-term daily dosing, the fraction of inor-
ganic mercury in rat tissues tended to approach a constant
value, which was different for each tissue. The kidney and
liver had the highest fractions, while the brain  had  one
of  the lowest.  Speciation of  mercury in  the  brain  of
monkeys  exposed  to  methylmercury for  several years was
studied by Lind et al. (1988b). At the end of the exposure
period, 10-30% of the brain mercury was in  the  inorganic
form  while  in  monkeys sacrificed  0.5-2 years after the
same treatment, about 90% was in the inorganic form. Simi-
lar  observation was reported  by Kawasaki et  al. (1986),
but in the cerebrum a substantially higher  proportion  of
the total mercury was methylmercury than in the cerebellum
(See  also WHO, 1976b). It is clear that the proportion of
inorganic mercury found at any time in a particular tissue
will  be determined by  a number of  processes, e.g.,  the
relative rates of uptake and loss of inorganic mercury and
methylmercury and the extent of biotransformation (if any)
in that tissue. Studies by Suda & Takahashi  (1986)  indi-
cate that macrophage cells, such as those present  in  the
spleen,  are capable of converting  methylmercury to inor-
ganic mercury.  The reaction may involve the production of
oxygen  free-radicals.  At present there are no definitive
data that prove that demethylation actually takes place in
brain tissue, but persuasive arguments have been presented
by Lind et al. (1988b).

    The  conversion of methylmercury to Hg++ may  be a key
step  in the processes  of excretion.  The  faecal pathway
accounts for about 90% of the total elimination of mercury
in man and other mammals after exposure  to  methylmercury
(WHO, 1976b).  Virtually all the mercury in  human  faeces
is in the inorganic form (Turner et al., 1975).  The  pro-
cess  of  faecal  elimination  begins  with  the   biliary
secretion  of  both  methylmercury and  Hg++,    complexed
mainly, if not entirely, with glutathione (GHS) (Refsvik &
Norseth,  1975)  or  other sulfhydryl  peptides (Norseth &
Clarkson,  1971; Ohsawa & Magos, 1974).  Inorganic mercury
is poorly absorbed across the intestinal wall (WHO, 1976b)
so  that most (approximately 90%) of the inorganic mercury
secreted  in bile passes directly into the faeces. Methyl-
mercury  secreted into the intestinal contents is in large
part  reabsorbed into the bloodstream and may subsequently
contribute   to  biliary  secretion,  thereby   forming  a
secretion-reabsorption  cycle (Norseth &  Clarkson, 1971).
This  cycle  (also  called enterohepatic  circulation) in-
creases  the amount of  methylmercury passing through  the
intestinal  contents and thus provides a continuous supply
of  methylmercury to serve as a substrate for the intesti-
nal  microflora.  These microorganisms are capable of con-
verting  methylmercury  to  inorganic mercury,  which then
becomes  the major contributor to total faecal elimination
in the rat (Rowland et al., 1980). Presumably about 10% of
the  inorganic mercury produced  by the intestinal  micro-
flora  is absorbed into the bloodstream and contributes to
the  inorganic mercury concentrations in  tissues, plasma,
bile,  breast milk, and  urine. This intestinal  microbio-
logical  activity  may explain  the  influence of  diet on
methylmercury  elimination rates in rats  (Rowland et al.,
1984,  1986), and the absence  of demethylating intestinal
microflora  may be the reason  for the low rate  of faecal
elimination  of mercury in  suckling mice (Rowland  et al,

    To what extent this model of enterohepatic circulation
and  intestinal conversion to inorganic mercury applies to
humans  is not yet known. Considerable species differences
exist  in rates of  biliary excretion (Naganuma  &  Imura,

1984).  Though the species  variation in the  secretion of
methylmercury  does not entirely correspond to the biliary
excretion  of GSH, high GSH secretion (rat, mice, and ham-
ster) is associated (on a group basis) with  high  methyl-
mercury  secretion and low  GSH secretion (guinea-pig  and
rabbit)  with low methylmercury  secretion (Stein et  al.,

    Animal  studies suggest that  multigeneration exposure
to methylmercury may change tissue distribution and metab-
olism (Yamamoto et al., 1986).

6.4 Elimination and Excretion

    The  rate of excretion of  mercury in both humans  and
laboratory  animals  dosed with  methylmercury is directly
proportional  to the simultaneous body  burden, and there-
fore  may be described  by a single  biological  half-time
(WHO,  1976b).   The reason  is  that methylmercury  is so
mobile in the body that the excretion process is the rate-
limiting  step.  Data  on biological  half-times  in human
beings were summarized in Environmental Health Criteria 1:
Mercury (WHO 1976b). Kershaw et al. (1980) and Sherlock et
al.  (1984)  reported  half-times  of  52  (39-67)  and 50
(42-70) days in blood, close to the valves  found  earlier
in  people who ate fish or had consumed contaminated bread
(WHO,  1976b).   The whole-body  half-times, determined in
volunteers  given a single  tracer dose, have  an  average
value  of about 70 days and a range of 52-93 days. Only 20
subjects have been studied to date.  Biological half-times
in  blood and hair have  been measured both in  volunteers
given  carefully  measured  doses and,  after cessation of
exposure, in individuals exposed as a result of accidental
intake  or high fish  consumption. Observations on  volun-
teers reveal values for blood half-time close  to  50 days
and  a  range of  39-70 days.  Results from  single tracer
doses agree well with those from volunteers given measured
doses in fish. It is clear that the blood half-times over-
lap  those for the  whole body, but  the average value  is
lower.   A shorter blood  half-time would account  for the
observation  that  the  amount of  methylmercury  in blood
constitutes  a decreasing fraction of the body burden with
time after a single tracer dose (Miettinen,  1973).   Lac-
tating  women have significantly shorter half-times (aver-
age  value,  42 days)  than non-lactating  women  (average
value,  79 days),  an  observation  confirmed  by  animals
studies (Greenwood et al., 1978).

    Observations  on  both volunteers  and environmentally
exposed  people indicate that  half-times in hair  closely
follow  those in blood (Amin-Zaki et al., 1976; Kershaw et
al., 1980; Hislop et al., 1983).  However, hair half-times
tend  to have a wider range; for example, Al-Shahristani &
Shihab  (1974) reported a bimodal distribution in 48 Iraqi
subjects,  90% having a  half-time of 35-100 days  and the

other 10% a half-time of 110-120 days. It is possible, but
not  proven, that analytical  artifacts may contribute  to
the wider range seen with hair (WHO, 1980). In  any  case,
data from animals point to the importance of sex, age, and
genetically  determined individual differences (Hirayama &
Yasutake, 1986).

    Animal  data indicate major ontogenic  effects on bio-
logical  half-times (Doherty et al.,  1977). Suckling mice
are completely unable to excrete methylmercury. At the end
of  the suckling period, excretion abruptly switches on at
the  adult rate.  Observations  on infant monkeys  confirm
this  finding (Lok, 1983).  Likewise, biliary secretion of
methylmercury  in suckling animals is virtually absent and
assumes the adult rate after weaning.  It is  of  interest
that biliary secretion of glutathione (GHS) shows parallel
ontogenic changes (Ballatori & Clarkson, 1985). Microflora
also  have  greatly  diminished  capacity  to  demethylate
methylmercury  during the suckling period (Rowland et al.,
1983). In view of the failure of infant animals to excrete
methylmercury,  human infants may  also have a  diminished
excretion.  Unfortunately, no direct observations have yet
been reported.

6.5 Retention and Turnover

    The  evidence summarized in section 6.4 indicates that
the accumulation and excretion of methylmercury in humans,
measured  in terms of  hair or blood  levels, can be  rep-
resented  by a single-compartment model.  The accumulation
phase  in  the whole  body or in  a tissue compartment  is
described by the equation:

          A = ( a / b )(1-exp(- b x  t ))       (equation 1)

   where  A = the accumulated amount
          a = the amount taken up by the body (or organ)
          b = the elimination constant
          t = time

    The  elimination constant is related to the biological
half-time ( T) by the expression:

          T = ln2/ b                    (equation 2)

and  a is  related to the daily dietary intake ( d )  by the

          a =  f x  d                      (equation 3)

where  f is  the fraction of the  daily intake taken up  by
the body (or organ).

    At  a steady state,  the accumulated amount  ( A )   is
given by:

          A =  a / b                       (equation 4)

while  the  steady-state  mercury concentration  in  blood
(C)   in g/litre  is related to the average daily dietary
intake (in g mercury) as follows:

                0.95 x 0.05 x  d 
 C =  f x  d / b =  ----------------    = 0.95 x  d      (equation 5)
                0.01 days-1 x 5 litres

assuming that 0.95 of the intake is absorbed, that 0.05 of
the  absorbed amount goes  to the blood  compartment, that
the  blood volume is  5 litres, and that  the  elimination
constant is 0.01 days-1.

    Sherlock et al. (1984) tested the validity of equation
1  by measuring blood mercury concentrations during a 100-
day  period of methylmercury  intake and a  100-day period
after intake ceased in 20 volunteers who consumed measured
daily  amounts of methylmercury in  fish.  Close agreement
was found between predicted and observed values.

    Equation 1 predicts that a steady state in  which  in-
take  equals excretion will  be attained in  about 5 half-
times.  Thus, in adult humans, the whole body would attain
a steady state in about one year (5 x 70 days = 350 days).
Thus,  an  important prediction  of the single-compartment
model  is that constant dietary  exposure to methylmercury
for  a period of  several years should  not result in  any
greater accumulation than after one year of exposure.

    Equation 4  predicts  that the  maximum amount accumu-
lated  in the whole body of adult humans will be 100 times
the average daily intake. In fact, steady blood levels may
also be calculated from equations 2, 3, and 4,  using  the
kinetic  parameters to the single-compartment model listed
in Table 7.

    It  is of interest to compare this predicted relation-
ship with those observed in field studies  on  populations
believed  to have attained  a steady state  from long-term
dietary  exposure to methylmercury in fish (Table 7).  The
coefficients  relating long-term dietary intake to steady-
state blood concentration are all lower than the predicted
value of 0.95 calculated in equation 5 above.  The reasons
for  this discrepancy are  not yet fully  understood.  The
measurement  of dietary intake in  populations with uncon-
trolled intakes is liable to considerable error (Turner et
al.,  1980).  However, this would not explain the consist-
ently  lower values from field studies.  It is more likely

that  these  populations were  not  in true  steady state,
since  intake is frequently seasonal  in fish-eating popu-
lations.   The fact that  close agreement is  seen between
single-dose  tracer studies, single-dose methylmercury in-
take  from fish, extended controlled intake from fish, and
longitudinal  hair analysis of individuals  with very high
intakes lends support to the validity of  the  single-com-
partment  model and the  values of the  kinetic parameters
listed  in Table 8.  Sherlock and Quinn (1988) presented a
more  detailed discussion of the  differences between con-
trolled  and  uncontrolled  studies  on  the  relationship
between blood concentration and intake of methylmercury.
Table 7.  Relationship between steady-state blood concentrations and average daily intake of
methylmercury in fish consumers and predicted relationships from experimental data
Number of  Duration of       Average mercury       Steady-state blood  Reference
subjects   exposure          intake (g/day per    concentration
                             70 kg body weight)    (ug mercury/litre)
                             (x)                   (y)

  Observed relationship 

32         years             0 - 800               y = 0.7x + 1        WHO (1976b)
165        years             0 - 400               y = 0.3x + 5        WHO (1976b)
20         years             0 - 800               y = 0.8x + 1        WHO (1976b)
725        years             0 - 800               y = 0.5x + 4        WHO (1976b)
22         years             0 - 800               y = 0.5x + 10       WHO (1976b)

  Predicted relationship 

15         1 dose            tracer                y = 1x              WHO (1976b)
30         1 - 2 months      0 - 2340              y = 0.8x            WHO (1976b)
5          1 dose            1400                  y = 1x              Kershaw et al. (1980)
20         100 days          0 - 230               y = 0.8x            Sherlock et al. (1984)

    It  should be emphasized that this model refers to the
"average"  adult human with a body weight of 70 kg.  The
gastrointestinal absorption rate for methylmercury is high
(about  95%) and is  not known to  vary with age,  but the
energy  intake varies greatly with  age and this tends  to
make  children and teenagers  more vulnerable to  high in-
takes of methylmercury.

    The  one compartment model  is a useful  working model
for  comparing blood or  hair levels to  daily intakes  of
methylmercury. Clearly this model is only an approximation
to the more complex kinetics of mercury  distribution  and
metabolism.  For example, determination of mercury in hair
and  blood will not  produce information concerning  small
compartments  in the body.  Methylmercury is slowly trans-
formed to inorganic mercury, a process which is  known  to
follow multiphasic kinetics (Berlin, 1986).

6.6 Reference or Normal Levels in Indicator Media

    Reference  values in non-exposed populations  for con-
centrations  of total mercury  in commonly used  indicator
media  are given in  Table 9.  The mean  concentration  in
whole  blood is probably about 8 g/litre,   in hair about
2 g/g,   in urine 4 g/litre,   and in the placenta about
10 g/g wet weight.

Table 8.  Principal kinetic parameters in the single-compartment model for
methylmercury in adult human beings
Number  Type of  Dose       Number           Compartment          Reference
of      subject  (g        of       ----------------------------
subjects         mercury    doses    Whole body         Blood
                 /kg)                ----------------------------
                                      f     T        f      T
                                           (days)          (days)

3       adult    tracer     1        0.95  72       -        -    WHO
15      adult    tracer              0.94  76       0.07     50   WHO
5       adult    20         1        -     -        0.05a    52   Kershaw
                                                                  et al.
5       adult    3.3        100      -     -        0.05a    53   Sherlock
                                                                  et al.
5       adult    1.5        100      -     -        0.055a   51   Sherlock
                                                                  et al.
4       adult    100        100      -     -        0.057a   48   Sherlock
                                                                  et al.
5       adult    0.6        100      -     -        0.064a   46   Sherlock
                                                                  et al.
a Calculations were made from concentrations in blood. The value of  f
  (fraction of dose which reached the compartment) was calculated assuming
  blood volume of 5 litres in a 70-kg adult.

Table 9.  Concentrations of mercury in indicator media in non-exposed populationsa
Country      Indicator         No. of      Mercury concentrationb  Reference
             media             Subjects    Mean    Range
Belgium      placenta          474         15      1.1 - 103       Roels et al. (1978)c
             whole blood       497         13d     0.1 - 47d       Lauwerys et al. (1978)

Italy        whole blood       80          20      0 - 46          Pallotti et al. (1979)

Japan        maternal blood    11          6.6     2.0 - 16.4      Suzuki et al. (1984b)
             umbilical blood   7           8.9     3.1 - 20.6      Suzuki et al. (1984b)

New Guinea   hair              40          4.5     0.9 - 12.1      Suzuki et al. (1988)

Norway       urine             103         4d      0.6 - 24d       Lie et al. (1982)

Poland       whole blood       270         11.3d   2.5 - 24d       Szucki & Kurys (1982)
             hair              505         2.2     0.02-10         Szucki & Kurys (1982)
             Maternal hair
               (scalp)         141         1.9     0.02 - 41       Sikorski et al. (1986)
               (pubic)         141         1.0     ND-32           Sikorski et al. (1986)
             Neonatal hair     141         0.11    ND-0.62         Sikorski et al. (1986)

Swedene      hair              18          0.4                     Ohlander et al. (1985)
             hair              41          0.53                    Forhammer et al. (1984)

United       whole blood       88          8.8d,f   1.1 - 42d       Sherlock et al. (1982)
Kingdom      urine             77          2.4g    ND - 8g         Taylor & Marks (1973)

USA          whole blood       210         8.1h    0 - 50h         Gowdy et al. (1977)
             whole blood       25          3.4     0 - 7i          Kuhnert et al. (1981)
             placenta          25          6.7j    0 - 13i         Kuhnert et al. (1981)

Yugoslavia   hair              34          1.5     0.4 - 3.3       Horvat et al. (1988b)
             maternal blood    34          3.7d    1.2 - 9.6d      Horvat et al. (1988b)
             umbilical blood   34          7.7d    1.2 - 21d       Horvat et al. (1988b)
             placenta          34          13      2.8 - 37        Horvat et al. (1988b)

Northern     hair              312         3.1     0 - 9           Airey (1983)

Northern     hair              4603        2.3     0 - 5           Airey (1983)

Southern     hair              1449        1.7     0.8 - 2.5       Airey (1983)
a  No known occupational exposure; fish consumption usually less than one meal per week.
b  The units for mercury concentrations are: g/kg for placenta, mg/kg for hair, and
   g/kg for blood and urine, unless otherwise stated.  ND = not detectable.
c  This reference contains data on levels published prior to 1976.
d  g/litre
e  Pregnant women.
f  Values are for adults
g  g/g creatinine
h  Values after exclusion of 9 samples >50g/kg as outliers; without the exclusion
   the mean was 14.2 and range 0-298 g/kg.
i  Range estimated as twice the standard deviation.
j  The placentae were perfused to remove blood before analysis.
k  North of 22 latitude.

    Additional data on levels in indicator media  in  dif-
ferent  populations are given in the following references:
Belgium  (Buchet  et  al., 1978),  Canada  (Galster, 1976;
Kershaw  et al., 1980; Phelps et al., 1980; McKeown-Eyssen
&  Ruedy, 1983a; McKeown-Eyssen et al., 1983; Valciukas et
al.,  1986), Federal Republic  of Germany (Lommel  et al.,
1985),  Finland (Mykkanen et al., 1986), Greenland (Hansen
et  al., 1984), Iceland  (Johannesson et al.,1981),  Italy
(Capelli et al., 1986), the East Pacific  area  (Yamaguchi
et  al., 1977), Japan (Suzuki  et al., 1984a), New  Guinea
(Kyle  & Ghani, 1982a,b; 1983), New Zealand (Kjellstrom et
al.,  1982), Seychelles (Matthews, 1983),  Spain (Gonzalez
et  al., 1985), and  Sweden (Skerfving, 1974).   Intake of
methylmercury  is  reflected  in elevated  levels in whole
blood  and  in  erythrocytes (approximately  95%  of blood
mercury  is in the erythrocytes).  Animal studies indicate
that,  at  non-toxic  levels, blood  methylmercury concen-
tration  is a good  index of brain  mercury  concentration
(Berlin, 1976).

    Urine  and blood concentrations correlate with mercury
vapour  levels  only  after long-term  exposures (Smith et
al.,  1970). Blood levels rise and fall sharply during and
after short-term exposures (Cherian et al., 1978).

    Hair  levels may be  increased as a  result of  direct
adsorption of mercury vapour onto the hair strands.  Airey
(1983)  reported that the  average hair mercury  levels in
the  northern hemisphere are  higher than in  the southern
hemisphere (Table 9).

    Long-term  fish  consumption  determines  almost  com-
pletely  the concentrations of methylmercury and, usually,
total mercury in blood. Thus, reference values  must  take
into  account fish consumption.  In  communities with high
fish consumption rates, individuals with long-term intakes
of 200 g  mercury/day will have blood levels in the range
of 200 g mercury/litre.

    Hair  concentrations of methylmercury are proportional
to  blood concentrations at the  time of formation of  the
hair  strand (Table 6).  In general,  the concentration in
hair is 250 times the simultaneous concentration in blood.
Once mercury is incorporated into a hair strand, that hair
mercury  concentration remains unchanged. Thus, longitudi-
nal  measurement of mercury  in hair provides  a recapitu-
lation  of  methylmercury  levels in  blood.  Airey (1983)
presented  a comprehensive evaluation of mercury levels in
hair.  The  author found  that  mean hair  mercury concen-
trations  corresponded  to  fish consumption  patterns  as
follows:  once or less a  month, 1.4 g/g;   once every  2
weeks,  1.9 g/g;   once a  week, 2.5 g/g;   and  once or
more  a  day,  11.6 g/g.    Owing  to  their higher-than-
average  fish consumption, fisherman may have higher-than-
average  methylmercury concentrations in their  hair.  For

example, in three Mediterranean countries, (Greece, Italy,
and Yugoslavia) 33% of 212 fishermen but only 0.33% of 918
other  residents  had  methylmercury levels  in hair above
10 g/g    (WHO/FAO/UNEP,  1989).  These  data support the
conclusion  that long-term fish intake  determines methyl-
mercury levels in hair and also in blood.

6.7 Reaction with Body Components

    Information  on the binding of methylmercury to tissue
ligands other than haemoglobin is sparse. Methylmercury is
believed to bind to cystinyl residues in  the  haemoglobin
molecule. The number and position of these residues in the
amino  acid  chains  differ in  haemoglobin from different
species  (Doi  & Kobayashi,  1982,  Doi &  Tagawa,  1983).
Methylmercury  is complexed to  glutathione (GHS) in  both
human  and  animal  erythrocytes (Naganuma  et al., 1980).
The only known exception is rat erythrocytes where practi-
cally  all methylmercury is  bound to haemoglobin  (Doi  &
Tagawa,   1983).  Methylmercury  complexes  may   also  be
involved in the urinary excretion of methylmercury (Mulder
&  Kostyniak, 1985a,b). Animal data  indicate that methyl-
mercury  complexes also exist  in brain tissue  (Thomas  &
Smith,  1979;  Berlin  et  al.,  1975),  bile  (Refsvik  &
Norseth, 1975), liver (Omata et al., 1978),  and  probably
in kidney tissue (Richardson & Murphy, 1975). Complexes of
methylmercury  with GHS and possibly  other low molecular-
weight  thiols play a role  in blood transport and  tissue
distribution (Hirayama, 1980; Thomas & Smith, 1982) and in
biliary  secretion (Ballatori &  Clarkson, 1985; Urano  et
al., 1988).  Glutathione-S-transferase   (ligandin) may be
involved   in  the  biliary  secretion  process  (Refsvik,
1984a,b;  Magos  et al.,  1985b),  but evidence  is  still
equivocal (Gregus & Varga, 1985).  The activity of hepatic
 y -glutamyltransferase    may  also  affect  methylmercury
secretion  in bile (Stein et al., 1988).  According to  in 
 vitro studies,  the transport of methylmercury across cell
membranes appears to be a diffusional process involving an
unchanged  complex  of methylmercury  chloride (Lakowicz &
Anderson,  1980;  Bienvenue  et al.,  1984).  However, the
relevance  of  these findings  to  in vivo transport across
membranes is not clear.  Due to the high affinity  of  the
methylmercury cation for sulfhydryl groups, it is unlikely
that methylmercury chloride will be present in significant
amounts  in plasma or other biological fluids.  Amino acid
complexes  may  be  involved  in  membrane  transport   of
methylmercury  (Hirayama, 1980, 1985; Aschner  & Clarkson,
1987; Watanabe et al., 1988).

    The  administration  of selenium  compounds to animals
protects   against  the  toxic  effects  of  methylmercury
(Ganther  et al., 1972; Iwata et al., 1973). It alters the
tissue   distribution   and  excretion   of  methylmercury
(Ganther,  1978, Prohaska &  Ganther, 1977) and  also  the
inorganic-to-methyl  mercury  ratio  in  tissues  (Komsta-
Szumska  & Miller, 1984; Brzeznicka & Chmielnicka, 1985a).

In  spite of the protective effect, selenite increases the
brain  concentration of methylmercury (Magos & Webb, 1977;
Brzeznicka  & Chmielnicka 1985b). The methylmercury cation
has a high affinity for selenides and diselenides (Sugiura
et  al., 1978), the latter  being formed by the  reductive
metabolism  of selenite (Hsieh  & Ganther, 1975;  Ganther,
1979).   It has been  reported that (CH3Hg)2Se      can be
formed  both  in  vitro and  in  vivo (Magos et  al.,  1979;
Naganuma & Imura, 1980; Masukawa et al., 1982).   To  what
extent the formation of this compound explains the altered
tissue  distribution  of  methylmercury is  not yet clear.
Selenium  may  also  divert mercury  from  its  endogenous
binding  sites, but Thomas & Smith (1984) were not able to
find   evidence  for  this.   Maternal  administration  of
selenium  to mice causes a specific alteration in the form
of selenium in fetal liver, as indicated by gel filtration
chromatography.   This  change  was not  found in maternal
liver  or kidney  or in  the placenta  (Nishikido et  al.,


    Data concerning the effects of methylmercury on organ-
isms  in  the  environment are  discussed in Environmental
Health  Criteria 86: Mercury - Environmental Aspects (WHO,


    Methylmercury  is a systemic poison  and, depending on
the  dose and the  length of exposure  period, can  affect
various  organ systems and  functions.  However, in  every
species the main target is the nervous system and  one  of
the  earliest objective clinical signs is ataxia. The sig-
nificance  of effects on  animals is confounded  by  well-
established  species differences in both  the localization
of  nervous system damage and in accompanying clinical and
pathological changes (Berlin, 1986). Another common target
is  the fetus.  As  methylmercury is capable  of corrosive
action, it can damage any tissue (skin, eye, upper part of
the  digestive  tract)  if presented  in sufficiently high
concentrations (WHO, 1976b).

8.1 Neurotoxicity and Nephrotoxicity

    The  effects of methylmercury given in a single lethal
dose  is uncharacteristic. After  intraperitoneal adminis-
tration,  rats  showed respiratory  and vascular disorders
and  hamsters  became  comatose (Hoskins  &  Hupp,  1978),
whereas after oral administration to pigs, central nervous
system depression, ending in coma, was preceded  by  diar-
rhoea and vomiting (Piper et al., 1971).   Rats  surviving
an  LD50    dose  showed general  debilitation with weight
loss, but did not develop specific motorial changes, while
a  squirrel  monkey that  had  survived the  severe  acute
effects  of a single dose (6.4 mg/kg) became uncoordinated
by 22 days and blind at 24 days (Hoskins and Hupp, 1978).

    The  cause of weight  loss is anorexia.   The anorexic
effect  shows  significant species  differences.  Anorexia
precedes  the clinical signs  of nervous system  injury in
rodents  treated  daily with  methylmercury (Magos, 1982).
In  cats (Davies & Nielsen, 1977) and dogs (Davies et al.,
1977),  anorexia  and  gait  disorder  ("bunny-hopping")
occur  simultaneously.  In the squirrel monkey only severe
methylmercury  intoxication is associated with weight loss
(Evans et al., 1977).

    Studies  on  the  neurotoxicity of  methylmercury were
reviewed  by WHO (1976b).  This review called attention to
species  differences in blindness  and the involvement  of
peripheral  nerves.   Blindness  may  be  caused  in  man,
monkeys,  and pigs, but not in cats.  In rats, the initial
damage appears in the dorsal root ganglions and associated
peripheral nerves, while in monkeys the cerebral cortex is
the first target.  One of the most common lesions  of  the
central  nervous system is  in the granular  layer of  the
cerebellum.   This type of damage has been observed in man
(Takeuchi  &  Eto,  1975) and  also  in  rats, cats,  hens
(Chang,   1977),  dogs  (Davies  et   al.,  1977),  calves
(Herigstad et al., 1972), guinea-pigs (Falk et al., 1974),
and rabbits (Jacobs et al., 1977), but not in pigs (Davies

et  al., 1976)  or monkeys  (Chang, 1977;  Mottet et  al.,
1987). Female rats, which accumulate higher concentrations
of methylmercury in their brain than males,  also  develop
more severe cerebellar lesions (Magos et al., 1981).

    These experimental studies (see also Mitsumori et al.,
1984 and Munro et al., 1980) confirmed  clinical  findings
in  human  beings of  irreversible  damage to  the nervous
system.   Other experimental studies carried out since the
publication  of  Environmental Health  Criteria 1: Mercury
(WHO,  1976b), which focused on the mechanism of toxicity,
are reported in section

    Renal damage is one of the most  frequently  described
non-neural  effect of methylmercury.   This damage may  be
caused  by inorganic mercury split from methylmercury.  In
rats,  treatment  with  methylmercury caused  renal damage
ranging  from ultrastructural changes to  the degeneration
of the distal convoluted tubules (see WHO,  1976b).   Male
rats are more sensitive to the renotoxic effect of methyl-
mercury  than females (Munro  et al., 1980).  Renal damage
was  also observed in other experimental species.  In most
of the dogs that showed clinical and histological signs of
methylmercury-induced neurotoxicity, there were also signs
of  renal necrosis, desquamation, and regeneration (Davies
et al., 1977). In the kidneys of methylmercury-intoxicated
guinea-pigs, only swelled epithelial cells in the proximal
tubules were reported (Falk et al., 1974). In cats (Davies
&  Nielsen, 1977)  and pigs  (Davies et  al., 1976),  only
hyalin  and cellular casts were seen.  Though treatment of
six monkeys ( Macaca  mulatta ) with daily doses of methyl-
mercury (80-120 g   mercury/kg in apple juice) for 3.5-12
months did not affect the general health status adversely,
it  caused ultrastructural changes in the kidneys (Chen et
al.,  1983). These changes included intracytoplasmic vacu-
oles  and  electron-dense  inclusion bodies.   In the same
studies,  degenerative  changes  in the  Paneth  cells  of
intestines  were also observed.   These changes were  most
pronounced  in  animals killed  immediately after exposure
(see also Mottet et al., 1987).

8.2 Reproduction, Embryotoxicity, and Teratogenicity

    Methylmercury  added  in vitro to a suspension of sperm
from  untreated monkeys ( Macaca fasicularis ) at 9-15 g/ml
decreased  sperm motility but did not decrease oxygen con-
sumption  (Mohamed et al.  1986a,b). In fact,  oxygen con-
sumption was increased at the 15 g/ml  concentration when
sperm  motility  was  almost zero.   Further  studies with
specific  inhibitors  revealed  that mitochondrial  energy
production  was  not  affected by  mercury.   The  authors
suggested that the primary effect was on the dynein/micro-
tubule sliding assembly.

    Lee  & Dixon (1975) reported damage to spermatogenesis
in  mice given a  methylmercury dose of  1 mg  mercury/kg,
much lower doses giving rise to neurological  effects.  No
special  susceptibility to sterility, resulting  from pre-
natal exposure, could be detected in mice (Gates  et  al.,

    When  female mice were given  a single intraperitoneal
injection  of methylmercury chloride (2.5, 5, or 7.5 mg/kg
body  weight) prior to  mating, dose-related increases  in
pre- and   early   post-implantation  fetal   losses  were
recorded  (Verschaeve & Leonard, 1984).   This observation
could  have a genetic  cause or result  from physiological
effects on the mother.

    Gunderson  et  al. (1986)  treated 11 monkeys ( Macaca 
 fasicularis ) with daily  oral  doses of  methylmercury in
apple juice (50-70 g/kg  per day) before and during preg-
nancy. The mean blood levels during pregnancy, measured in
each trimester and at delivery, were within the  range  of
1080-1330 g/litre,   with maximum values within the range
of  1510-1840 g/litre.    The  mean blood  levels  of the
offspring  at  birth  were  1690 g/litre    (range,  880-
2460 g/litre).  When tested 190 days post-conception, the
mean  blood levels had fallen to 1040 g/litre.    The ex-
posed  animals showed recognition deficits  (compared with
10 untreated  controls) when administered an adaptation of
a standardized test of visual recognition memory. The same
blood mercury concentration (600-2000 g/litre)   in preg-
nant squirrel monkeys exposed to methylmercury resulted in
a  22.5% (mean of six  results) reduction in the  cerebral
weight  of fetuses (Logdberg  et al, 1988).   Three months
treatment  with daily oral doses of methylmercuric hydrox-
ide (50 or 90 g/kg)   increased the frequency  of  repro-
ductive  failure (i.e., non-conception, abortion)  in non-
human  primates and decreased  the birth weight  of  their
offspring (Burbacher et al., 1984). Offspring from treated
animals  directed  significantly  less attention  to novel
stimuli than did controls.

    At  doses which are not toxic to the rat dam, prenatal
exposure  produced  hydrocephalus, decreased  thickness of
the  cerebral  cortex  in the  parietal section, increased
thickness  of  the  hippocampus in  the  occipital  region
(Kutscher   et   al.,  l985),   and  delayed  ossification
(Chmielnicka  et  al.,  1985).  A  variety  of  structural
changes,  detectable at both the light and electron micro-
scopic  levels,  were  also  observed  by  Reuhl  et  al.,
(1981a,b).  Similar effects have been  noted in prenatally
exposed   mice  where  the  development  of  communicating
hydrocephalus  was  associated  causally  with  aqueductal
stenosis (Choi et al., 1988).

    Prenatal exposure at doses not affecting the mother is
known  to produce abnormal  behaviour in the  offspring of
several animal species (Spyker et al., 1972; Bornhausen et
al.,  1980; Zimmer  et al.,  1980; Shimai  & Satoh,  1985;
Elsner et al., 1988). The behavioural effects may  be  the
consequence  of  an  effect on  neurotransmitters  in  the
brain.   Thus a single dose of 5.0 mg mercury/kg, given as
methylmercury  on  postnatal day 2,  resulted in increased
serotonin  concentration  and  movement and  postural dis-
orders  by day 22-24 (O'Kusky et al., 1988).  In addition,
Bartolome et al. (1982) showed both acute and long-lasting
effects  on the maturation of central catecholamine neuro-
transmitter  systems  following early  postnatal exposure.
Eccles  & Annau (1982a,b) demonstrated altered behavioural
sensitivity  to amphetamine in adult  offspring, and Cuomo
et  al. (1984) showed alterations in response to apomorph-

    Prenatal  exposure of rodents can produce a variety of
effects on non-nervous tissues.  It is well known that the
administration of large doses of methylmercury to pregnant
rodents  produces cleft palate  (e.g., Lee et  al.,  1979;
Harper et al., 1981). Prenatal exposure of rats  can  pro-
duce  renal  functional  abnormalities detectable  in off-
spring at 42 days of age (Smith et al., 1983;  Slotkin  et
al. 1986).

8.3 Mutagenicity and Related End-Points

    Methylmercury  is capable of causing chromosome damage
in  cell cultures (Morimoto  et al., 1982;  Curle et  al.,
1983),  in  the golden  hamster  (Watanabe et  al.,  1982;
Gilbert  et al., l983),  and in ovulating  Syrian hamsters
(Mailhes,  1983).  It can  induce histone protein  pertur-
bations  (Gruenwedel & Diaham, 1982) and influence factors
regulating  the nucleolus-organizing activity  (Verschaeve
et  al., 1983). The mutagenic response of V79 Chinese ham-
ster  cells to methylnitrosourea is enhanced by methylmer-
cury  (Onfelt  &  Jenssen, 1982).   Methylmercury has been
reported  to  interfere  with gene expression in  in vitro 
cultures   of  glioma  cells at  low concentrations (0.05-
0.1 mol/litre)    (Ramanujam & Prasad, 1979).  The induc-
tion  of  non-disjunction and  sex-linked recessive lethal
mutations  was  found in  Drosophila  melanogaster  treated
with methylmercury.  Tolerance to methylmercury was corre-
lated  with the uptake of mercury and not with the rate of
excretion (Magnusson & Ramel, 1986).

8.4 Carcinogenicity

    Methylmercury  has been reported to produce renal car-
cinomas  in  mice  given  diets  containing  methylmercury
chloride  (15 mg/kg) for about one year (Mitsumori et al.,
1981).   Animals  given  30 mg/kg died  from neurotoxicity
after 6 months.  Nixon et al. (1979) found  that  prenatal

exposure  to methylmercury increased the incidence in rats
of  neural tumours caused by sodium nitrite and ethylurea.
The  mothers  had  been  exposed  since  weaning  to 10 mg
methylmercury/kg  diet.   These  are the  only  reports of
potential  carcinogenicity.   Blakley (1984)  administered
methylmercury  chloride  to Swiss  mice  (0.2, 0.5,  or  2
mg/litre  drinking-water)  for  15 weeks and  gave  them a
single  dose  (1.5 mg/kg)  of urethane  by intraperitoneal
injection  at the end  of the third  week.   Methylmercury
produced a dose-related increase in the size of lung aden-
omas  induced by urethane.  However, only the highest dose
(2 mg/kg) increased the  incidence of adenomas.  No effects
on  weight gain or water consumption related to methylmer-
cury treatment were seen.

8.5 Special Studies

    Kato  et  al. (1981)  reported  that the  detection of
electro-oculographic changes in monkeys is one of the most
sensitive  indices  of methylmercury  effects.  Using high
doses  of methylmercury, Wassick &  Yonovitz (1985) demon-
strated  auditory deficits over  a 4- to 78-kHz  frequency
range  in mice.  Methylmercury is known to affect auditory
performance in human beings (section 9.1).

    Methylmercury  has been found to  depress both primary
and  secondary immune responses in rodents (Koller & Roan,
1980; Koller et al., 1980). Other effects reported in ani-
mal  studies include impairment of  adrenal and testicular
function  in rats (Burton  & Meikle, 1980),  impairment of
thyroid  function in mice (Kawada  et al., 1980), and  im-
pairment of sleep-walking rhythms in rats (Arito  et  al.,
1983).   Effects  of  methylmercury on  glucose transport,
glucose  metabolism, and blood flow in the central nervous
system were described by Hargreaves et al. (1986).

    Long-term  treatment  of  Brown-Norway  rats  produces
proteinuria  (Bernaudin  et  al., 1981).   This  strain is
genetically  susceptible  to immune-mediated  renal damage
produced by inorganic mercury.

8.6 Factors Modifying Toxicity; Toxicity of Metabolites

    Several  substances  have  been found  to  affect  the
chronic  toxicity  of methylmercury.   Of these, selenium,
usually  administered to animals  as sodium selenite,  has
been the most widely studied, following the  first  report
by  Ganther et  al. (1972).   In general,  selenium has  a
protective  action  in  that  it  delays  the   onset   of
methylmercury  toxicity  or  reduces the  severity  of its
effects (Chang & Suber, 1982). Simultaneous administration
of sodium selenite to mice during pregnancy was  found  to
protect   the  offspring  from  effects  on  developmental
reflexes caused by a 6 mg/kg dose of  methylmercury  given
on  day 9 (Satoh et  al., 1985).  In  mice given  selenium

(11.6 nmol/ml  in  the  drinking-water)  before  and after
gestation,  the incidence of methylmercury-induced resorp-
tion was increased.  The incidence of cleft palate in mice
was  not  affected by  excess  selenium (Nobunaga  et al.,
1979)  nor  by  selenium  deficiency  (Nishikido  et  al.,
1988a),  but selenium deficiency  enhanced the fetal  tox-
icity of methylmercury (Nishikido et al., 1987).

    Another  antioxidant,  vitamin E, has  also been found
to  be protective against  methylmercury toxicity in  both
normal  and selenium-deficient rats  (Chang et al.,  1978;
Welsh,   1979).  The  antioxidant N,N'-diphenyl-p-phenyly-
lenediamine,  however, was more protective than vitamin E.
The  latter  also  protected against  the  in vitro  damage
caused  by  methylmercury  to chromosomes  in  human blood
cells  (Morimoto et al.,  1982), hamster fibroblast  cells
(Gilbert  et  al.,  1983),  and  glioma  cells  (Prasad  &
Ramanujam,  1980).  Phospholipids  have been  reported  to
protect  against  the  in vitro action  of methylmercury on
rat liver enzymes (Magnaval & Batti, 1980).  The  signifi-
cance of these findings to human health is not  clear,  as
high  doses  were  used  and  methylmercury  poisoning  in
rodents  may not be the same as in human beings.  Moreover
selenite  only delays the  onset of methylmercury  intoxi-
cation  (Chang  &  Suber, 1982)  and  is  not the  form of
selenium  found in human diets.  Though selenium in marine
food  may  have the  same  protective action  as  selenite
(Newberne  et  al.,  1972; Ohi  et  al.,  1980; Thrower  &
Andrewartha,  1981),  the  bioavailability  of  biological
selenium  for reaction with mercury  is less than that  of
selenite (Magos et al., 1984) and its potential, free from
other dietary effects, to delay the onset of methylmercury
intoxication has not been proved.

    Ethanol  has been found  to potentiate the  effects of
methylmercury  in rats (Turner et al., 1981).  This single
finding  should be investigated further, preferentially in
primates, as it could have considerable public health sig-

    Yamini  & Sleight (1984)  found that guinea-pigs  on a
diet  deficient in vitamin C  suffered more severe  neuro-
logical  damage when exposed to  44 mg methylmercury/kg in
their  diet for  20 days than  controls fed  a  diet  with
adequate vitamin C.

    It  has been postulated that  methylmercury might pro-
duce its effects via cleavage of the  mercury-carbon  bond
(Ganther, 1978). This could produce free radicals, causing
lipid  peroxidation.  This  might explain  the  protective
action   of  vitamin E  and  selenium.  Inorganic  mercury
released  from  methylmercury  might be  the  actual toxic
species. However ethylmercury, which decomposes faster and
raises inorganic mercury concentration in the brain  to  a
higher  level than does methylmercury, produces less brain
damage at equal doses (Magos et al., 1985a).


9.1 General Population Exposure

    The  effects of methylmercury on the adult differ both
quantitatively  and qualitatively from effects  seen after
prenatal and, possibly, postnatal exposure.  Thus, effects
on  adults  will be  treated  separately from  effects  on
developing tissues.

9.1.1 Effects on adults

    The  effects  of  methylmercury on  adult human beings
have  been  thoroughly  described in  Environmental Health
Criteria 1: Mercury (WHO, 1976b).  They will be summarized
here with relevant new material added as appropriate. Effects on the nervous system

    The  nervous system is the principal target tissue for
the effects of methylmercury on adult human  beings.   The
sensory,  visual,  and  auditory functions,  together with
those  of the brain areas, especially the cerebellum, con-
cerned with coordination, are the most common functions to
be  affected.  The earliest effects are non-specific symp-
toms,  such  as  complaints of  paraesthesia, malaise, and
blurred vision. Subsequently, signs appear such as concen-
tric  constriction of the  visual field, deafness,  dysar-
thria, and ataxia.  In the worst cases, the patient may go
into a coma and ultimately die. In less severe cases, some
degree  of  recovery  in  each  symptom  occurs;  this  is
believed to be a functional recovery that depends  on  the
compensatory  function of the central nervous system.  The
subjective  complaint of paraesthesia  was found to  be  a
permanent  symptom  in  patients exposed  in  the Japanese
outbreak,  whereas in the Iraqi outbreak, paraesthesia was
transient in many cases.  The reason for  this  difference
is not known.

    At  high  doses, methylmercury  affects the peripheral
nervous system (Rustam et al., 1975).  In  Iraq,  patients
had  symptoms  of  neuromuscular weakness  that  could  be
ameliorated by treatment with acetylcholinesterase inhibi-

    Methylmercury  poisoning  has  several important  fea-

-   a long latent period usually lasting several months;

-   damage  almost exclusively limited to the nervous sys-
    tem, especially the central nervous system;

-   areas  of  damage to  the  brain are  highly localized
    (focal), e.g., in the visual cortex and  the  granular
    layer  of the cerebellum,  especially in the  infolded
    regions (sulci);

-   effects  in severe cases  are irreversible due  to de-
    struction of neuronal cells;

-   the  earliest effects are non-specific subjective com-
    plaints,  such  as  paraesthesia, blurred  vision, and
    malaise. Effects on non-nervous tissue

    The only effect on human beings not involving the ner-
vous system is the claim that chromosome damage is associ-
ated  with  long-term  exposure to  methylmercury (Wulf et
al., 1986).  No further reports have appeared on this sub-
ject  since the review in Environmental Health Criteria 1:
Mercury (WHO, 1976b).

9.1.2 Effects on developing tissues Effects on the nervous system

    Observations  on both human subjects and animals indi-
cate  that the developing  central nervous system  is more
sensitive to damage from methylmercury than the adult ner-
vous system. The first indications arose from the outbreak
of  methylmercury  poisoning  in Minamata,  Japan,  in the
1950s,  when it was found  that mothers who were  slightly
poisoned gave birth to infants with severe cerebral palsy.
Subsequent  studies on experimental animals  confirmed the
increased sensitivity of the fetus.  The Iraqi outbreak in
1971-1972 resulted in cases of severe damage to  the  cen-
tral  nervous system in infants  prenatally exposed.  More
recent follow-up studies in Iraq indicated a  milder  syn-
drome at lower dose levels (Marsh et al., 1980).  In fact,
it has been possible to demonstrate a relationship between
the  maximum hair level  in the  mothers  during pregnancy
and the frequency of abnormalities in their infants (Marsh
et al., 1981).

    The  clinical picture is dose dependent.  In those in-
fants  who have been exposed to high maternal blood levels
of  methylmercury, the picture is of cerebral palsy indis-
tinguishable from that caused by other factors. Microceph-
aly, hyperreflexia, and gross motor and mental impairment,
sometimes  associated with blindness  or deafness, is  the
main  pattern (for review, see WHO, 1976b). Milder degrees
of  the affliction  are not  easy to  diagnose during  the
first  few months of  life, but they  later become  clear.
Patients  show mainly psychomotor impairment  and persist-
ence of pathological reflexes (Marsh et al.,  1977,  1980,

1981;  McKeown-Eyssen  et  al., 1983).   Milder cases have
findings  quite  similar to  the  findings in  the minimal
brain damage syndrome.

    Post-mortem  observations  in  Japan  indicated   that
damage  is generalized throughout the brain in the case of
prenatal  exposure,  in  contrast to  adult exposure where
focal  lesions are predominant. The Japanese cases of pre-
natal  poisoning  indicated  disturbed development  in the
cytoarchitecture  of the brain and the brain size was dim-
inished  in  severe cases.   Similar pathological findings
were reported on autopsies of two prenatally exposed Iraqi
infants (Choi et al., 1978).  The pathological findings in
these  studies were attributed to  incomplete and abnormal
migration of neuronal cells to the cerebellar and cerebral
cortices (section 9.3.2).

9.2 Occupational Exposure

    This  type of exposure  was reviewed in  Environmental
Health  Criteria 1: Mercury  (WHO,  1976b). No  new infor-
mation  has  become  available. In  fact, occupational ex-
posure  results in effects  similar to those  reviewed  in
section 9.1 (e.g., Hunter & Russell, 1954).

9.3 Mechanisms of Toxicity

    Section 9  is concerned with effects  on human beings.
However,  in  discussing mechanisms  of methylmercury tox-
icity, animal and other experimental data are  used  where
they throw light on how damage is inflicted on  the  human

9.3.1 The mature organism Mechanism of selective damage

    The mechanism of selective damage is not  well  under-
stood.   In  a  review of  publications,  Syversen  (1982)
claimed that the selective effects relate to  the  ability
of certain cells in the central nervous system  to  repair
the  damage  initially inflicted  by methylmercury.  Thus,
those  cells capable of repairing  injury survive, whereas
those  cells that lack the  facility to repair the  damage
are the ones that are destroyed.  For example,  the  small
granule cells in the cerebellum lack the  repair  capacity
and  are the  first cells  in that  area of  the brain  to
succumb. Jacobs et al. (1977) noted that the small neurons
in the central nervous system appear to be especially vul-
nerable.  Such cells have very little cytoplasm  and  only
limited  protein synthetic machinery to  carry out repair.
On  the other hand, Berlin (1986) has proposed that selec-
tive  damage results from the inter-neuronal axonal trans-
port of methylmercury. Thus, the sensory centres, e.g., in
the  visual cortex, are affected  because axonal transport

is  in the afferent direction  leading to a local  accumu-
lation of methylmercury.  The motor systems are relatively
unaffected  by  methylmercury because  axonal transport is
in  the efferent direction  leading to removal  of mercury
from the motor areas. The latent period

    The  reason for the long  latent period is not  under-
stood.  The mean latent period ranged from 16  to  38 days
in  Iraq, and, in  many cases, initial  symptoms  appeared
after  the cessation of  intake of contaminated  bread. In
the  Japanese outbreaks, it was difficult to determine the
exact  latent period because  in many cases  the  starting
point  of intake was unclear.   However, in some cases  in
Japan, a very long latent period (up to several years) was
reported (WHO, 1980).  Included in these cases  were  some
patients who showed only slight signs and symptoms but who
later  developed the clinical features of severe poisoning
after they had stopped eating the polluted fish.   In  the
same  period of time,  the other patients  showed relative
improvement  or progression.  A  latent period of  several
years  may be partially explained  by psychogenic overlay,
which  modifies the symptoms, or  by sub-clinical lesions,
which  may be revealed by the aging factor.  However, slow
accumulation  in the brain  of methylmercury (or  of inor-
ganic  mercury split off from the methylmercury) cannot be
the explanation. Cellular and molecular mechanisms

    Since the publication of Environmental Health Criteria
1: Mercury (WHO, 1976b), numerous studies on the mechanism
of action at the cellular and molecular levels  have  been
reported  (Clarkson,  1983;  Berlin, 1986).  Inhibition of
protein  synthesis in target nerve  cells is a well  docu-
mented  effect in animals  that appears before  the  first
clinical  signs  of  intoxication (Yoshino  et  al., 1966;
Carmichael  et  al.,  1975;  Omata  et  al.,  1980,  1982;
Syversen,  1982; Fair et  al., 1987). It  occurs also   in
vitro before other cellular functions are affected (Nakada
et al., 1980; Sarafian et al., 1984).

    Verity  and  his  colleagues (Cheung  &  Verity, 1985;
Sarafian & Verity, 1985, 1986) have identified the step in
protein synthesis that is most sensitive to methylmercury.
The  peptide-elongation  process  can be  affected at high
levels of methylmercury, but the first stage of synthesis,
associated with transfer RNA, may be the  most  sensitive.
It  appears that the  inhibition of protein  synthesis  is
general;  there is no selective inhibition of formation of
any special proteins or group of proteins.

    The  reason  for  the special  sensitivity  of protein
synthesis  to methylmercury is  not known. Jacobs  et  al.
(1977)  noted  that  the mammalian  ribosome  contains 120
sulfhydryl  groups, of which  about half are  exposed  and
reactive  during  peptide  formation, and  that the chain-
initiation  factor  is  strongly inhibited  by  sulfhydryl
reagents, at least in the case of bacteria. They suggested
that  the sulfhydryl groups  of active ribosomes  are more
vulnerable  than those in other  proteins, where disulfide
bridge  formation  may  predominate.  Methylmercury   also
interferes with lipids (Nakada & Imura, 1983; Ando et al.,
1985),  myelin  (Ganser &  Kirschner, 1985), mitochondrial
DNA  synthesis (Miller et al., 1985), and glutathione per-
oxidase (Hirota et al., 1980).

    Effects  on neurotransmitters and receptors (Kobayashi
et  al.,  1979,  1981;  Concas  et  al.,   1983),   lipids
(Macfarlane,  1981; Rebel et  al., 1983; Leblanc  et  al.,
1984),  adenyl cyclase activity (Spuhler  & Prasad, 1980),
membrane structure (Kasuya, 1980), and on the integrity of
microtubules have been reported in a variety of experimen-
tal  systems (Araki et  al., 1981; Nakada  & Imura,  1982;
Sager et al., 1981a,b).  Methylmercury inhibits amino acid
transport  in  rat  brain microvessels  at  concentrations
similar  to  those  known  to  cause  toxicity  in  humans
(Tayarani  et  al.,  1988).  Changes  in glucose transport
across  the blood-brain barrier in rats have been observed
in the latent period before overt signs  of  methylmercury
intoxication  appear (Hargreaves et al., 1986). When given
systemically,  methylmercury accelerates axonal  transport
of  proteins in the optic nerve (Aschner, 1986).  However,
when  it is given by intra-ocular injection, methylmercury
inhibits  protein transport along the optic nerve (Aschner
et al., 1986).  The relevance of the above findings to the
pathogenesis  of methylmercury poisoning is still a matter
of speculation.

    Perhaps  more firmly established is the connection be-
tween  muscular weakness seen in severe cases of poisoning
in  the Iraqi outbreak and the inhibition of acetylcholine
transmission  at  the  neuromuscular junction  (Von Burg &
Landry, 1976; Shamoo et al., 1976; Atchison  &  Narahashi,
1982;  Quandt et al.,  1982; Atchison, 1986).  The  stimu-
latory  action of methylmercury on  the miniature endplate
potentials of the neuromuscular junction appears to result
from  the loss  of calcium  ions from  the nerve  terminal
mitochondria (Levesque & Atchison, 1988).

9.3.2 Developing tissues

    Post-mortem observations derived from the Japanese and
Iraqi outbreaks suggested that the severe prenatal effects
seen  resulted from incomplete  and abnormal migration  of
neuronal cells to the cerebellar and cerebral cortices. In
support  of  their  autopsy findings  indicating  abnormal

neuronal  migration, Choi et al. (1979) noted that methyl-
mercury  inhibited the  in vitro migration and  movement of
cultured  human cells. Changes in  astrocyte membranes and
in motility were also observed in cultures when methylmer-
cury  was added  (Choi &  Lapham, 1980).   The ability  of
methylmercury  to damage astrocytes  in vitro was confirmed
by findings of decreased DNA synthesis (Choi et al., 1980;
Choi  & Kim, 1984).  The toxic effect on astrocytes may be
relevant  to the pathological  picture, since these  cells
are  believed to play a role in supporting normal neuronal
migration in the developing brain (Choi &  Lapham,  1976).
More recently, Peckham & Choi (1986) showed  that  methyl-
mercury  alters  the  anionic surface  charge  on cultured
fetal mouse astrocytes. Cell-to-cell recognition processes
were  found to be affected in aggregates of mouse cerebel-
lar  cells (Jacobs et  al., 1986).  The  authors suggested
that   the  mechanism  involved  depressed   synthesis  of
specific  proteins  followed  by alterations  in  microtu-

    A  second general mechanism by which brain development
could be impaired is the inhibition of cell division (Chen
et  al., 1979; Sager  et al., 1982,  1983; Rodier et  al.,
1984; Slotkin et al., 1985; Howard & Mottet,  1986;  Vogel
et  al., 1986). Inhibition of  cell proliferation probably
explains the production of cleft palates in rats  (Lee  et
al.,  1979; Olson &  Massaro, 1980), although  this effect
has  not been seen in  humans.  Methylmercury is known  to
inhibit cell division by causing metaphase arrest, similar
to that observed with colchicine, presumably by disruption
of the mitotic spindle (Onfelt, 1983). Both spindle micro-
tubules  (Miura et al., 1978) and cytoplasmic microtubules
in  cultured rat glioma cells (Imura et al., 1980; Miura &
Imura,  1987) and human  fibroblasts (Sager et  al., 1983)
are disrupted by methylmercury.  Damage to the microtubule
system  appears to underly the toxic effects of methylmer-
cury on lymphocytes (Brown et al., 1988). Sager & Matheson
(1988)  have shown that  disassembly of microtubules  pre-
cedes  changes in other elements.  In vitro  polymerization
of microtubules is also inhibited by methylmercury (Abe et
al.,  1975;  Imura et  al., 1980; Sager  et al., 1983;  De
Saint-Georges  et  al., 1984;  Miura  et al.,  1984).  The
effect  on microtubules appears  to be selective  and does
not  involve other components  of the cytoskeleton  (e.g.,
vimentin or actin filaments) (Sager, 1988). Vogel  et  al.
(1985)  suggested that methylmercury  binds to free  sulf-
hydryl groups on the ends and on the surface  of  microtu-

    Sager et al. (1982, 1984) hypothesized that methylmer-
cury  might  arrest the  division  of immature  neurons at
critical  stages  of brain  development. They administered
methylmercury  to newborn mice at a time when the external
granule layer (EGL) of the cerebellar cortex  was  rapidly
dividing.  They found fewer  granule cells in  the treated

animals  as well as a  decrease in the percentage  of late
mitotic  figures.  This incomplete  mitosis may have  been
responsible for the decreased cell numbers.

    Destruction  or  arrest  of neuron  growth  during the
development  of the central nervous  system may be an  im-
portant  general mechanism in the pathobiology of prenatal
damage   (Rodier,  1977).   The  deranged  cell  migration
reported  by Choi et al. (1978) and the arrested cell div-
ision  found  by  Sager et  al.  (1984)  might both  be an
expression  of the action of methylmercury on microtubules
and thus be consistent with the hypothesis  that  microtu-
bule  protein is an important molecular target for methyl-
mercury in the developing brain.

    Enzymes  associated  with  myelin formation  have been
found to be affected in the early postnatal period in rats
(Grundt  &  Neskovic,  1985).  Morphological  de-differen-
tiation  of cultured brain cells  has been shown to  occur
after  addition  of  methylmercury (Grundt  et  al., 1981,
1982).   These effects occur at lower methylmercury levels
than  those affecting energy metabolism  (Grundt & Bakken,

    Choi  et al. (1981)  noted incomplete arborization  of
the  dendritic tree of Purkinje  cells in mice dosed  with
methylmercury in the early postnatal period.

9.3.3 Summary

    In  summary,  the  clinical  and  epidemiological  evidence
indicates  that prenatal life  is more sensitive  to the  toxic
effects of methylmercury than is adult life.  The inhibition of
protein synthesis is one of the earliest detectable biochemical
effects  in the  adult brain,  though the  sequence  of  events
leading to overt damage is not yet  understood.   Methylmercury
can also react directly with important receptors in the nervous
system, as shown by its effect on the acetylcholine receptor in
the   peripheral  nerves.  Concerning  prenatal  exposure,  the
effects  of methylmercury seem to  be quite different and  of a
much  more general basic  nature.  It affects  normal  neuronal
development  and leads to  altered brain architecture,  hetero-
topic  cells, and decreased brain size.  Methylmercury may also
be exerting an effect, perhaps through inhibition of the micro-
tubular  system,  on cell  division  during critical  stages of
formation of the central nervous system.

9.4 Dose-Effect and Dose-Response Relationships in Human Beings

    The  relationships between concentrations in indicator
media  (e.g., blood and hair) or body burdens and the mag-
nitude of an effect or frequency of an  effect  (response)
were discussed in Environmental Health Criteria 1: Mercury
(WHO, 1976b) using data from the Japanese and  Iraqi  out-
breaks.   They will be  summarized here and  considered in

conjunction  with  studies  reported subsequently.   Other
extensive  and detailed reviews have  been published since
1976  (Tsubaki  &  Irukayama, 1977;  Inskip  & Piotrowski,
1985; Tsubaki & Takahashi, 1986).

    Prenatal  and adult exposures  will be treated  separ-
ately  in view of  the differences, both  qualitative  and
quantitative, in effects and dose-response relationships.

9.4.1 Adult exposure

    This  section  will  examine new  data published since
1976  and include a re-analysis of samples of hair, brain,
and other tissues obtained from patients in  Minamata  and
Niigata,  Japan,  the  clinical follow-up  of  individuals
exposed to methylmercury in Niigata, a new analysis of the
Iraqi data, and reports on high fish consumers  in  Canada
and elsewhere. The Minamata and Niigata outbreaks

    Many of the original samples collected in Minamata and
Niigata,  Japan, had been  analysed by the  dithizone pro-
cedure.  Previous risk estimates were based on  blood  and
hair  mercury levels measured by  this procedure.  Tsubaki
et  al. (1978) reported on  the repeat analysis of  a hair
sample  from the patient in  Niigata with the lowest  hair
mercury   concentration   at   the   onset   of   symptoms
(52 g/g).     Re-analysis by atomic absorption  yielded a
value  of  82.6 g/g.   Other hair  samples collected from
Niigata yielded values of about 100 g/g  for the onset of
symptoms.  As for blood  samples, none were  available for
re-analysis  by atomic absorption. The   patient  with the
lowest  blood  level had  a  concentration of  just  below
200 g/litre    when  extrapolated  to time  of  onset  of
symptoms. However, the extrapolation used in Environmental
Health Criteria 1: Mercury (WHO, 1976b) was based on a few
points  only,  and  the  statistical  uncertainty  in  the
extrapolated value was high. Furthermore, the hair samples
from  the same patient  indicated that the  blood  concen-
tration  was probably higher. Other blood samples extrapo-
lated  to values above 300 g/litre.   Further evidence by
Tsubaki et al. (1978) indicates that hair and  blood  mer-
cury levels at the onset of symptoms may not have been the
true maximum values in these patients.  Analyses  of  hair
samples  from  Niigata  indicate that  the mercury concen-
trations  may  have  attained peak  values  about 2 months
before  the  onset  of symptoms.  A  stringent  government
warning  against the consumption of  contaminated fish was
issued by June 1965; in many patients,  symptoms  appeared
about 2 months later (WHO, 1980).

    Such  evidence indicates that previous  evaluations of
the  earlier data from Niigata may have underestimated the
blood and hair concentrations associated with poisoning in
the  most sensitive patient and,  therefore, overestimated

the risk of poisoning.  However, it should be  noted  that
the  atomic absorption method  does need not  always yield
higher  results than the dithizone method.  Tsubaki et al.
(1978) quote data from two hair samples in which agreement
between  the two results was  excellent.  Furthermore, the
brain  and  other tissues  were  preserved for  many years
before   the  atomic  absorption  measurements  were  made
(1973),  whereas the dithizone  method was used  on  fresh
tissue (1956-1960).

    Information  from the clinical follow-up  from Niigata
(Tsubaki & Irukayama, 1977; Tsubaki et al., 1978) suggests
that there may be a latent period of several years between
peak mercury concentrations and onset of symptoms.  Such a
latent  period was reported in four patients whose maximum
hair  concentrations were in the range of 50-300 mg/kg, as
measured by atomic absorption (Tsubaki et al., 1978).  The
results  of studies on primates indicate latent periods of
up  to  1 year  under conditions  of  continuous exposure.
These latent periods are apparently dose dependent in ani-
mals  (Evans et al., 1977).  A relationship between length
of latent period and maximum hair concentrations  was  not
apparent in the few Niigata cases.  The delayed cases were
mild,  showing  non-specific  symptoms, so  that  cases of
methylmercury  poisoning could not be  diagnosed with com-
plete  certainty.   Follow-up studies  examining mortality
patterns   in  the  Minamata  population,  including  both
poisoning  cases and controls,  did not reveal  any  clear
pattern of mercury-related deaths (Tamashiro et al., 1984,
1986, 1987). The Iraqi outbreak

    This  outbreak  of mass  poisoning  took place  in the
winter of 1971-1972 (Bakir et al., 1973; Kazantzis et al.,
1976a,b;  Al-Mufti et al.,  1976; Greenwood, 1985).   Seed
grain treated with a methylmercury fungicide was  used  to
prepare homemade bread in rural communities throughout the
country.   Consumption probably began in October-November,
1971,  and the first cases of severe poisoning were admit-
ted to hospital at the end of December, 1971. Total hospi-
tal  admissions rose to just over 6000, with most of these
occurring in January, 1972.  Over 400 deaths attributed to
methylmercury  were recorded in hospital.   Both sexes and
all  ages were affected.  Individual  exposure ranged from
a  low non-toxic intake  (when a few  contaminated  loaves
were  consumed)  to  prolonged daily  intake (1-2 months),
which  in some cases  produced severe signs  of poisoning.
The  first  effects  were complaints  of  paraesthesia  or
malaise,  followed  by  signs of  ataxia,  constriction of
visual  fields, and hearing loss.  Some people experienced
muscular  weakness, which improved after treatment with an
acetylcholinesterase  inhibitor.   Changes  in  peripheral
nerve  velocity were recorded  in some severe  cases. How-
ever,  most of the signs  and symptoms were attributed  to

damage  to the central  nervous system.  Effects  on  non-
nervous tissue appeared to be absent or negligible.

    Early  in the outbreak,  it was noted  that some  pre-
natally  exposed infants showed  signs of severe  cerebral
palsy similar to the cases reported in the  Minamata  out-
break (Amin-Zaki et al., 1974). Later, more subtle effects
on the developing nervous system were detected  (Marsh  et
al.,  1980). Fig. 2, reproduced from  Environmental Health
Criteria 1: Mercury  (WHO, 1976b), demonstrates both dose-
effect and dose-response relationships. For any given sign
or  symptom,  e.g.,  paraesthesia, there  is  a background
frequency indicated by the line parallel to the horizontal
axis. Two scales are given for the horizontal axis because
two  different methods were  used to estimate  the maximum
body  burden.  At higher  values of the  body burden,  the
frequency of response rises in proportion to the logarithm
of  the body burden (the horizontal axis has a logarithmic
scale).   The two lines  (the horizontal and  sloped line)
form  the shape of  a "hockey stick",  and this type  of
dose-response analysis is referred to by this name.

    The body burden corresponding to the point  of  inter-
section  of the  two lines  in the  "hockey  stick"  was
referred  to as a  "practical threshold" by  the authors
(Bakir  et  al.,  1973).  This  threshold  increases  with
increasing severity of the effects.  Thus, using the upper
scale  in Fig. 2, the threshold for paraesthesia occurs at
a body burden of about 25 mg, for ataxia at  about  50 mg,
for dysarthria at about 90 mg, for hearing loss  at  about
180 mg, and for death at over 200 mg.

    The  dose-response relationship is illustrated  by the
"hockey-stick" line for each sign and symptom. Thus, the
increase  in frequency of  paraesthesia increases in  pro-
portion  to the log of  the maximum body burden  above the
practical threshold. This increase is assumed to be caused
by  methylmercury. In fact, the only proof that methylmer-
cury  produced certain effects in this population is that:
(a)  these  effects  followed  a  known  high  exposure to
methylmercury;  (b)  the  frequency and  severity of these
effects  increased with increasing exposure  to methylmer-
cury; (c) these effects are similar to those seen in other
outbreaks  of methylmercury poisoning;  and (d) the  major
signs have been reproduced in some animal models.


    This  cause-effect  relationship is  most difficult to
establish at body burdens close to threshold levels. Here,
the  only effect may be the patient's complaint of paraes-
thesia.  This  is  a  non-specific  end-point  that  has a
variety  of causes other  than methylmercury. The  overall
conclusion  depends  on a  group-based statistical associ-
ation  between paraesthesia and exposure to methylmercury.
Fig. 2 shows that the practical threshold value  for  par-
aesthesia is a body burden of 25-40 mg mercury.  Using the
metabolic model discussed in section 6, the body burden of
25-40 mg  mercury is equivalent to  a blood level of  250-
400 g/litre.  This range of blood values compares favour-
ably with the lowest-observed-effect level in Niigata. The
"hockey-stick"  analysis depicted in Fig. 2  implies the
existence  of a population threshold  for the neurological
effects  of methylmercury in adults. Though the true popu-
lation  threshold  cannot  be determined,  "the practical
threshold"  serves  as  an  estimate  of  the  population

    A  re-analysis  of Iraqi  data  has been  published by
Nordberg  & Strangert (1976,  1978, 1982).  This  analysis
assumed a continuous distribution of individual thresholds
superimposed  on a background frequency  for such symptoms
as  paraesthesia.  The analysis also took into account the

inter-individual  variation in whole-body biological half-
times.  The half-time was  used together with  other  par-
ameters  of the metabolic model for methylmercury to esti-
mate blood concentrations that would result from long-term
daily intake of methylmercury. In turn, the  blood  levels
can  be related to the maximum body burdens by the distri-
bution parameters presented in section 6.  Thus, these two
distributions of thresholds and biological half-times were
combined to give an overall estimate of the risk  of  par-
aesthesia for a given steady-state daily intake of methyl-
mercury.  The results are presented in Fig. 3.  The calcu-
lations indicate that an intake of 50 g/day   in an adult
would involve a risk of about 0.3% of the symptoms of par-
aesthesia, whereas an intake of 200 g/day   would involve
a risk of about 8%. As pointed out by Nordberg & Strangert
(1976, 1978, 1982), the background frequency of these non-
specific  symptoms, such as paraesthesia, plays a key role
in determining the accuracy of the estimates  of  response
of low frequencies.  From the same Iraqi data, the authors
estimated  the background frequency of  paraesthesia to be
6.3%. However, there is considerable uncertainty in deter-
mining  the precise value of the background frequency, and
this  uncertainty becomes the  dominant cause of  error at
low rates of exposure.


    The re-analysis by Nordberg & Strangert is  in  agree-
ment with the conclusions of Environmental Health Criteria
1:  Mercury  (WHO,  1976b)  that  the  prevalence  of  the
earliest  effects could be expected to be approximately 5%
in  the  adult  population  following  a  long-term  daily
methylmercury  intake of 3-7 g   mercury/kg  body weight.

Such  a long-term daily intake  should give rise to  blood
concentrations of approximately 200 g   mercury/litre and
maximum hair concentrations of about 50 g   mercury/g. It
should be noted that estimates of the frequency of paraes-
thesia below daily intakes of about 200 g   are extrapol-
ations  beyond the observed data and assume the absence of
a population threshold. Exposed populations in Canada

    More  recently,  clinical and  epidemiological assess-
ments  have  become  available from  studies  of  Canadian
Indian  population groups exposed  seasonally over a  long
period  of time to methylmercury through fish consumption.
The levels of exposure, as determined by the  analysis  of
blood  and hair samples  (or both), were  generally  lower
than  those in the diagnosed cases of poisoning studied in
Iraq  and in the Niigata  epidemic in Japan.  The  highest
blood   level   of   mercury  recorded   in   Canada   was
660 g/litre (Wheatly, 1979).

    Harada  et al. (1976) clinically examined 89 residents
of two Indian reservations who had been exposed to methyl-
mercury  by ingestion of  contaminated fish. They  found a
number  of signs and  symptoms that have  been  associated
with  methylmercury intoxication.  However, as the authors
pointed out, the signs and symptoms were  relatively  mild
and  many of them were thought to be due to other factors.
In  the absence of controls,  it is difficult to  evaluate
the  possible  role  of  methylmercury  in  the   clinical
findings reported in this study.

    A report of the Medical Services Branch of the Depart-
ment  of National Health and Welfare, Canada, recorded the
clinical examination of 84 subjects who had a  history  of
blood  mercury  levels  above  100 g/litre     (Wheatley,
1979).  Mild symptoms and signs were found that  could  be
attributed  to  possible  methylmercury exposure,  but the
causal  relationship between exposure and  effects was un-
certain.   However, of the 84 subjects  examined, 11 cases
were   found  where  such  an  association  could  not  be

    A  major epidemiological study was carried out on Cree
Indians  from  northwestern  Quebec,  Canada,  exposed  to
methylmercury  in fish (McKeown-Eyssen &  Ruedy, 1983a,b).
The  authors claimed to find  an association in adult  men
and  women between a set of neurological abnormalities and
the  estimated  exposure  to  methylmercury.  However,  it
should  be pointed out that  this association was seen  by
only  four  of  seven observers  who  reviewed  videotaped
recordings   of  the  neurological  screening  tests.  The
severity  of these neurological abnormalities is described
as  mild or questionable.  It was not possible to estimate
any  threshold  body burden  or  hair levels  because this

population  had been exposed  possibly for most  of  their
lives and, therefore, peak values in previous  years  were
unknown.   However,  observations on  this population over
several years indicated maximum blood concentrations below
600 g/litre.     On  examining  the  reports  from  these
studies,  a WHO expert  group (WHO, 1980)  pointed to  the
potential importance of the long duration of  exposure  in
the  Canadian Indians and raised the possibility that this
might  be the first example  of an endemic disease  due to
exposure to methylmercury. Other fish-eating populations

    In  addition  to  the extensive  Canadian studies men-
tioned above, some other reports have been published since
1976  on the blood or  hair mercury levels in  populations
exposed to methylmercury through fish (Bacci et al., 1976;
WHO,  1976b; Riolfatti, 1977 ; Haxton et al., 1979; Turner
et al., 1980; Valciukas et al., 1986).  Taking all reports
into  consideration, it seems  that about 100 adults,  who
were  exposed to methylmercury  in fish, have  been ident-
ified  outside Japan or  Iraq as having  had blood  levels
above  200 g/litre.    In none of these cases has a diag-
nosis  of Minamata disease been  made, but it is  possible
that  some may have suffered mild methylmercury poisoning.
Even if it is assumed that none of these  people  suffered
any  adverse effects from  the exposure, such  a  negative
finding  is still consistent  (95% confidence level)  with
the maximum risk for paraesthesia of about 3%. Special groups

    The  above-mentioned risk estimates  may not apply  to
pregnant women. Some severe cases of poisoning among preg-
nant  women exposed to  high doses were  reported in  Iraq
(WHO,  1980).  At lower doses,  transient paraesthesia and
other   mild  symptoms  have  been   reported  (Tsubaki  &
Irukayama, 1977; Marsh et al., 1977, 1980, 1981). Maternal
paraesthesia  coincided  with peak  hair concentrations of
methylmercury  (Marsh  et al.,  1987).  These observations
suggest  a greater risk for  pregnant women than for  non-
pregnant women. Summary

    The  overall conclusion is that  the reported relationships
between  response  and  body  burden,  hair,  or  blood mercury
concentrations  are essentially the  same as those  reported in
Environmental  Health  Criteria 1: Mercury (WHO,  1976b). It is
possible  that the latent  period after cessation  of  exposure
may  extend to  one year  or thereabouts.   Pregnant women  may
exhibit  paraesthesia  at  lower methylmercury  exposure levels
than non-pregnant women, suggesting a greater risk for pregnant

9.4.2  Prenatal exposure

    In  contrast to the  adult exposure situation,  a con-
siderable amount of new data has been published  on  dose-
response  relationships  for  human prenatal  exposure. In
1976,  when Environmental Health Criteria 1: Mercury (WHO,
1976b)  was published, it was known that prenatal exposure
could  cause fetotoxic effects  in human beings.   In  the
Minamata  outbreak, 23 children believed to be exposed  in
utero had  severe  cerebral involvement  (palsy and retar-
dation),  whereas their mothers had mild manifestations or
none  at  all (Takeuchi,  1977).   Mercury levels  in  the
mothers  during pregnancy were not  recorded (WHO, 1976b).
There  were  no  reports  of  prenatal  poisonings  in the
Niigata outbreak. Psychological studies carried out in the
Minamata  area with children  from elementary schools  and
junior  high schools did not  reveal major defects of  IQ,
compared  with  children from  a  control area  (Harada  &
Moriyama,  1977).  However, data on maternal exposure were
not available.  In another study from Minamata there was a
correlation  between mercury levels in umbilical blood and
the  occurrence of mental retardation  in children (Harada
et al., 1977).

    Studies of prenatal exposure to methylmercury based on
populations in Canada, Iraq, and New Zealand have now been
published. Iraq

    Since  the  publication  of WHO  (1976b), results have
been  obtained  from  a  clinical  follow-up  study  on 29
infant-mother  pairs in Iraq  (Marsh et al.,  1977, 1980).
These reports described psychomotor retardation in infants
caused  by prenatal exposure (social bias excluded). A re-
lationship  was noted between maximum hair concentrations,
measured in 1-cm segments during pregnancy, and  the  fre-
quency  of neurological effects in the infants.  These ef-
fects  included delayed achievement of developmental mile-
stones  with or without  neurological signs.  The  infants
were 4-5 years of age at the time of last examination.

    At  hair mercury levels  below 180 mg/kg, the  infants
showed  minimal clinical neurological signs, but there was
clear evidence of effects on psychomotor function, such as
delayed walking or talking (Marsh et al., 1977).  The fol-
lowing  criteria were adopted for developmental abnormali-

    "motor  retardation if the  child was not  walking at
    18 months,  speech  retardation  if not  talking by 24
    months, mental retardation or seizures (or convulsive-
    like attacks) according to the history provided by the
    mother, and neurological signs by agreement of the two

    examiners. No standards are available for head circum-
    ference  or height of Iraqi children, so these factors
    were  evaluated in terms of  standard deviations below
    the mean for the group".

    Subsequently,  a more complete  report (Marsh et  al.,
1981)  became available on 84 infant-mother pairs, includ-
ing  the 29 pairs described above.  The peak maternal hair
levels  ranged from 0.4 to 640 mg/kg.  Severe neurological
deficits  were observed in five children. These severe ef-
fects are illustrated by the case report of one  of  these
children.  At the age of 4 years and 9 months,  the  child
was blind and deaf and was unable to stand, walk, or talk.
Tonic  neck responses were  present.  All limbs  showed an
increase  in tone and  deep tendon reflexes  with extensor
plantar  responses  and  abnormal posture  of  the  wrist.
Microcephaly  was  present,  with a  head circumference of
43 cm.  The boy's height was 98 cm (Marsh et al., 1977).

    These  severely affected children had  been exposed to
peak  maternal levels during the second trimester of preg-
nancy.   These findings agree with a histopathological re-
port of Choi et al. (1978), who found evidence of abnormal
neuronal migration in the brain of Iraqi  victims  exposed
maximally  in the third  and fourth months  of  pregnancy.
This is known to be the critical period for  neuronal  mi-
gration (Sidman & Rakic, 1973).

    These reports (Marsh et al., 1977, 1981) were based on
the  analysis of 1-cm segments of hair bundles.  Peak hair
concentrations  probably  underestimated  the actual  peak
blood  concentrations due to misalignment  of hair strands
during collection and to the differences in  growth  rates
of   individual  strands  (for  further   discussion,  see
Giovanoli-Jakubczak  & Berg, 1974). Furthermore,  the ana-
lytical methods used in the hair analysis had  a  recovery
of 73  10% (Wigfield et al., 1981).

    Analysis of these Iraqi hair samples has been repeated
using single-strand sampling and X-ray fluorescence giving
complete  recovery (Jaklevic et  al., 1978). Detailed  re-
sults  from the Iraqi outbreak have been reported by Marsh
et al. (1987) are given in the Appendix.  The  effects  in
mothers during pregnancy were mild and transient, the most
frequent  symptom  being  paraesthesia. Symptoms  were re-
ported  by the mother  more frequently as  exposure  level
increased.  The severity of effects in the mother was much
less than that in her offspring. Two of the mothers of the
four  most severely affected infants (pair numbers 45, 56,
68,  and 70)  recalled no  symptoms, and  the others  com-
plained  only of transient paraesthesia  during pregnancy.
This  confirmed the findings  of Harada (1968)  on infant-
mother pairs in the Minamata outbreak.

    According to Marsh et al. (1987), the physical examin-
ation of the children included:

    "observation,  measurement of head  circumference and
    body  length, cranial nerve signs, speech, involuntary
    movements,  strength,  deep  tendon reflexes,  plantar
    responses,   coordination,  dexterity,  primitive  re-
    flexes, sensation, posture, and ability to sit, stand,
    walk,  and run. A scoring system was adopted. When the
    neurological examination result was absolutely normal,
    the  score was 0.  In attempting  to identify  minimal
    signs,  points  were  awarded for  borderline findings
    such  as possibly increased  reflexes.  Scores of  0-3
    indicated  no definite abnormality.  The highest score
    in the most severely affected child was 11. The neuro-
    logical  score was limited  to signs found  on examin-
    ation,  and points were  not awarded for  features  of
    retardation reported by the mother".

    Four  cases received a neurological  score of 11.  The
evidence  is strong that these  were severe cases of  pre-
natal  methylmercury poisoning. The  lowest-observed maxi-
mum  maternal hair level for these severe cases was 404 mg
mercury/kg  (mother-infant pair number 56).  However, none
of  these  observed  symptoms were  specific  to  prenatal
methylmercury  poisoning.  The possibility  of confounding
factors was considered by the authors:

    "Maternal alcohol consumption was not a problem. They
    followed the Moslem precept to avoid alcohol,  so  the
    fetal  alcohol syndrome was not a consideration.  None
    of  them  smoked.  The absence  of  antenatal  medical
    supervision was uniform, so that no prescription medi-
    cation  were  taken  and non-prescription  medications
    were  rarely  available.  There were  no  drug-induced
    fetotoxic effects to account for.  These were agricul-
    tural communities with little socio-economic variation
    and no evidence of malnutrition".

    The  evidence  that  such non-specific  symptoms  were
caused by methylmercury is based on a  statistical  corre-
lation  of the frequency of these symptoms with methylmer-
cury exposure and the absence of confounding factors. This
was  the first  report of  a milder  syndrome of  prenatal
methylmercury  poisoning, as opposed  to the severe  cases
discussed above.

    An  example  of  one such  statistical  correlation is
given  in Fig. 4.   The frequency  of a  symptom of  motor
retardation  (delayed onset of walking) is plotted against
the  logarithm of the maximum  maternal hair concentration
during pregnancy. The continuous line in Fig. 4a gives the
best  fit  to  the data  calculated  according  to a  non-
parametric  model.   The  frequency of  response increases
smoothly  from virtually zero  at a maternal  hair mercury

level  of 5 mg/kg to approximately 70% at the highest con-
centration.   The shaded area is made up of individual 95%
confidence limits for the individual response frequencies.
The  narrow confidence limits  at the lowest  hair  levels
(about  1 mg/kg) indicate a  low background response  fre-
quency of less than 5%. Marsh et al. (1987) noted that, in
five European countries, 10% of infants were  not  walking
by the age of 16 months and 5% of a sample of  infants  in
Paris, France, were not walking by 18 months,  this  being
the criterium used in their study.

Fig. 4. The  relationship  between  the maximal  maternal  hair concentrations
        during  pregnancy and the frequency  of cases of motor  retardation in
        offspring.   Calculated from  data in  the Appendix  according to  the
        method of Cox et al. (1989).


    The  non-parametric 95% confidence limits are superim-
posed  on two parametric models  (the "hockey-stick" and
logit  models)  in Fig. 4b.   The  figure shows  that both
parametric  models are consistent  with the data  and with
each  other.  The two curves  are close to each  other and
both  lie  entirely  within the  non-parametric confidence


    The  collection of non-simultaneous  confidence inter-
vals,  as depicted in the  shaded area, cannot be  used to
obtain  confidence intervals for  such parameters as  hair
concentration for a 10% or 50% risk.  Instead,  the  para-
metric  models were used.  The result for the hockey-stick
model are given in Table 10.

    The  best estimate of  a predicted threshold  with the
hockey-stick  model  is  a maximum  maternal  hair concen-
tration  during  pregnancy  of 7.3 g    mercury/g with an
upper  confidence limit of  13.6 g  mercury/g. This  best
fit corresponds to a background of zero.  This probably is
the  outcome of the small number of infant-mother pairs in
the  low exposure region.  An assumed background frequency
of  2% or 4%  does not greatly  change the estimated  pre-
dicted threshold values (8 and 9%, respectively). However,
an  assumed background of  4% greatly increases  the upper
95%  confidence  limit, and  an  assumed background  of 8%
dramatically  increases the estimate  of the threshold  to
119 g    mercury/g.  These changes with  increased values
for  the  background  frequency are  due  in  part to  the
distribution  of the data (the four abnormal values in the
hair mercury concentration range from 10 to 50 g/g)   and
in  part  to the  assumed  higher background  values being
further away from the best fit (0%).

Table 10.  The dependence of "practical" threshold
values of hair mercury concentration and upper
confidence limits on background frequency of responsesa
                            "Hockey-stick" model
Response   Background  Practical        Upper 95%
           (%)         threshold        limit
                       (mg mercury/kg)  (best fit)
Retarded   0b          7.3              13.6
walking    2c          8                17
           4c          9                190
           8c          119              230

Central    2c          7.8              24
nervous    4c          8.4              32
system     9b          10               287
a Data in Appendix according to Cox et al. (1989).
b The best fit of the background frequency from data.
c Assumed background frequency.

    However,  a population threshold  might not exist  and
the  hockey-stick  model will  not  then be  applicable to
these data.  Thus the assumption that there is  zero  risk

at the threshold value estimated by the hockey-stick model
would  be in error.  The logit model provides a continuous
relationship  between  dose  and response  and will there-
fore give an estimate of the error in assuming  zero  risk
at the threshold dose estimated by the hockey-stick model.
Thus  according to logit  analysis, the excess  risk  over
background  is 5% at the  threshold hair mercury level  of
7.3 mg/g  determined by the hockey-stick model.  In short,
if the hockey-stick model is not applicable, the estimated
threshold  of 7.3 mg/g will  underestimate the risk  by 5%
(Fig. 4b).

    The  logit model, in  agreement with the  hockey-stick
model,  gives a background frequency value of 0% according
to best fit of the data.

    The logit and hockey-stick curves for abnormal central
nervous system signs are depicted in Fig 5. The curves are
superimposed  on the 95% confidence  limits estimated non-
parametrically as described for Fig. 4.


    The  two  parametric  models are  consistent with each
other  and with the non-parametric confidence limits. With
all   three  models,  a  statistically  significant  dose-
response relationship exists.

    The hockey-stick model gives the best estimates of the
practical threshold at 10 g   mercury/g but with  a  very
high confidence limit (287 g mercury/g) (Table 10).

    Lower  assumed values of the  background frequency (2%
and 4%) give roughly the same practical  threshold  value,
but  with  lower upper  confidence  limits (24  and  32 g
mercury/g, respectively). The lower upper limit values are
due  to  the fact  that a definite  assumed value for  the
background  frequency was used, whereas 9% is the best-fit
estimate of background and consequently the overall uncer-
tainty is greater.

    The  logit model estimates  a similar background  fre-
quency (9.3%).  The excess risk over background  is  about
5% (Fig. 4).

    Thus, the data in the Appendix can be used  to  demon-
strate a statistically significant dose-response relation-
ship  for signs and symptoms of prenatal poisoning.  Esti-
mates  of  a  "threshold" or  highest  no-effect concen-
tration were made with the hockey-stick model. These esti-
mates are subject to considerable uncertainty due  to  the
small number of infant-mother pairs. As in the adult dose-
response  relationships (see Fig. 3  and section,
the  background frequency can greatly  influence estimates
of risk at low (close to background) response  rates,  yet
cannot  be estimated accurately due to the small number of
data points at the lowest hair mercury levels. Canada

    McKeown-Eyssen et al. (1983) examined the relationship
between  prenatal exposure to methylmercury and neurologi-
cal  and developmental abnormalities among 234 Cree Indian
children aged 12-30 months from four communities in north-
ern  Quebec, Canada.  The authors described their study as

    "A  medical team visited each  community and examined
    95%  of  the  eligible  children  and  their  mothers,
    `blinded'  to their methylmercury exposure. One of the
    four  pediatric  neurologists documented  each child's
    height,  weight,  and  head  circumference,   assessed
    dysmorphic  and congenital features, and  reported the
    presence  or absence of acquired disease. A neurologi-
    cal  examination  was  also conducted  and included an
    assessment  of special senses, cranial nerves, sensory
    function, muscle tone, stretch reflexes, coordination,
    and  persistence  of  the Babinski  response which was
    judged  to be abnormal for the child's age, as well as
    a summary of the presence or absence  of  neurological
    abnormality.   Finally,  the neurologist  assessed the
    child's development by use of the Denver developmental
    scale; for each child, the results were  expressed  as
    the percentage of total test items that  were  passed,
    separately  for  gross  and  fine  motor  development,
    language development, and personal/social skills.

    "Each  mother was interviewed  about her alcohol  and
    tobacco consumption both during the relevant pregnancy
    and at the time of the interview. Because of  the  un-
    certainty  about the accuracy of  the reporting, women
    were  classified  simply as  users  of alcohol  or ab-
    stainers,  and as smokers  or nonsmokers according  to
    whether  they reported ever drinking or smoking.  Caf-
    feine  intake was calculated from answers to questions
    on tea and coffee consumption.

    "Information  on pregnancy, labour, and delivery were
    sought  from the medical certificate  of childbirth, a
    standard  form that reports the  major characteristics
    of  pregnancy and delivery  for all births  in Quebec.
    Because  some deliveries occurred  in the bush,  these
    certificates  could be obtained  for only 85%  of  the

    "Methylmercury   concentrations  of  the   hair  were
    measured  in alternate one centimeter segments, begin-
    ning  with the scalp-end segment.  The maximum concen-
    tration  in the segment  of hair corresponding  to the
    period from one month before conception to  one  month
    after  delivery  was  used  as  an  index  of prenatal

    "A  search was conducted to  establish which measures
    (if  any) of neurologic function  and development were
    associated  with  methylmercury  exposure.   This  was
    achieved  by  use  of  a  regression  analysis  of the
    relationship  between the methylmercury exposure index
    and the results of four tests of  neurologic  function
    (coordination,  cranial  nerves,  muscle tone  or  re-
    flexes,  and  an  overall neurologic  assessment)  and
    measures  of four aspects of  the Denver developmental
    scale  (gross  and  fine motor  development,  language
    development,  and  personal/social skills).   Once the
    measure of neurologic function most closely associated
    with exposure was identified, the odds ratio was esti-
    mated  from a discriminant analysis  in which children
    were  classified as cases or controls depending on the
    presence  or  absence  of abnormality  of the relevant
    neurologic   function.   The  analysis   distinguished
    between the cases and controls first on the  basis  of
    confounding  variables potentially associated with the
    neurologic  abnormality  (child's  age,  duration   of
    breast-feeding,  mother's  age,  and mother's  smoking
    habit  and consumption of beverages containing alcohol
    and caffeine), and then on the basis of  the  prenatal
    indices of methylmercury exposure".

    The ages of the mothers covered a wide range: 13% were
below  20 years of age and 15% were at least 35 years old.
About  two-thirds said they consumed  alcohol and slightly

more  were smokers.  The  percentages of high  risk  preg-
nancies, complications at delivery, and duration of breast
feeding  were similar for boys and girls. The birth weight
of  the children tended  to be above  normal (34%  weighed
over 4 kg).

    The  mean index of mercury  exposure (maximum maternal
hair   concentration   during  pregnancy)   was  the  same
(6 g/g),   for both boys and girls, and only 6% of values
were  above 20 g/g.    None of the children showed abnor-
mal  physical  development, but  "abnormality" of muscle
tone or reflexes was positively associated with  the  pre-
natal index of methylmercury exposure (P <0.05, 2-tailed).
The  highest maternal hair level in this study group of 97
males  was  23.9 g/g    (Table 10). No  other  measure of
neurological  function  or  development was  significantly
associated  with  methylmercury exposure  either before or
after  adjustment for confounding variables.  In girls, no
adverse effects  were associated with mercury exposure. In
fact,  a negative association was found between one neuro-
logical  abnormality (incoordination) and prenatal mercury
exposure.   McKeown-Eyssen  et  al. (1983)  expressed some
reasons  to  doubt the  "importance"  of the  finding of
methylmercury  effects in boys.  They noted that the "ab-
normality  of  muscle tone  or reflexes . . . was . . . of
doubtful  clinical importance", that  previously reported
prenatal effects were at higher exposures, that a consist-
ent  dose-response relationship was  not seen in  the boys
(Table 11),  and that the effect was only seen in boys and
not in girls. Consequently, in their interpretation of the
data, the authors did not exclude the possibility that the
positive findings were chance observations.

Table 11.  Prevalence of abnormality of
muscle tone or reflexes according to
maternal mercury levels during pregnancya
Prenatal        Number    % abnormal
exposureb     of boys
index (mg/kg)

0 - 1.9         19        15.8
2 - 2.9         18        5.6
3 - 4.9         19        26.3
5 - 6.9         14        0
7 - 12.9        14        7.1
13 - 23.9       13        38.5

Total           97        15.5
a Adapted from: McKeown-Eyssen et al. (1983).
b Maximum maternal hair concentration during pregnancy. New Zealand

    Kjellstrom  et  al. (1986)  reported preliminary tests
carried  out  on prenatally  exposed  children in  a fish-
eating  group in New  Zealand.  The study  started with  a
cohort  of  11 000  recent mothers  and  their  offspring.
Approximately 1000 of these mothers reported that they had
consumed  fish more than three times per week during preg-
nancy.  Analysis of samples of maternal head hair revealed
that 73 of the mothers had levels above 6 mg/kg. People of
Pacific  Island descent accounted for 62%, Maoris for 27%,
and Europeans 11% of this group of 73.

    Only  31 offspring from this group of 73 mothers could
be  contacted by the time they were 4 years old. They were
matched  according to ethnic  group, maternal age,  birth-
place, and birth date with offspring having  low  prenatal
exposure  to  methylmercury  (maternal hair  mercury below
6 mg/kg).  The Denver Development Test, carried out  on  a
double-blind  basis,  was used  to  assess the  effects of
methylmercury. Abnormal or questionable results were found
in  17% of the controls, compared with 50% in the children
exposed  to  high  mercury levels  (maternal  hair mercury
levels  above 6 mg/kg).  The difference  was statistically

    A statistically significant dose-response relationship
was found between mean maternal hair mercury levels during
pregnancy  and  the  frequency of  deficient  Denver  Test
results.  No influence of socio-economic factors (based on
place  of residence), maternal  health status, or  smoking
habits  was  seen.   However,  other  confounding  factors
inherent  in these studies make it difficult to draw final

    In  1985, it was possible to locate 61 of the original
73  high-exposure children and to conduct detailed psycho-
logical  and scholastic tests  (carried out on  a  double-
blind basis) at the age of 6-7 years (Kjellstrom  et  al.,
1989).  At this stage, the children had completed at least
one year at school.  These tests included,  among  others,
the  revised  Wechsler  Intelligence  Scale  for  Children
(WISC-R) and the Test of Language Development (TOLD).

    The  high-exposure  children  (maternal  hair  mercury
levels  within the range  of 6-86 mg/kg, with  the  second
highest  value being 19.6 mg/kg) were  compared with three
matched  groups:  one  group with  maternal  hair  mercury
levels  of  3-6 mg/kg and  two  groups with  levels  below
3 mg/kg (one group with high fish consumption and one with
low  fish  consumption).  The  mothers  were  matched  for
child's  sex  and  maternal  ethnic  group,  age,  smoking
habits,   residence  area,  and  residence   time  in  New

    The  results of the  different tests were  correlated,
and showed that individual children with low scores in the
TOLD  or  WISC-R tests  also had low  scores in the  other
tests.  For those children who had been tested both at age
4  (Kjellstrom et al., 1986) and at age 6-7 (Kjellstrom et
al.,  1989),  there was  also  a correlation  between  the
Denver  Test and the  IQ scores (WISC-R  scale). The  sub-
groups were small, but the data indicated that a child who
had  poor Denver Test results  was highly likely to  score
very poorly in the IQ test at school age. According to the
authors'  summary, although "methylmercury  exposure con-
tributes  only a  small part  of the  variation  in  tests
results"  and "results of  the psychological test  vari-
ables  are influenced by the  child's ethnic background",
the  study suggests that  "an average hair  mercury level
during  pregnancy  of  13-15 mg/kg  (equivalent  to  about
25 mg/kg  peak  mercury level)  may  be associated  with a
decreased test performance" (Kjellstrom et al., 1989).

    It should be noted that the studies in Canada and Iraq
used maximum maternal hair concentrations during pregnancy
based  on 1-cm segments (roughly one month's hair growth).
Kjellstrom  et  al. (1986,  1989)  state that  their  mean
maternal hair values should be multiplied by a  factor  of
1.5 to obtain the maximum 1-cm value during pregnancy. Summary

    Severe derangement of the developing central nervous system
can be caused by prenatal exposure to methylmercury. The lowest
level (maximum maternal hair mercury concentration during preg-
nancy)  at which severe effects were observed was 404 g/g   in
the Iraqi outbreak. The highest no-observed-effect-level (NOEL)
for  severe effect was 399 g/g.     Fish-eating populations in
Canada  and New  Zealand have  also been  studied for  prenatal
effects,  but exposure levels were  far below the highest  NOEL
for severe effects in Iraq and no severe effects were seen.

    Evidence of psychomotor retardation (delayed achievement of
developmental  milestones,  a  history  of  seizures,  abnormal
reflexes)  were seen in the  Iraqi population at maternal  hair
levels  well  below those  associated  with severe  effects.  A
statistical  analysis revealed that one of these effects (motor
retardation)  rose above the  background frequency at  maternal
hair  mercury  levels  (maximum  level  during  pregnancy)   of
10-20 g/g.   This range of values in maternal hair is consist-
ent  with  all available  evidence and can  be accepted as  the
range  of  critical  concentrations.  The  Canadian study found
that  maternal  hair  levels were  positively  associated  with
abnormal   muscle tone or  reflexes in boys,  but not in  girls
(the highest maximum maternal hair level during  pregnancy  was
23.9 g/g).

    The  New  Zealand  study found  evidence  of  developmental
retardation  (according  to  the  Denver  Test)  in  4-year-old
children  at  average  maternal  hair  mercury  levels   during
pregnancy within the range of 6-86 g/g   (the  second  highest
value  was 20 g/g).   The New Zealand mercury values should be
multiplied by 1.5 to convert to maximum maternal hair levels in


10.1 Exposure Levels and Routes

    In  view of the  restrictions placed upon  the use  of
methylmercury  in  most  countries, occupational  exposure
will be low.

    The major source of human exposure to methylmercury is
through  the diet, more specifically  from the consumption
of fish and fish products.  In most countries, the import-
ant  food fishes have methylmercury levels in their edible
portion not exceeding 200-300 g/kg.    However, levels in
such predatory species as ocean tuna, shark, and swordfish
(even  from  non-polluted  areas), as  well  as freshwater
pike,  walleye, and bass, may contain methylmercury levels
in  excess of 1000 g/kg.   In view of the worldwide vari-
ation in dietary patterns and extent of pollution,  it  is
difficult  to  calculate  a  general  exposure  level  for
methylmercury.  However,  assuming  an average  daily con-
sumption  of  20 g  of  non-predatory  species  containing
200 g/kg,   the daily methylmercury intake would be 4  g.
It  has been estimated that long-term intake at this level
would  raise the blood methylmercury  levels by 4  g/litre,
and hair levels by 1 g/g.  However, in some countries the
average  consumption can be as  high as 100 g/day and  may
consist  mainly  of  predatory species.   In  these cases,
methylmercury intakes can exceed 100 g/day.

10.2 Toxic Effects

10.2.1  Adults

    Concerning  the risks in adults  exposed to methylmer-
cury,  the  conclusions  reached in  Environmental  Health
Criteria 1: Mercury  (WHO,  1976)  and  the  1980  interim
evaluation  remain unchanged.  A daily  methylmercury con-
sumption  of 0.48 g/kg  body weight (WHO, 1989b) will not
result in any detectable adverse effects. However, a daily
intake  of  3-7 g/kg   body weight  would  cause  adverse
effects on the nervous system, manifested as  an  approxi-
mately  5% increase in the incidence of paraesthesia. Hair
concentrations would be approximately 50-125 g/g  at this
level  of intake. Clinical observations  in Iraq suggested
that  women are  more sensitive  to the  toxic effects  of
methylmercury during pregnancy.

10.2.2 Prenatal exposure

    The  report  (WHO,  1980) that  evaluated  the  health
hazards  from exposure to  methylmercury through the  con-
sumption of fish underlined that damage to the fetal brain
caused  by prenatal exposure to methylmercury could be the
critical  effect, and that more information was needed for

a  proper risk assessment.  Since  1980, experimental evi-
dence to elucidate the mechanisms involved in  the  neuro-
toxic action of methylmercury on the fetal brain  has  ac-
cumulated and has been reviewed in this monograph. Further
analysis  of data from  the Iraqi outbreak  has  extracted
additional information relating to the effects of prenatal
methylmercury  exposure.  From these  sets of evidence,  a
pattern  has emerged that  permits the construction  of  a
biological  model for the neurotoxic  action of methylmer-
cury on the fetal brain.

    Methylmercury  inhibits the growth of  the fetal brain
and the migration of neurons from the embryological gener-
ation  layer to the final destination in the brain cortex.
This  has been demonstrated in clinical cases in Japan and
Iraq.  An inhibition  of brain  growth is  indicated by  a
decrease  in brain  size and  weight, as  was observed  in
studies  on monkeys and  humans.  The inhibition  of fetal
brain development caused by methylmercury exposure results
in the behavioural changes and reduced cognitive and motor
ability  found in clinical cases. It has been demonstrated
that  methylmercury interferes with microtubule formation,
cell  division,  and  neuronal protein  synthesis,  all of
which could explain the effects described above.

    The model emerging to explain the neurological effects
of methylmercury is a continuous dose-effect relationship,
with  a range from subtle changes in brain function (indi-
cated  by psychological  tests) at  low dose  levels to  a
severe  neurological syndrome of cerebral  palsy with pro-
nounced  changes in the organization of brain structure at
high   exposure  levels.   However,  the   possibility  of
detecting  and  characterizing the  methylmercury level at
which  the subtle and early  adverse effects on the  fetal
brain may arise is limited by the availability  of  sensi-
tive test procedures.  At present, some effects  can  only
be  detected and adequately characterized  in the epidemi-
ological studies of fairly large populations.

    The  crucial question is the actual exposure level (or
body  burden) of methylmercury in humans which can lead to
subtle  changes  in  the offspring.  The  actual  exposure
levels  and patterns are  usually unknown, but  the effect
can be related to the hair mercury level and  an  approxi-
mate  daily  exposure  calculated from  the  known kinetic
parameters  for methylmercury accumulation,  distribution,
and excretion.

    The  statistical analysis of data  on 84 infant-mother
pairs  (maternal peak hair mercury levels during pregnancy
of  0.4-640 g/g)   showed that, at  maternal hair concen-
trations  above 70 g/g,   children exhibited  evidence of
abnormal  neurological signs, e.g., increased  muscle tone
in  the leg and  exaggerated deep tendon  reflexes,  often

accompanied  by ataxia together with a history of develop-
mental  delay.  This statistical analysis  indicated a 30%
risk of these abnormal findings at maternal  hair  mercury
concentrations  around 70 g/g.    The data from the Iraqi
outbreak do not permit firm conclusions to be  drawn  con-
cerning  the  risk of  adverse  effects below  that level.
However, by applying the biological model described above,
the  extrapolation method of  Cox et al.  (1989), and  the
evaluation  of other currently  available data, it  can be
calculated  that a maternal hair  mercury concentration of
10-20 g/g   implies a 5% risk.  The possibility cannot be
excluded  that  effects  detectable by  psychological  and
behavioural  testing or subclinical effects might occur at
even lower levels of exposure, but evidence is lacking.

10.3 Conclusions

    The  general  population  does not  face a significant
health risk from methylmercury. Certain groups with a high
fish  consumption may attain  a blood methylmercury  level
(about 200 g/litre,   corresponding to 50 g/g   of hair)
associated  with a low (5%) risk of neurological damage to

    The fetus is at particular risk. Recent evidence shows
that  at peak maternal  hair mercury levels  above 70  g/g
there  is a  high risk  (more than  30%)  of  neurological
disorder  in the offspring.   A prudent interpretation  of
the  Iraqi data implies that  a 5% risk may  be associated
with  a peak mercury level of 10-20 g/g   in the maternal

    There is a need for epidemiological studies  on  chil-
dren  exposed  in utero to levels of methylmercury that re-
sult in peak maternal hair mercury levels  below    20 g/g,
in  order to screen for  those effects only detectable  by
available psychological and behavioural tests.


11.1 Gaps in Knowledge

    In  spite of significant advances in our understanding
of  the  toxicity  and potential  hazard of methylmercury,
there  remain areas in which  there is an urgent  need for
additional studies.

    The  most important of these areas is the lower end of
the  dose-response  relationship  for prenatal  exposures.
This  will require well  coordinated and designed,  inter-
national  epidemiological  studies that  consider all rel-
evant confounding factors (e.g., drugs, alcohol, smoking).
As  part of  these studies,  there is  a need  to  develop
objective  measurements  of clinical  manifestations.  The
potential ability of selenium and other dietary components
(e.g., antioxidants) to alter the toxic responses elicited
by  methylmercury  should be  investigated.  These studies
will  not only need to describe this interaction, but also
to  provide data that can be used quantitatively in a risk
assessment  of methylmercury, particularly for  the fetus.
The mechanisms of damage to both the mature and developing
nervous system remain to be elucidated.  As no information
on  the relative vulnerability of the brain during differ-
ent  periods of pregnancy is  available, more experimental
work  is  needed to  shed light on  this aspect, which  is
important for risk assessment and clinical judgement.  The
selective  damage to the  nervous system and  to  specific
areas in the brain, the long period in the case  of  adult
poisoning,  and the high  vulnerability of the  developing
nervous  system  (including  sex differences  in suscepti-
bility) are still unexplained.

11.2 Preventive Measures

    In  populations  that  consume large  amounts  of fish
(e.g.,  100 g/day),  the  hair levels  of methylmercury in
women  of child-bearing age  should be monitored.   If the
results  of these monitoring activities indicate excessive
exposure  to  methylmercury,  appropriate  and   practical
measures, such as dietary recommendations, should be taken
to  reduce  the  possibility of  long-term exposure during
pregnancy and to keep it below internationally recommended
allowable intakes.

    Measures to reduce methylmercury exposure via the con-
sumption of fish will need to consider the impact of these
measures  on  the  overall dietary  requirements  of these


    The  human health risks from exposure to methylmercury
were previously evaluated in Environmental Health Criteria
1:  Mercury (WHO, 1976b). This was followed by a brief up-
date (WHO, 1980), based upon a technical  report  prepared
by  the Monitoring and  Assessment Research Centre  (MARC,

    In   the  thirty-third  report of  the  Joint  FAO/WHO
Expert  Committee on Food  Additives (JECFA), it  was rec-
ommended  that  the  permissible tolerable  weekly  intake
(PTWI)  for  methylmercury  in  adults  be  maintained  at
200 g  (3.3 g/kg   body weight) (WHO, 1978; WHO, 1989b).
However,  the  Committee  noted that  pregnant  women  and
nursing mothers are likely to be at greater risk, although
the  available  data  were  insufficient  to  recommend  a
specific mercury intake for these population groups.

    Regulatory  standards  established  by  some  national
bodies in different countries and the EEC  are  summarized
in  the  data profile  of  the International  Register  of
Potentially Toxic Chemicals (IRPTC, 1987).


ABE,  T.,  HAGA,  T., &  KUROKAWA,  M.  (1975) Blockage  of  axoplasmic
transport   and   depolymerization   of  reassembled   microtubules  by
methylmercury. Brain Res., 86: 504-508.

AIREY,  D. (1983) Total mercury  concentrations in  human hair  from 13
countries  in relation  to fish  consumption and  location. Sci.  total
Environ., 31: 157-180.

R.M., & MAJID, M.A. (1976) Epidemiology of organomercury  poisoning  in
Iraq: I.  Incidence in a defined area and relationship to the eating of
contaminated  bread.  Bull.  World Health  Organ.,  53(Suppl.):  23-36.

AL-SHAHRISTANI,  H. & SHIHAB, K.  (1974) Variation of biological  half-
life of methylmercury in man.  Arch. environ. Health, 28: 342-344.

DOHERTY,    R.A.  &  GREENWOOD, M.  (1974)  Intra-uterine methylmercury
poisoning in Iraq. Pediatrics, 54(5): 587-595.

(1976)   Perinatal methylmercury poisoning in Iraq. Am. J. dis. Child.,
130:  1070-1076.

ANDO, S., TOYODA,  Y., NAGAI, Y., & IKUTA, F. (1985)  Abnormalities  in
gangliosides and other lipids of monkey, rabbit and human  brains  with
chronic organic mercury intoxication. Jpn. J. exp.  Med., 55(1): 1-6.

ARAKI,    K.,   WAKABAYASHI,   M.,    SAKIMURA,   K.,   KUSHIYA,    E.,
OZAWA,  H.,  KUMAMOTO,  T., &  TAKAHASHI,  Y.  (1981) Decreased  uptake
of GABA by dorsal ganglia in methylmercury treated rats. Neurotoxicity,
2:  557-566.

ARITO,   H., NOBORU, H.,  & SHITZU, T.  (1983) Effect of  methylmercury
chloride on sleep-waking rhythms in rats. Toxicology, 28: 335-345.

ASCHNER,  M. (1986) Changes in axonally transported proteins in the rat
visual   system   following   systemic  methylmercury   exposure.  Acta
Pharmacol. toxicol., 59(2): 151-157.

ASCHNER,  M.  &  CLARKSON, T.W.  (1987)  Mercury  203  distribution  in
pregnant and non-pregnant rats following systemic infusions with thiol-
containing amino acid. Teratology, 36: 321-328.

ASCHNER,  M., RODIER,  P.M., &  FINKELSTEIN, J.N.  (1986) Reduction  of
axonal  transport in the rat  optic system after direct  application of
methylmercury. Brain Res., 381(2): 244-250.

ATCHISON,  W.D. (1986) Extracellular calcium-dependent  and independent
effects of methylmercury on spontaneous and potassium-evoked release of
acetylcholine  at the neuromuscular junction. J. Pharmacol. exp. Ther.,
237(2): 672-680.

ATCHISON,   W.D.   &   NARAHASHI,   T.   (1982)   Methylmercury-induced
depression  of neuromuscular transmission in  the rat. Neurotoxicology,
3: 37-50.

BACCI,    E.,   ANGOTZI,   G.,   BRALIA,   A.,   LAMPARIELLO,   L.,   &
ZANETTE,  E.   (1976)  Etude sur  une  population  humaine  expose  au
mthylmercure par la consommation de poisson. Rev. int. Ocanogr. md.,
41/42: 127-141.

BAKIR,    F.,   DAMLUJI,   S.F.,    AMIN-ZAKI,   L.,   MURTADHA,    M.,
T.W.,  SMITH, J.C., & DOHERTY,  R.A. (1973) Methylmercury poisoning  in
Iraq.  Science, 181:  230-241.

BALLATORI,  N. & CLARKSON, T.  (1985) Biliary secretion of  glutathione
and  of glutathione-metal complexes.  Fundam. appl. Toxicol.,  5:  816-

DESKIN, R.,  & SLOTKIN, T.A. (1982) Neonatal methylmercury poisoning in
the   rat:    effects   on   development   of   central   catecholamine
neurotransmitter systems. Toxicol. appl. Pharmacol., 65: 92-99.

BEGLEY,   T.P.,   WALTS,  A.E.,   &   WALSH,  C.T.   (1986)   Bacterial
organomercurial lyase: overproduction, isolation, and characterization.
Biochemistry, 25: 7186-7192.

BEIJER,  J.  & JERNELOV,  A. (1979) Methylation  of mercury in  aquatic
environments. In: Nriagu, J.O., ed. The biogeochemistry of  mercury  in
the   environment,  Amsterdam,  Oxford,  New   York,  Elsevier  Science
Publishers, pp. 203-210.

BERLIN,  M. (1976) Dose-response  relations and diagnostic  indices  of
mercury  concentrations in critical organs upon exposure to mercury and
mercurials.   In:  Nordberg,  G.F.,   ed.  Effects  and   dose-response
relationships  of toxic metals,  Amsterdam, Oxford, New  York, Elsevier
Science Publishers, pp. 235-245.

BERLIN,  M. (1986) Mercury. In:  Friberg, L., Nordberg, G.F.,  & Voulk,
V.,  ed. Handbook  on the  toxicology of  metals, 2nd  ed.,  Amsterdam,
Oxford, New York, Elsevier Science Publishers, pp. 387-445.

BERLIN,   M.,   BLOMSTRAND,  C.,   GRANT,   C.A.,  HAMBERGER,   A.,   &
TROFAST,  J.  (1975) Tritiated methylmercury  in the brain of  squirrel
monkeys. Arch.  environ. Health, 30: 591-597.

BERNAUDIN,   J.F.,  DRUET,   E.,  DRUET,   P.,  &   MASSE,  R.   (1981)
Inhalation  or ingestion of  organic or inorganic  mercurials  produces
auto-immune   disease in rats.  Clin. Immunol. Immunopathol.,  20: 129-

BERNHARD,  M.  &  ANDREAE, M.O.  (1984)  Transport  of trace  metals in
marine  food chains. In:  Nriagu, J.O., ed.  Changing metal cycles  and
human health, Berlin, Heidelberg, New York, Springer-Verlag,  pp.  143-

BERNHARD,   M.,   BUFFONI,  R.,   &  RENZONI,  A.   (1982)  Mercury  in
Mediterranean  tuna. Why is their  level higher than in  Atlantic tuna?
Thalassia (Yugosl.), 18: 231-243.

BIENVENUE,    E.,   BOUDOU,   A.,    DASMAZES,   J.P.,   GAVACH,    C.,
Transport  of  mercury  compounds across  biomolecular lipid membranes:
effect of lipid composition, pH and chloride concentration. Chem.-biol.
Interact., 48:  91-101.

BJORNBERG,  A.A.,  HAKANSON,  L., &  LUNDBERGH,  K.,  (1988)  A  theory
on  the mechanisms regulating the bioavailability of mercury in natural
water.  Environ. Pollut., 49: 53-61.

BLAKLEY,  B.R. (1984) Enhancement of  urethan-induced adenoma formation
in Swiss mice exposed to methylmercury. Can. J. comp. Med., 48(3): 299-

BORNHAUSEN,  M., MUSCH,  H.R., &  GREIM, H.  (1980)  Operant  behaviour
performance  changes  in  rats after  prenatal methyl-mercury exposure.
Toxicol. appl. Pharmacol., 56: 305-310.

BROWN,  D.,  RUEHL,  K., BORMANN,  S.,  LITTLE,  J. (1988).  Effects of
methylmercury  on the microtubule system of mouse lymphocytes. Toxicol.
appl. Pharmacol., 94: 66-75.

BRZEZNICKA,   E.A.   &   CHMIELNICKA,   J.   (1985a)   Interaction   of
alkylmercury  compounds  with sodium  selenite. III. Biotransformation,
levels  of metallothioneinlike proteins  and endogenous copper  in some
tissues  of rats exposed to  methyl or ethylmercuric chloride  with and
without sodium selenite. Environ. Health Perspect., 60: 423-431.

BRZEZNICKA,   E.A.   &   CHMIELNICKA,   J.   (1985b)   Interaction   of
alkylmercuric  compounds  with  sodium  selenite.  II.  Metabolism   of
methylmercuric  chloride  administered  alone and  in  combination with
sodium selenite in rats. Environ. Health Perspect., 60: 411-421.

BUCHET,  J.P.,  ROLES,  H.,  HUBERMONT,  G.,  &  LAUWERYS,  R.   (1978)
Placental  transfer of lead, mercury,  cadmium, and carbon monoxide  in
women.   Environ. Res., 15: 494-503.

(1983)  Oral  daily  intake  of  cadmium,  lead,  manganese,  chromium,
mercury,  calcium,  zinc,  and arsenic  in Blegium.  A  duplicate  meal
study. Food chem.  Toxicol., 21: 19-24.

BURBACHER,   T.M.,   MONNETT,  C.,   GRANT,   K.S.,  &   MOTTET,   N.K.
(1984)   Methylmercury  exposure  and reproductive  dysfunction  in the
nonhuman primate. Toxicol. appl. Pharmacol., 75(1): 18-24.

BURTON,  G.V. &  MEIKLE, A.W.  (1980) Acute  and chronic  methylmercury
poisoning  impairs  rat adrenal  and  testicular function.  J. Toxicol.
environ. Health, 6: 597-606.

BYRNE,   A.R.  &  KOSTA,  L.  (1974)  Simultaneous  neutron  activation
determination   of  selenium  and  mercury  in  biological  samples  by
volatilization. Talanta, 21: 1083-1090.

CANADA-ONTARIO    STEERING    COMMITTEE   (1983)    Mercury   pollution
in  the  Wabigon-English  river  system  of  Northwestern  Ontario, and
possible  remedial measures. Summary  of a technical  report,  Toronto,
Canada-Ontario   Steering   Committee,   Provincial  Ministry   of  the

CAPELLI,  R., MINGANTI,  V., SEMINO,  G., &  BERTARINI, W.  (1986)  The
presence  of  mercury  (total  and  organic)  and  selenium  in   human
placentae. Sci. total Environ., 48(1/2): 69-79.

CAPPON, C.J. (1981) Mercury and selenium content and chemical  form  in
vegetable  crops grown on  sludge-amended soil. Arch.  environ. Contam.
Toxicol., 10: 673-689.

CAPPON,  C.J. (1987) Uptake and  speciation of mercury and  selenium in
vegetable  crops grown on compost-treated soil. Water Air Soil Pollut.,
3: 353-361.

CAPPON,  C.J. & SMITH, J.C. (1978) A simple and rapid procedure for the
gas   chromatographic  determination  of  methylmercury  in  biological
samples. Bull. environ. Contam. Toxicol., 19: 600-607.

CARMICHAEL,   N.,   CAVANAGH,  J.B.,   &   RODDA,  R.A.   (1975)   Some
effects  of methylmercury  salts on  the rabbit  nervous  system.  Acta
neuropathol., 32: 112-125.

CHANG, L.W. (1977) Neurotoxic effects of mercury - a  review.  Environ.
Res., 14: 329-373.

CHANG,  L.W.  &  SUBER, R.  (1982)  Protective  effect of  selenium  on
methylmercury  toxicity: a possible  mechanism. Bull. environ.  Contam.
Toxicol., 29: 285-289.

CHANG,  L.W.,  GILBERT,  M., &  SPRECHLER,  J.  (1978) Modification  of
methylmercury neurotoxicity by vitamin E. Environ. Res., 17: 356-366.

CHEN,  W.J.,  BODY,  R.L.,  &  MOTTET,  N.K.  (1979)  Some  effects  of
continuous  low-dose  congenital  exposure to  methylmercury  on  organ
growth in the rat fetus. Teratology, 20: 31-36.

CHEN,  W.J.,  BODY,  R.L.,  &  MOTTET,  N.K.  (1983)  Biochemical   and
morphological  studies of monkeys chronically exposed to methylmercury.
J. Toxicol. environ. Health, 12: 407-416.

CHERIAN,  M.G.,  HURSH,  J.B.,  CLARKSON,  T.W.,  &  ALLEN,  J.  (1978)
Radioactive  mercury distribution in biological fluids and excretion in
human  subjects  after  inhalation  of  mercury  vapor.  Arch. environ.
Health, 33: 109-114.

CHEUNG,   M.K.  &  VERITY,   M.A.  (1985)  Experimental   methylmercury
neurotoxicity: locus of mercurial inhibition of brain protein synthesis
in vivo and in vitro. J. Neurochem., 44(6): 1799-1808.

(1985)  The effect of methylmercury on prenatal development  and  trace
metal distribution in pregnant and fetal rats.  Biol. Trace Elem. Res.,
8:  191-201.

CHOI, B.H. & LAPHAM, L.W. (1976) Interactions of neurons and astrocytes
during  growth and development of human fetal brain in vitro. Exp. Mol.
Pathol., 24: 110-125.

CHOI,   B.H.   &   LAPHAM,   L.W.   (1980)   Effects    of    meso-2-3,
dimercaptosuccinic acid on methylmercury injured human fetal astrocytes
in vitro: a lapse cinematographic phase and electron microscopic study.
Fed. Proc., 39: 396.

CHOI, B.H. & KIM, R.C. (1984) The comparative effects of methylmercuric
chloride  and  mercuric  chloride upon  DNA  synthesis  in mouse  fetal
astrocytes in vitro. Exp. Mol. Pathol., 41(3): 371-376.

CHOI,   B.H.,   LAPHAM,  L.W.,  AMIN-ZAKI,  L.,  &  SALEEM,  T.  (1978)
Abnormal  neuronal  migration, deranged  cerebral cortical organization
and  diffuse white matter  astrocytosis of human  fetal brain. A  major
effect  of   methylmercury poisoning  in  utero. J.  Neuropathol.  exp.
Neurol., 37:  719-733.

CHOI, B.H., CHO, K.H. & LAPHAM, L.W. (1979) Effects of methylmercury on
human  fetal brain cells in culture: a time lapse cinematographic phase
and electron microscopic study. J. Neuropathol. exp. Neurol., 33: 307.

CHOI, B.H., CHO, K.H., & LAPHAM, L.W. (1980) Effects  of  methylmercury
on DNA synthesis of human fetal astrocytes: a  radioautographic  study.
Brain Res., 202: 238-242.

CHOI,  B.H., KUDO,  M., &  LAPHAM, L.W.  (1981) A  golgi and  electron-
microscopic  study  of  cerebellum in  methylmercury  poisoned neonatal
mice. Acta neuropathol., 54: 233-237.

CHOI, B.H., KIM, R.C., & PECKHAM, N.H. (1988)  Hydrocephalus  following
prenatal methylmercury poisoning. Acta neuropathol. 75: 325-330.

CLARKSON,   T.W.  (1983)  Methylmercury  toxicity  in  the  mature  and
developing  nervous  system: possible  mechanism.  In: Sarker,  B.  ed.
Biological  aspects of  metals and  metal related  diseases, New  York,
Raven Press, pp. 183-192.

CLARKSON,   T.W.,   FRIBERG,   L.,   HURSH,   J.B.,   &   NYLANDER,  M.
(1988)   The prediction of intake  of mercury vapor from  amalgams. In:
Clarkson,  T.W.,  Friberg,  L., Nordberg,  G.F.,  &  Sager,  P.R.,  ed.
Biological  monitoring of toxic metals, New York, London, Plenum Press,
pp. 247-264.

CONCAS,   A.,  CORDA,  M.G.,  SALIS,   M.,  MULAS,  M.L.,  MILIA,   A.,
CORONGIU,  F.P.,  & BIGGIO,  G. (1983) Biochemical  changes in the  rat
cerebellar  cortex  elicited  by chronic  treatment with methylmercury.
Toxicol.  Lett., 18: 27-33.

S.,  & MYERS, G.G. (1989). Dose-response analysis of infants prenatally
exposed  to methylmercury. An application of a single compartment model
to single-strand hair analysis. Environ. Res., 49: 318-332.

COYLE,  P. & HARTLEY, T.  (1981) Automated determination of  mercury in
urine and blood by the Magos reagent and cold vapor  atomic  absorption
spectrometry. Anal. Chem., 53: 354-356.

RACAGNI, G. (1984) Behavioural and neurochemical changes  in  offspring
of rats exposed to methylmercury during gestation. Neurobehav. Toxicol.
Teratol., 6(3): 249-254.

CURLE, D.C., RAY, M., & PERSAUD, T.V.N. (1983)  Methymercury  toxicity:
in vivo evaluation of teratogenesis and cytogenic changes.  Anat.  Anz.
(Jena), 153: 69-82.

DAVIES,   T.W.   &  NIELSEN,   S.W.   (1977)  Pathology   of   subacute
methylmercurialism in cats. Am. J. Vet. Med., 38: 59-67.

DAVIES, T.W., NIELSEN, S.W., & KIRCHNER, C.H. (1976) The  pathology  of
subacute methylmercurialism in swine. Cornell Vet., 66: 32-55.

DAVIES,  T.W.,  NIELSEN,  S.W., &  JORTNER,  B.S.  (1977) Pathology  of
chronic  and  subacute canine  methylmercurialism.  J. Am.  Anim. Hosp.
Assoc., 13: 369-381.

DE  SAINT-GEORGES,  I.,  VERSHAEVE,  L.,  &  LEONARD,  A.  (1984)   The
inhibitory  effect of methylmercury  chloride and mercuric  chloride on
microtubule polymerization in vitro. C.R. Sances Soc.  Biol.  (Paris),
178: 562-566.

P.L.,  & ZWIERS, J.H.L. (1974)  Mercury and other elements  in blood of
the  Dutch population. In: Proceedings of an International Symposium on
Recent  Advances in the Assessment of the Health Effects of Environmen-
tal  Pollution,  Paris,  24-28  June,  Luxembourg,  Commission  of  the
European Communities, Vol. 2, pp. 1017-1027.

DOHERTY,  R.A.,  GATES,  A.H.,  &  LANDRY,  T.   (1977)   Methylmercury
excretion: developmental changes in mouse and man. Pediatr.  Res.,  11:

DOI,  R. & KOBAYASHI, T. (1982) Organ distribution and biological half-
time of methylmercury in four strains of mice. Jpn. J. exp.  Med.,  52:

DOI,  R.  & TAGAWA,  M. (1983) A  study on the  biochemical behavior of
methylmercury. Toxicol. appl. Pharmacol., 69: 407-416.

ECCLES,  C.U.  & ANNAU,  Z.  (1982a) Prenatal  methylmercury  exposure:
alterations in neonatal activity. Neurobehav. Toxicol., 4: 371-376.

ECCLES, C.U. & ANNAU, Z. (1982b) Prenatal methylmercury  exposure.  II.
Alterations  in  learning and  psychotropic  drug sensitivity  in adult
offspring. Neurobehav. Toxicol. Teratol., 4: 377-382.

ELSNER,   J.,   HODEL,  B.,  SUTER,  K.E.,  OEKLKE,  D.,  ULBRICH,  B.,
KARLSSON,  J.E., & HAGLID,  K.G. (1988) Detection  limits of  different
approaches  in behavioral teratology,  and correlation of  effects with
neurochemical parameters. Neurotoxicol. Teratol., 10: 155-167.

EVANS, H.L., GARMAN, R.H., & WEISS, B. (1977)  Methylmercury:  exposure
duration  and regional distribution as determinants of neurotoxicity in
non-human primates. Toxicol. appl. Pharmacol., 41: 15-33.

(1987).   In vivo incorporation of 14C   leucine into brain protein  of
mice treated with methylmercury and thiol complexes  of  methylmercury.
Toxicol. Lett., 36: 213-220.

F.A.  (1974) Acute methylmercury intoxication and ototoxicity in guinea
pigs.  Arch. Pathol., 97: 297-305.

FANG, S.C. (1980) Comparative study of uptake and  tissue  distribution
of  methylmercury  in  female rats  by  inhalation  and oral  routes of
administration. Bull. environ. Contam. Toxicol., 24: 65-72.

FARANT,   J.P.,   BRISSETTE,   D.,   MONCION,   L.,   BIGRAS,   L.,   &
CHARTRAND,  A.  (1981) Improved cold-vapor  atomic absorption technique
for the microdetermination of total and inorganic mercury in biological
samples. J. anal. Toxicol., 5: 47-51.

FORHAMMER,   M.,   ALBANUS,   L.,   BRUCE,   A.,   MATTSON,    P.,    &
OHLIN,  B.  (1984)  Fish  consumption and mercury  in hair in  pregnant
women. Var Fda, 36:  2-13.

FOUASSIN,  A.  & FONDU,  M. (1978) Evaluation  de la teneur  moyenne en
mercure  de la ration  alimentaire en Belgique.  Arch. Belg. Med.  Soc.
Hyg. Med Trav. Med Leg., 36: 481-490.

FRIBERG,   L.  (1983)  Quality  control  in  laboratories  testing  for
environmental pollution. In: Clarkson, T.W., Nordberg, G.F.,  &  Sager,
P.R.,  ed. Reproductive and developmental toxicity of metals, New York,
London, Plenum Press, pp. 811-829.

FRIBERG,  L. (1988) Quality assurance. In: Clarkson, T.W., Friberg, L.,
Nordberg,  G.F., &  Sager, P.R.,  eds. Biological  monitoring of  toxic
metals, New York, London, Plenum Press, pp. 103-126.

FRIBERG,   L.,  KULLMAN,   L.,  LIND,   B.,  &   NYLANDER,  M.   (1986)
Mercury  in the central nervous system in relation to amalgam fillings.
Lakartidningen, 83: 519-522.

FUJIKI, M. & TAJUMA, S. (1975) Studies on the  methylmercury  formation
in the environment. In: Studies on the health effects  of  alkylmercury
in Japan, Tokyo, Environment Agency, pp. 11-19.

FURUTANI,  A. & RUDD, J.W. (1980) Measurement of mercury methylation in
lake  water and sediment samples.  Appl. environ. Microbiol., 40:  770-

GALSTER,  W.A. (1976) Mercury  in Alaskan Eskimo  mothers and  infants.
Environ. Health Perspect., 15: 135-140.

GANSER,  A.L. & KIRSCHNER,  D.A. (1985) The  interaction of  mercurials
with   myelin:   comparison   of  in   vitro  and   in  vivo   effects.
Neurotoxicology, 6(1): 63-77.

GANTHER,  H.E.  (1978)  Modification  of  methylmercury  toxicity   and
metabolism  by selenium and  vitamin E: possible  mechanisms.  Environ.
Health Perspect., 25: 71-76.

GANTHER,  H.E. (1979) Metabolism  of hydrogen selenide  and  methylated
selenide. Adv. Nutr. Rev., 2: 107-128.

GANTHER,    H.E.,   GOUDIE,   C.,   SUNDE,    M.L.,   KOPECKY,    M.J.,
WAGNER,  P., OH, S.H.,  & HOEKSTRA, W.G.  (1972) Selenium: relation  to
decreased  toxicity of methylmercury  added to diets  containing  tuna.
Science, 175:  1122-1124.

E.L.   (1985a)  Pesticides, selected  elements  and other  chemicals in
adult total diet samples: October 1978-September 1979. J.  Chem. Assoc.
Off.  Anal. Chem., 68: 862-875.

E.L.   (1985b)  Pesticides, selected  elements  and other  chemicals in
adult  total diet samples: October 1979-September 1980. J. Chem. Assoc.
Off.  Anal. Chem., 68: 1184-1197.

E.L. (1986)  Pesticides, selected elements and other chemicals in adult
total diet samples: October 1980-March 1982. J. Chem. Assoc. Off. Anal.
Chem., 68:  146-161.

GATES,  A.H., DOHERTY, R.A., &  COX, C. (1986) Reproduction  and growth
following  prenatal methylmercuric chloride  exposure in mice.  Fundam.
appl. Toxicol., 7: 486-493.

GESAMP  (1986)  Review  of  potentially  harmful  substances:  arsenic,
mercury     and    selenium,    Geneva.    IMO/FAO/UNESCO/WMO/WHO/IAEA/
UN/UNEP  Joint  Group of  Experts on the  Scientific Aspects of  Marine
Pollution, World Health Organization (Reports and Studies No. 28).

GILBERT,  M.M.,  SPRECHER,  J., CHANG,  L.W.,  &  MEISNER, L.F.  (1983)
Protective  effect of vitamin  E on genotoxicity  of methylmercury.  J.
Toxicol. environ. Health, 12: 767-773.

GIOVANOLI-JAKUBCZAK,    T.   &   BERG,   G.   (1974)   Measurement   of
mercury in human hair. Arch. Environ. Health, 28: 139-144.

GONZALEZ,  M.J.,  RICO,  M.C., HERNANDEZ,  L.M.,  &  BALUJA, G.  (1985)
Mercury  in human hair:  a study of  residents in Madrid,  Spain. Arch.
environ. Health, 40: 225-228.

GOWDY,   J.M.,  YATES,  R.,  &   DEMERS,  F.X.  (1977)  Blood   mercury
concentration in an urban population. Sci. total Environ., 8: 247-251.

GREENWOOD,   M.R.   (1985)   Methylmercury  poisoning   in   Iraq.   An
epidemiological  study  of the  1971-72   outbreak. J.  appl. Toxicol.,
5(3): 148-159.

AMIN-ZAKI,  L., ELHASSANI, S.,  & MAJEED, M.A.  (1978) Blood  clearance
half-times  in  lactating  and  nonlactating  members  of  a population
exposed to methylmercury. Environ. Res., 16: 48-54.

GREGUS,  Z.  &  VARGA,  F.  (1985)  Role  of  glutathione  and  hepatic
glutathione  S-transferase in the  biliary excretion of  methylmercury,
cadmium,  and  zinc:  a study  with  enzyme  inducers  and  glutathione
depletors. Acta pharmacol. toxicol., 56: 398-403.

GRUENWEDEL,   D.W.   &  DIAHAM,   B.  (1982)  Methylmercury(II)-induced
histone  perturbations  in  nuclei  isolated  from  calf  thymus.  Mol.
Pharmacol., 22:  121-126.

GRUNDT,   I.K.   &   NESKOVIC,  N.M.   (1985)  UDP-Galactose:  ceramide
galactosyltransferase and  2',3'-cyclic-nucleotide-3'-phosphodiesterase
activities  in rat brain after  long-term exposure to methylmercury  or
triethyl-lead. Exp. Neurol., 88(3): 580-589.

GRUNDT,  I.K. &  BAKKEN, A.M.  (1986) Adenine  nucleotides in  cultured
brain  cells after exposure  to methylmercury and  triethyl lead.  Acta
pharmacol. toxicol., 59: 11-16.

GRUNDT,  I.K.,  AMMITZBOLL,  T.,  &  CLAUSEN,  J.  (1981) Triethyl-lead
treatments  of  cultured  brain  cells.  Effect  on   accumulation   of
radioactive precursors in callactolipids. Neurochem. Res., 6: 193-201.

FOURNIER,  E.  (1982)  Effects  of  methylmercury  and  triethyllead on
Na+K+ATPase  and   Pyruvate   dehydrogenase  activities  in  glioma  C6
cells. Acta pharmacol. toxicol., 51: 6-11.

&  MOTTET, N.K. (1986) The  effect of low-level prenatal  methylmercury
exposure on visual recognition memory of infant  carb-eating  macaques.
Child Dev., 57: 1076-1083.

HANSEN,   J.C.,   KROMANN,  N.,   WULF,  H.C.,  &   ALBOGE,  K.  (1984)
Selenium  and its interrelation with mercury in whole blood and hair in
an east Greenlandic population. Sci. total Environ., 38: 33-40.

HARADA,   M.,  FUJINO,   T.,  AKAGI,   T.,  &   NISHIGAKI,  S.   (1976)
Epidemiological and clinical study and historical background of mercury
pollution  on Indian reservations in northwestern Ontario. Canada Bull.
Inst. Const. Med., 26: 169-184.

HARADA,   M.,  FUJINO,  T.,   &  KABASHIMA,  K.   (1977)  A  study   of
methylmercury concentration in the umbilical cords of  the  inhabitants
born in the Minamata area. Brain Dev., 9: 79-84 (In Japanese).

HARADA,  Y. (1968)  Congenital (or  fetal) Minamata  Bay  disease.  In:
Minamata disease, Kumamoto, Study Group of Minamata  Disease,  Kumamoto

HARADA,  Y. & MORIYAMA, H. (1977) [Study on the motor ability of school
children in the Minamata district.] Environ. Health Rep., 40: 97-99 (in

HARGREAVES,     R.J.,    MOORHOUSE,    S.R.,    GANGOLI,     S.D.,    &
PELLING, D.  (1986)  The effects of methylmercury on glucose transport,
glucose  metabolism and blood flow in the central nervous system of the
rat. In:  Suckling, A.J., Rumsbury, M.G., & Bradbury, M.W.B.,  ed.  The
blood-brain barrier in health and disease, Chichester,  Ellis  Horwood,
pp. 165-176.

HARPER, K., BURNS, R., & ERICKSON, R.P. (1981) Genetic aspects  of  the
effects  of methylmercury in  mice: the incidence  of cleft palate  and
concentrations  of adenosine 3':5'  cyclic monophosphate in  tongue and
palatal shelf. Teratology, 23: 397-401.

HATCH,  R.W.  &  OTT,  W.L.  (1969)  Determination   of   sub-microgram
quantities  of  mercury  by atomic  absorption spectrophotometry. Anal.
Chem., 40: 2085-2087.

EVANS,  W.H.,  REID,  J.R.,  HEWITT,  C.J.,  &  JEFFRIES,  D.F.  (1979)
Duplicate  diet study  on fishing  communities in  the United  Kingdom:
mercury exposure in a "critical group". Environ. Res., 18: 351-368.

& ZABIK, M.J. (1972) Chronic methylmercury toxicosis in calves.  J. Am.
Vet.  Med. Assoc., 160: 173-182.

HIRANO,  M.,  MITSUMORI, K.,  MAITA, K., &  SHIRASU, Y. (1986)  Further
carcinogenicity  study on methylmercury  chloride in ICR  mice.  Nippon
Juigaku Zasshi, 48: 127-135.

HIRAYAMA,   K.  (1980)  Effect  of  amino  acids  on  brain  uptake  of
methylmercury. Toxicol. appl. Pharmacol., 55: 318-323.

HIRAYAMA,  K.  (1985)  Effects  of  combined  administration  of  thiol
compounds and methylmercury chloride on mercury distribution  in  rats.
Biochem. Pharmacol., 34: 3030-3032.

HIRAYAMA,  K.  &  YASUTAKE,  A.  (1986)  Sex  and  age  differences  in
mercury  distribution and excretion in methylmercury-administered mice.
J.  Toxicol. environ. Health, 18: 49-60.

HIROTA,   Y.,   YAMAGUCHI,  S.,   SHIMOJOH,  N.,  &   SANO,  K.  (1980)
Inhibitory  effect  of methylmercury  on  the activity  of  glutathione
peroxidase.  Toxicol. appl. Pharmacol., 53: 174-176.

HISLOP,   J.S.,  COLLIER,  T.R.,   WHITE,  G.F.,  KHATHING,   D.T.,   &
FRENCH,  E.   (1983)  The use  of  keratinised  tissues to  monitor the
detailed exposure of man to methyl mercury from fish. In: Brown, S.S. &
Savory,  J., ed.  Chemical toxicology and clinical chemistry of metals,
New York, Academic Press, pp. 145-148.

HORVAT,  K.,  MAY, M.,  STOEPPLER, A., &  BYRNE, R. (1988)  Comparative
studies  of methylmercury determination in biological and environmental
samples. Appl. organomet. Chem., 2: 515-524.

HORVAT,    M.,    STEGNAR,   A.,    BYRNE,    R.,   DERMELJ,    M.,   &
BRANICA, A.  (1988)  A study of trace elements in human placenta, blood
and  hair  from  the Yugoslav  central  Adriatic.  In: Braetter,  P.  &
Schramel,  P., ed.  Trace elements-analytical chemistry in medicine and
biology, Berlin, W.  de Gruyter & Co., pp. 243-250.

HOSKINS,  B.B.  &  HUPP, E.W.  (1978)  Methylmercury  effects  in  rat,
hamster, and squirrel monkey. Environ. Res., 15: 5-19.

HOWARD,  J.D.  & MOTTET,  N.K. (1986) Effects  of methylmercury on  the
morphogenesis of the rat cerebellum. Teratology, 34: 89-95.

HSIEH,  H.S. & GANTHER,  H.E. (1975) Acid-volatile  selenium  formation
catalyzed by glutathione reductase. Biochemistry 14(8): 1632-1636.

HULTBERG,  H. &  HASSELROT, B.  (1981) Mercury  in the  ecosystem.  In:
Project  coal, health and  environment, Vallingby, Swedish  State Power
Board, pp. 33-51.

HUNTER, D. & RUSSELL, D.S. (1954) Focal cerebral and cerebellar atrophy
in  a  human  subject due  to  organic  mercury compounds.  J.  Neurol.
Neurosurg. Psychiatr., 17: 235-241.

IMURA,   N.,   MIURA,   K.,   INOKAWA,   M.,   &   NAKADA,  S.   (1980)
Mechanism   of    methylmercury   cytotoxicity:  by   biochemical   and
morphological   experiments using cultured cells.  Toxicology, 17: 241-

INOUYE,   M.,   KAJIWARA,   Y.,  &   HIRAYAMA,  K.   (1986)  Dose   and
sex-dependent  alterations  in  mercury  distribution  in  fetal   mice
following methylmercury exposure. J. Toxicol. environ. Health, 19: 425-

INSKIP,  M.J. & PIOTROWSKI, J.K. (1985) Review of the health effects of
methylmercury. J. appl. Toxicol., 5: 113-133.

IRPTC (1987) IRPTC Legal file 1986, Geneva, International  Register  of
Potentially Toxic Chemicals, United Nations Environment Programme, Vol.

IWATA,  H., OKAMOTO,  H., &  OHSAWA, Y.  (1973) Effect  of selenium  on
methylmercury  poisoning.  Res.  Commun. chem.  Pathol.  Pharmacol., 5:

JACOBS,   A.J.,   MANISCALCO,   W.M.,  &   FINKELSTEIN,   J.N.   (1986)
Effects of methylmercuric chloride, cyclohexamide and colchicine on the
reaggregation  of  dissociated  mouse cerebellar  cells. Toxicol. appl.
Pharmacol., 86: 362-371.

JACOBS,    J.M.,    CARMICHAEL,    N.,   &    CAVANAGH,   J.B.   (1977)
Ultrastructural  changes in the nervous system of rabbits poisoned with
methylmercury.  Toxicol. appl. Pharmacol., 39: 249-261.

M.R.  (1978)  X-ray fluorescence analysis applied to small samples. In:
Barrett,  C.S., Leyden, D.E., Newkirk, J.B., & Rudd, C.O., ed. Advances
in  X-ray analysis, New York, London, Plenum Press, Vol. 21,  pp.  171-

JERNELOV,  A. (1972) Mercury and food chains. In: Hartung, R. & Binman,
B.D., ed. Environmental mercury contamination, Ann Arbor, Michigan, Ann
Arbor Science Publishers, pp. 174-177.

JOHANNESSON,  T., LUND,  G., &  STEINNES, E.  (1981) Mercury,  arsenic,
cadmium, selenium and zinc in human hair and salmon fries  in  Iceland.
Acta pharmacol. toxicol., 48: 185-189.

JOHNSON, D.C. & BRAMAN, R.S. (1974) Distribution of atmospheric mercury
species near ground. Environ. Sci. Technol., 8: 1003-1009.

JUNGHANS,  R.P.  (1983)  A review  of  the  toxicity  of  methylmercury
compounds  with application to  occupational exposures associated  with
laboratory uses. Environ. Res. 31: 1-31.

KASUYA,  M.  (1980) The  effect of methylcobalamin  on the toxicity  of
methylmercury  and  mercuric chloride  on  nervous tissue  in  culture.
Toxicol. Lett., 7: 87-93.

(1981)   Electrooculographic  evaluation of  methylmercury intoxication
 in monkeys. Exp. Neurol., 72: 51-62.

KAWADA,   J.,  NISHIDA,  M.,  YOSHIMURA,   Y.,  &  MITANI,  K.   (1980)
Effects  of organic and inorganic mercurials on thyroidal functions. J.
Pharm.  Dyn., 3: 149-159.

KAWASAKI,   Y.,  IKEDA,   Y.,  YAMAMOTO,   T.,  &   IKEDA,  K.   (1986)
Long-term  toxicity study of methylmercury chloride in monkeys. J. Food
Hyg. Soc.  Jpn, 27(5): 528-552.

Y.,    MAJID,   M.A.,   MAHMOUD,   R.M.,   SOUFI,   M.,   TAWFIQ,   K.,
IBRAHIM,  M.A.,  & DABAGH,  H.  (1976a) Epidemiology  of  organomercury
poisoning  in Iraq: II.   Relationship of mercury  levels in blood  and
hair to exposure and to clinical findings. Bull. World  Health  Organ.,
53(Suppl.): 37-48.

MAHMOUD,  R.M. (1976b) Epidemiology of organomercury poisoning in Iraq:
III.  Clinical features and their changes with time. Bull. World Health
Organ., 53(Suppl.): 49-60.

KELMAN, B.J., WALTER, B.K., & SASSER, L.B. (1982) Fetal distribution of
mercury  following introduction of methylmercury  into porcine maternal
circulation. J. Toxicol. environ. Health, 10: 191-200.

KELMAN,  B.J., STEINMETZ  ,S.E., WALTER,  B.K., &  SASSER, L.B.  (1980)
Absorption  of methylmercury by the fetal guinea pig during mid to late
gestation. Teratology, 21: 161-165.

KERSHAW,   T.G.,   CLARKSON,   T.W.,   &   DHAHIR,   P.H.   (1980)  The
relationship  between blood levels  and dose of  methylmercury in  man.
Arch. environ.  Health, 35(1): 28-36.

KHM  (1981) Summary  situation report.  In: Project  coal,  health  and
environment, Valingby, Swedish State Power Board.

KJELLSTROM,   T.,  REEVES,  R.,   &  MITCHELL,  J.   (1982)  Comparison
of  mercury in hair  with fish-eating habits  of children in  Auckland.
Commun.  Health Stud. (Adelaide), 6: 57-63.

KJELLSTROM,   T.,   KENNEDY,  P.,   WALLIS,   &  MANTELL,   C.   (1986)
Physical and mental development of children with prenatal  exposure  to
mercury from fish. Stage 1. Preliminary tests at age 4, Solna, National
Swedish Environmental Board, 96 pp (Report No. 3080).

KJELLSTROM,    T.,    KENNEDY,    P.,   WALLIS,    S.,   STEWART,   A.,
FRIBERG,  L.,  LIND,  B.,  WUTHERSPOON,  P.,  &  MANTELL,  C.    (1989)
Physical and      mental development of children with prenatal exposure
to mercury from fish.  Stage 2. Interviews and psychological  tests  at
age  6, Solna, National Swedish Environmental Board, 112 pp (Report no.

KOBAYASHI,   H.,   YUYAMA,   A.,   MATSUSAKA,   N.,   TAKENO,   K.,   &
YANAGIVA,  I.   (1979) Effects  of  methylmercury chloride  on  various
cholinergic parameters in vitro. J. toxicol Sci., 4: 351-362.

KOBAYASHI,   H.,   YUYAMA,   A.,   MATSUSUAKA,   N.,   TAKENO,   K.,  &
YANAGIVA,  I.  (1981) Neuropharmacological  effect of methylmercury  in
mice  with special reference to the central cholinergic system. Jpn. J.
Pharmacol., 31: 711-718.

KOLLER,  L.D.  &  ROAN,  J.G.  (1980)  Effects  of  lead,  cadmium  and
methylmercury on immunological memory. J. environ. Pathol. Toxicol., 4:

KOLLER,  L.D.,  ROAN,  J.G.,  &  BRAUNER,  J.A.  (1980)  Methylmercury:
Effects of B-lymphocyte receptors and phagocytosis of  macrophages.  J.
environ.  Pathol. Toxicol., 3: 407-411.

KOMSTA-SZUMSKA,  E.  & MILLER,  D.R. (1984) A  kinetic analysis of  the
interaction  between methylmercury and  selenium. Toxicology, 33:  247-

KOSTA,  L.  &  BYRNE, R.  (1969)  Activation  analysis for  mercury  in
biological samples at nanogram level. Talanta, 16: 1297-1302.

KUHNERT,  P.M.,  KUHNERT,  B.R., &  ERHARD,  P.  (1981)  Comparison  of
mercury  levels in  maternal blood,  fetal cord  blood,  and  placental
tissues. Am.  J. Obstet. Gynecol., 139: 209-213.

(1985)    Effects   of  the   high  methylmercury  dose   used  in  the
collaborative behavioral teratology study on brain anatomy. Neurobehav.
Toxicol.  Teratol., 7(6): 775-777.

KYLE,  J.H. & GHANI, N. (1982a) Methylmercury in human hair: a study of
a  Papua New Guinean population  exposed to methylmercury through  fish
consumption. Arch. environ. Health, 37: 266-270.

KYLE, J.H. & GHANI, N. (1982b) Elevated mercury levels in  people  from
Lake Murray, Western Province. Papua New Guinea med. J., 25: 81-88.

KYLE,  J.H.  & GHANI,  N. (1983) Mercury  concentrations in canned  and
fresh  fish  and  its accumulation  in  a  population of  Port  Moresby
residents. Sci. total Environ., 26: 157-162.

LAKOWICZ, J.R. & ANDERSON, C.J. (1980) Permeability of  lipid  bilayers
to methylmercuric chloride: quantification by fluorescence quenching of
a carbazole-labelled phospholipid. Chem.-biol. Interact., 30: 309-323.

LAUWERYS,  R.,  BUCHET,  J.P.,  ROELD,  H.,  &  HUBERMONT,  G.   (1978)
Placental  transfer of lead, mercury,  cadmium, and carbon monoxide  in
women.  I.  Comparison of the frequency distributions of the biological
indices in maternal and umbilical cord blood. Environ. Res.,  15:  278-

LEBLANC,  R.M.,  JOLY,  L.P.,  &  PAIEMENT,  J.   (1984)   pH-Dependent
interaction   between   methylmercury   chloride  and   some   membrane
phospholipids. Chem.-biol. Interact., 48: 237-241.

LEE, I.D. & DIXON, R.L. (1975) Effects of mercury  on  spermato-genesis
studied by velocity sedimentation, cell separation and  serial  mating.
J.  Pharmacol. exp. Ther., 194: 171-181.

LEE,  M., CHAN,  K.S., SAIRENJI,  E., &  NIIKUNI, T.  (1979) Effect  of
sodium  selenite on methylmercury-induced  cleft palate in  the  mouse.
Environ.  Res., 19: 39-48.

LEVESQUE,  P.  &  ATCHISON, W.  (1988)  Effect  of alteration  of nerve
terminal  Ca2+ regulation on  increased spontaneous quantal  release of
acetylcholine by methylmercury. Toxicol. appl. Pharmacol., 94: 55-65.

LIE,  A.,  GUNDERSEN,  N.M.,  &  KORSGAARD,  K.J.  (1982)  Mercury   in
urine-sex,  age and geographic  differences in a  reference population.
Scand.  J. environ. Health, 8: 129-133.

OHLIN,  B.   (1988a) Quality  control of analyses  of mercury in  hair.
Fresenius Z. anal. Chem., 332: 630-632.

LIND,  B.,  FRIBERG, L.,  & NYLANDER, M.  (1988b) II. Demethylation  of
mercury in brain. J. Trace Elem. exp. Med., 1: 49-56.

LINDBERG,  S.,  STOKES,  P., GOLDBERG,  E.,  &  WREN, C.  (1987)  Group
report:   Mercury.  In:  Hutchinson, T.W.  &  Meema,  K.M.,  ed.  Lead,
mercury, cadmium  and arsenic in the environment, New York, Chichester,
Brisbane, Toronto, John Wiley & Sons, pp. 17-34.

LINDQVIST,  O.,  JERNELOV,  A.,  JOHANSSON,  K.,  &  RODHE,  R.  (1984)
Mercury  in the Swedish environment:  global and local sources,  Solna,
National  Swedish  Environment Protection  Board,  105 pp  (Report  No.

LOGDBERG,  B.,  BRUN, A.,  BERLIN, M., &  SCHUTZ, A. (1988)  Congenital
lead encephalopathy in monkeys. Acta neuropathol., 77: 120-127.

LOK,  E. (1983) The effect of weaning on blood, hair, fecal and urinary
mercury  after chronic ingestion  of methylmercury chloride  by  infant
monkeys. Toxicol. Lett., 15: 147-152.

LOMMEL,  A., KRUSE,  H., &  WASSERMANN, O.  (1985)  Organochloride  and
mercury  in blood  of a  fish-eating population  at the  River Elbe  in
Schleswig-Hostein, FRG. Arch. Toxicol., 8(Suppl.):  264-268.

MACFARLANE,  D.E.  (1981) The  effects  of methylmercury  on platelets.
Mol.  Pharmacol., 19: 470-476.

MCKEOWN-EYSSEN,  G.E.  & RUEDY,  J.  (1983a) Methylmercury  exposure in
northern Quebec. I. Neurological findings in adults. Am. J. Epidemiol.,
118: 461-469.

MCKEOWN-EYSSEN,  G.E. & RUEDY,  J. (1983b) Prevalence  of  neurological
abnormality  in  Cree  Indians  exposed  to  methylmercury  in northern
Quebec.  Clin. invest. Med., 6: 161-169.

MCKEOWN-EYSSEN,  G.E.,  RUEDY, J.,  &  NEIMS, A.  (1983)  Methylmercury
exposure  in northern Quebec.  II. Neurological findings  in  children.
Am.  J. Epidemiol., 118: 470-479.

MCKONE,  C.E., YOUNG,  C.A., BACHE,  C.A., &  LISK, D.J.  (1971)  Rapid
uptake  of mercuric ion by  goldfish. Environ. Sci. Technol.,  5: 1138-

MAGNAVAL,  R. & BATTI, R. (1980) Protective effect of phospho-lipids in
methylmercury  inhibition  of  hydroxybutyrate dehydrogenase.  Toxicol.
Lett., 5: 353-356.

MAGNUSSON,   J.  &   RAMEL,  C.   (1986)  Genetic   variation  in   the
susceptibility  to  mercury and  other  metal compounds  in  Drosophila
melanogaster.  Teratog. Carcinog. Mutagen., 6: 4.

MAGOS, L. (1971) Selective atomic-absorption determination of inorganic
mercury  and methylmercury in undigested  biological samples.  Analyst,
96:  847-853.

MAGOS, L. (1982) Neurotoxicity, anorexia and the preferential choice of
antidote  in  methylmercury  intoxicated  rats.   Neurobehav.  Toxicol.
Teratol., 4: 643-646.

MAGOS,  L. (1987) The absorption, distribution, and excretion of methyl
mercury.  In: Edccles, C.U.  & Annau, Z.,  ed. The toxicity  of methyl-
mercury, Baltimore, John Hopkins University Press, pp. 24-44.

MAGOS,  L. & BUTLER,  W.H. (1972) Cumulative  effects of  methylmercury
dicyandiamide given orally to rats. Food Cosmet. Toxicol. 10: 513-517.

MAGOS,  L. & CLARKSON, T.W.  (1972) Atomic absorption determination  of
total,  inorganic and organic  mercury in blood.  J. Assoc. Off.  Anal.
Chem., 55: 966-971.

MAGOS,  L. & WEBB, M. (1977) The effect of selenium on the brain uptake
of methylmercury. Arch. Toxicol., 38: 201-207.

MAGOS,   L.,   BAKIR,   F.,   CLARKSON,   T.W.,   AL-JAWAD,   A.M.,   &
AL-SOFFI, M.H.  (1976) Tissue levels of mercury in autopsy specimens of
liver and kidney.  Bull. World Health  Organ., 53: 93-96.

MAGOS,  L., WEBB, M., &  HUDSON, A.R. (1979) Complex  formation between
selenium and methylmercury. Chem.-biol. Interact., 28: 201-207.

S., & SNOWDEN, R.T. (1981) Comparative study of the sensitivity of male
and female rats to methylmercury. Arch. Toxicol., 48: 11-20.

MAGOS,  L., CLARKSON, T.W.,  & HUDSON, A.R.  (1984) Differences in  the
effects  of selenite and biological  selenium on the chemical  form and
distribution  of mercury after the simultaneous administration of HgCl2
and selenium to rats. J. Pharmacol. exp. Therap. 228(2): 478-483.

SKIPP,   W.R.  (1985a)  The   comparative  toxicology  of   ethyl-  and
methylmercury.  Arch. Toxicol., 57: 260-267.

MAGOS, L., CIKRT, M., & SNOWDEN, R. (1985b) The dependence  of  biliary
methylmercury   secretion   on   liver  GSH   and   ligandin.  Biochem.
Pharmacol., 34: 301-305.

MAILHES,  J.B. (1983) Methylmercury effects on Syrian hamster metaphase
II oocyte chromosomes. Environ. Mutagen., 5: 679-686.

MARC  (1981) Health effects  of methylmercury, London,  Monitoring  and
Assessment  Research Centre, University of  London, 82 pp (MARC  Report
Number 24).

MARSH,   D.O.,   MYERS,  G.J.,   CLARKSON,   T.W.,  AMIN-ZAKI,   L.,  &
TIKRITI,  S. (1977) Fetal methylmercury poisoning. New data on clinical
and toxicological aspects. Trans. Am. Neurol. Assoc., 102: 69-71.

S., & MAJEED, M.A. (1980) Fetal methylmercury poisoning:  clinical  and
toxicological data on 29 cases. Ann. Neurol., 7: 348-355.

S,  MAJEED, M.A., & DABBAGH, A.R. (1981) Dose-response relationship for
human fetal exposure to methylmercury. Clin. Toxicol., 18: 1311-1318.

& AL-TIKRITI, S. (1987) Fetal methylmercury poisoning.  Arch.  Neurol.,
44:  1017-1022.

MASUKAWA,  T., KITO,  H., HAYASHI,  M., &  IWATA, H.  (1982)  Formation
and  possible role of bis(methylmercuric) selenide in rats treated with
methylmercury and selenite. Biochem. Pharmacol., 31: 75-78.

MATTHEWS, A.D. (1983) Mercury content of commercially important fish of
the  Seychelles, and  hair mercury  levels of  a selected  part of  the
population. Environ. Res., 30: 305-312.

LEVIN,  S.G. (1981) Early effects of methylmercury on the visual evoked
response of the dog. Neurotoxicity, 2: 499-514.

MAY,  K., STOEPPLER, M.,  & REISINGER, K.  (1987) Studies in  the ratio
total  mercury/methylmercury  in  the  aquatic  food  chain.   Toxicol.
environ. Chem., 13: 153-159.

MIETTINEN,  J.K. (1973) Absorption  and elimination of  dietary mercury
(Hg++) and methylmercury in man. In: Miller, M.W. & Clarkson, T.W., ed.
Mercury,  mercurials and mercaptans, Springfield,  Illinois, Charles C.
Thomas, pp. 233-246.

MILLER,    C.T.,    KREWSKI,    D.,    &    TRYPHONAS,    L.     (1985)
Methylmercury-induced  mitochondrial DNA synthesis in  neural tissue of
cats. Fundam.  appl.  Toxicol., 5(2): 251-264.

T. (1980) Accumulation route and chemical form of mercury  in  mushroom
species.  Bull. environ. Contam. Toxicol., 25: 382-388.

Carcinogenicity of methylmercury chloride in ICR mice: preliminary note
on renal carcinogenesis. Cancer Lett., 12: 305-310.

MITSUMORI,  K.,  MAITA, K.,  & SHIRASU, Y.  (1984) Chronic toxicity  of
methylmercury  chloride in rats: pathological study. Jpn. J. vet. Sci.,
46: 549-557.

MIURA, K. & IMURA, N. (1987) Mechanism of  methylmercury  cytotoxicity.
Crit. Rev. in Toxicol., 18(3): 161-188.

MIURA, K., SUZUKI, K., & IMURA, N. (1978) Effects of  methylmercury  on
mitotic mouse glioma cells. Environ. Res., 17: 453-471.

MIURA,  K., INOKAWA, M.,  & IMURA, N.  (1984) Effects of  methylmercury
and some metal ions on microtubule networks in mouse glioma  cells  and
in  vitro tubulin polymerization.  Toxicol. appl. Pharmacol.,  73: 218-

MOHAMED,   M.K.,  EVANS,  T.C.,   MOTTET,  N.K.,  &   BURBACHER,   T.M.
(1986a)  effects  of methylmercury  on  sperm oxygen  consumption. Acta
pharmacol.  toxicol., 58: 219-224.

MOHAMED,   M.K.,   LEE,  W.I.,   MOTTET,   N.K.,  &   BURBACHER,   T.M.
(1986b)   Laser  ligh-scattering  study   of  the  toxic   effects   of
methylmercury on sperm motility. J. Androl., 5(1): 11-15.

MORIMOTO,  K., IIJIMA, S., &  KOIZUMI, A. (1982) Selenite  prevents the
induction  of sister-chromatid exchanges by  methylmercury and mercuric
chloride in human whole-blood cultures. Mut. Res., 102: 183-192.

MOTTET,  N.K., SHAW, C.M.,  & BURBACHER, T.M.  (1987) The  pathological
lesions  of methyl mercury intoxications in monkeys. In: Eccles, C.U. &
Annau,  Z., ed. The toxicity of methyl mercury, Baltimore, John Hopkins
University Press, pp. 73-103.

MULDER,  K.M. &  KOSTYNIAK, P.J.  (1985a) Effects  of L-(alpha)  S,5S)-
alpha-3-chloro-4,5-dihydro-5-isoxazoleacetic  acid on urinary excretion
of methylmercury in the mouse. J. Pharmacol. exp. Ther., 234: 156-160.

MULDER,  K.M. & KOSTYNIAK, P.J.  (1985b) Involvement of glutathione  in
the  enhanced  renal  excretion of  methylmercury  in  CFW Swiss  mice.
Toxicol. appl. Pharmacol., 78: 451-457.

MUNRO,   I.C.,   NERA,  E.A.,   CHARBONNEAU,   S.M.,  JUNKINS,   B.,  &
ZAWIDZKA,  Z. (1980) Chronic toxicity  of methylmercury in the  rat. J.
environ.  Pathol.  Toxicol., 3: 347-447.

MUSHAK,  P. (1987) The  quantitative measurement of  methylmercury. In:
Eccles,  C.U.  &  Annau,  Z.,  ed.  The  Toxicity  of  methyl  mercury,
Baltimore, Johns Hopkins University Press, pp. 1-12.

MYKKANEN,  H., RASANEN,  L., AHOLA,  M., &  KIMPPA, S.  (1986)  Dietary
intakes  of mercury,  lead, cadmium  and arsenic  by Finnish  children.
Hum.  Nutr.  appl. Nutr., 40: 32-39.

NABRZYSKI,  M.  &  GAJEWSKA,  R.  (1984)  Determination   of   mercury,
cadmium, and lead in food. Rocz. PZH, 35(1): 1-11 (in Polish).

NAGANUMA,  A. &  IMURA, N.  (1980) Bis(methylmercuric)  selenide  as  a
reaction  product from methylmercury and selenite in rabbit blood. Res.
Commun. chem. Pathol. Pharmacol., 27: 163-173.

NAGANUMA,  A.  &  IMURA,  N.  (1984)  Species  differences  in  biliary
excretion of methylmercury. Biochem. Pharmcol., 33: 679-682.

NAGANUMA,   A.,   KOYAMA,   Y.,  &   IMURA,  N.   (1980)  Behavior   of
methylmercury in mammalian erythrocytes. Toxicol. appl. Pharmacol., 54:

NAKADA,  S. & IMURA,  N. (1982) Uptake  of methylmercury and  inorganic
mercury  by mouse glioma and mouse neuroblastoma cells. Neurotoxicology
3: 249-258.

NAKADA, S. & IMURA, N. (1983) Susceptibility of lipids  to  mercurials.
J. appl. Toxicol., 3: 131-135.

NAKADA,  S.,  NOMOTO, A.,  & IMURA, N.  (1980) Effect of  methylmercury
and   inorganic  mercury  on  protein  synthesis  in  mammalian  cells.
Ecotoxicol.  environ. Saf., 4: 184-190.

NATIONAL  ACADEMY  OF  SCIENCES (1978)  An  assessment  of  mercury  in
the environment, Washington, DC, National Academy of Sciences, National
Research Council.

Chronic  exposure  of rats  to methyl mercury  in fish protein.  Nature
(Lond.), 237: 40-41.

IMURA, M. (1987) Maternal selenium deficiency enhances  the  fetolethal
toxicity of methylmercury. Toxicol. appl. Pharmacol., 88: 322-328.

NISHIKIDO,  N.,  SATOH, Y.,  NAGANUMA, A., &  IMURA, N. (1988a)  Effect
of maternal selenium deficiency on the teratogenicity of methylmercury.
Toxicol. Lett., 40: 153-157.

IMURA,  A. (1988b) Specific alteration of the form of selenium in fetal
liver  on maternal methylmercury treatment.  Toxicol. appl. Pharmacol.,
92(3):  497-499.

NIXON,  J.E., KOLLER, L.D., & EXON, J.H. (1979) Effect of methylmercury
chloride  on  transplacental  tumors  induced  by  sodium  nitrites and
ethylurea in rats. J. Natl Cancer Inst., 63: 1057-1063.

NOBUNAGA,  T.,  SATOH,  H.,  &  SUZUKI,  T.  (1979) Effects  of  sodium
selenite  on methylmercury embryotoxicity  and teratogenicity in  mice.
Toxicol.  appl. Pharmacol., 47: 79-88.

NORDBERG,  G.F. & STRANGERT, P.  (1976) Estimations of a  dose-response
curve for long-term exposure to methylmercury compounds in human beings
taking  into account variability  of critical organ  concentrations and
biological  half-times.  A  preliminary communication.   In:  Nordberg,
G.F.,  ed. Effects and dose-response  relationships, Amsterdam, Oxford,
New York, Elsevier Science Publishers, pp. 273-282.

NORDBERG,  G.F. &  STRANGERT, P.  (1978) Fundamental  aspects of  dose-
response  relationships  and  their extrapolation  for non-carcinogenic
effects of metals. Environ. Health Perspect., 22: 97-108.

NORDBERG,  G.F. & STRANGERT, P.  (1982) Risk estimation models  derived
from  metabolic and damage parameter  variation in the population.  In:
Vouk,  V.B., Butler, G.C., Hoel, D.G., & Peakall, D.B., ed. Methods for
estimating  risk of  chemical injury:  Human and  non-human  biota  and
ecosystems, Chichester, West Sussex, John Wiley and Sons,  pp.  477-491

NORSETH,  T. &  CLARKSON, T.W.  (1971) Intestinal  transport of  203Hg-
labeled  methyl mercury chloride.  Role of biotransformation  in  rats.
Arch.  environ. Health, 22: 668-577.

NRIAGU,  J.O. (1979) The biogeochemistry of mercury in the environment,
Amsterdam, Oxford, New York, Elsevier Science Publishers.

NYLANDER, N., FRIBERG, L., & LIND, B. (1987) Mercury  concentration  in
the  human  brian  and kidneys  in  relation  to exposure  from  dental
amalgams.  Swed. dent. J., 11: 179-187.

O'KUSKY,    J.R.,    BOYES,    B.E.,    &    MCGEER,    E.G.     (1988)
Methylmercury-induced  movement  and  postural disorders  in developing
rat:  regional analysis of brain catecholamines and indoleamines. Brain
Res., 439(1/2): 138-146.

SHIMAMURA,   Y.,   MIZOGUCHI,   I.,   INABA,   Y.,   TAZIKAWA,   Y.,  &
KAWANISHI,  Y. (1980)  The protective  potency of  marine  animal  meat
against the neurotoxicity of methylmercury: its relationship  with  the
organ  distribution of mercury and selenium. Food Cosmet. Toxicol., 18:

OHLANDER,  E.H.,  OHLIN, B.,  ALBANUS, L., &  BRUCE, A. (1985)  Mercury
levels in the hair of pregnant women eating Swedish fresh  water  fish.
Var Fda, 8: 393-394.

OHSAWA,  M.  &  MAGOS, L.  (1974)  The  chemical form  of methylmercury
complex in rat bile. Biochem. Pharmacol., 23: 1903-1906.

OHSAWA,  M., FUKUDA, K.,  & KAWAI, K.  (1981) Accelerated  accumulation
of  methylmercury  in the  rat fetus at  the late pregnant  stage. Ind.
Health, 19: 219-221.

OLSON,  F.C. &  MASSARO, E.J.  (1980) Developmental  pattern  of  cAMP,
adenyl  cyclase, and  cAMP phosphdiesterase  in the  palate, lung,  and
liver  of  the  fetal mouse:  alterations  resulting  from exposure  to
methylmercury  at  levels  inhibiting palate  closure.  Teratology, 22:

OMATA,  S.,  SAKIMURA,  K., ISHII,  T.,  &  SUGANO, H.  (1978) Chemical
nature  of  methylmercury complex  with a low  molecular weight in  the
liver  cytosol  of rats  exposed  to methylmercury  chloride.  Biochem.
Pharmacol., 27: 1700-1701.

OMATA,    S.,    HORIGOME,    T.,   MOMOSE,    Y.,    KAMBAYASHI,   M.,
MOCHIZUKI,  M., & SUGANO, H.  (1980) Effects of methylmercury  chloride
on the in vivo rate of protein synthesis in the brain of the   rat:  in
vivo  rate of protein  synthesis in the  brain of the  rat: examination
with the injection of a large quantity of 14C- valine.  Toxicol.  Appl.
Pharmacol., 56: 207-215.

OMATA,  S., MOMOSE, Y., UEKI,  H., & SUGANO, H.  (1982) In vivo  effect
of  methylmercury on protein synthesis in peripheral nervous tissues of
the rat. Arch. Toxicol., 49: 203-214.

ONFELT, A. (1983) Spindle disturbances in mammalian cells.  I.  Changes
in the quantity of free sulfhydryl groups in relation to  survival  and
C-mitosis in V79 Chinese hamster cells after treatment  with  colcemid,
diamide,  carbaryl and methylmercury.  Chem.-biol. Interact., 46:  201-

ONFELT, A. & JENSSEN, D. (1982) Enhanced mutagenic response of  MNU  by
post-treatment with methylmercury, caffeine or thymidine in V79 Chinese
hamster cells. Mutat. Res., 106: 297-303.

PACYNA, J.M. (1987) Atmospheric emissions of arsenic, cadmium, lead and
mercury  from  high  temperature  processes  in  power  generation  and
industry.   In: Hutchinson,  T.C. &  Meema, K.M.,  ed.  Lead,  Mercury,
Cadmium and Arsenic in the environment, New York, Chichester, Brisbane,
Toronto, John Wiley & Sons, pp. 69-88 (SCOPE 31).

PALLOTTI,  G., BENCIVENGA,  B., &  SIMONETTI, T.  (1979) Total  mercury
levels in whole blood, hair and fingernails for a population group from
Rome and its surroundings. Sci. total Environ., 2: 69-72.

PECKHAM, N.H. & CHOI, B.H. (1986) Surface change alterations  in  mouse
fetal astrocytes due to methylmercury: an ultra-structural  study  with
cationized ferritin. Exp. mol. Pathol., 44: 230-234.

PETER,  F. & STRUNC,  G. (1984) Semiautomated  analysis for mercury  in
whole  blood,  urine and  hair by on-stream  generation of cold  vapor.
Clin. Chem., 30(6): 893-895.

(1980)   Interrelationships of blood and hair mercury concentrations in
a  North American population  exposed to methylmercury.  Arch. environ.
Health, 35: 161-168.

PIPER,  R.C.,  MILLER,  V.L., &  DICKINSON,  E.O.  (1971) Toxicity  and
distribution  of mercury in pigs with acute methylmercurialism.  Am. J.
vet. Res., 32: 263-273.

PRASAD, K.N. & RAMANUJAM, S. (1980) Vitamin E and vitamin C  alter  the
effect  of methylmercuric chloride on neuroblastoma and glioma cells in
culture. Environ. Res., 21: 343-349.

PROHASKA,  J.R. & GANTHER,  H.E. (1977) Interactions  between  selenium
and methylmercury in rat brain. Chem.-biol. Interact. 16: 155-167.

QUANDT,   F.N.,  KATO,   E.,  &   NARAHASHI,  T.   (1982)  Effects   of
methylmercury   on   electrical   responses  of   neuroblastoma  cells.
Neurotoxicology, 3:  205-220.

RAMANUJAM,  M. &  PRASAD, K.N.  (1979) Alterations  in gene  expression
after  chronic treatment of glioma cells in culture with methylmercuric
chloride. Biochem. Pharmacol., 28: 2979-2984.

RAMLAL,  P.S.,  RUDD,  J.W.M.,  FURUTANI,  A.,  &  XUN, L.  (1985)  The
effect  of pH  on methylmercury  production and  decomposition in  lake
sediments.  Can. J. Fish. aquat. Sci., 42: 685-692.

RAMLAL,   P.S.,   RUDD,  J.W.M.,  &  HECKY,  R.E.  (1986)  Methods  for
measuring  specific rates of  mercury methylation and  degradation  and
their  uses in  determining factors  controlling net  rates of  mercury
methylation.  Appl. environ. Microbiol., 51: 110-114.

REBEL, G., GUERIN, P., & PRASAD, K.N. (1983) Effect  of  methylmercuric
chloride  on  gangliosides of  mouse  neuroblastoma cells  in  culture.
Lipids, 18: 664-667.

REFSVIK,  T.  (1984a)  N-Acetylpenicillamine potentiated  excretion  of
methylmercury  in  rat  bile:  influence  of  S-methyl-cysteine.   Acta
pharmacol. toxicol., 55: 121-125.

REFSVIK,  T.  (1984b)  N-Acetylpenicillamine  potentiation  of  biliary
excretion  of methylmercury: influence  of glutathione depletors.  Acta
pharmacol. toxicol., 55: 58-64.

REFSVIK,  T. & NORSETH, T. (1975) Methylmercuric compounds in rat bile.
Acta pharmacol. toxicol., 36: 67-78.

REUHL,  K.R.,  CHANG,  L.W.,  &  TOWNSEND,  J.W.  (1981a)  Pathological
effects  of  in  utero methylmercury  exposure  on  the  cerebellum  of
methylmercury  exposure on  the cerebellum  of the  golden hamster.  I.
Early effects upon the neonatal cerebellar cortex. Environ.  Res.,  26:

REUHL,  K.R.,  CHANG,  L.W.,  &  TOWNSEND,  J.W.  (1981b)  Pathological
effects  of  in  utero methylmercury  exposure  on  the  cerebellum  of
methylmercury  exposure on the  cerebellum of the  golden hamster.  II.
Residual effects on the adult cerebellum. Environ. Res., 26: 307-327.

RICHARDSON,  R.J. & MURPHY, S.D. (1975) Effect of glutathione depletion
on  tissue  deposition  of  methylmercury  in  rats.   Toxicol.   appl.
Pharmacol., 31: 505-519.

RIOLFATTI,  M.  (1977)  [Further  epidemiological  studies  on  mercury
concentrations in edible fish and in human blood and hair.]  Ig.  mod.,
70:  169-186 (in Italian).

RODIER,  P.M. (1977) Correlation between prenatally-induced alterations
in  CNS cell populations and  postnatal function. Teratology, 16:  235-

RODIER,  P.M., ASHNER, M., &  SAGER, P.R. (1984) Mitotic  arrest in the
developing  CNS after prenatal  exposure to methylmercury.  Neurobehav.
Toxicol. Teratol., 6: 379-385.

RODIER,   P.M.  &  KATES,   B.  (1988)  Histological   localization  of
methylmercury  in mouse brain  and kidney by  emulsion  autoradiography
203Hg. Toxicol. appl. Pharmacol., 92: 224-234.

ROELS,  H.,  HUBERMONT,  G.,  BUCHET,  J.P.,  &  LAUWERYS,  R.   (1978)
Placental  transfer of lead,  mercury, cadmium and  carbon monoxide  in
women.  III.  Factors influencing the  accumulation of heavy metals  in
the placenta and the relationship between metal concentration  and  the
placenta and in maternal and cord blood. Environ. Res., 16: 236-247.

ROWLAND,  I.R., DAVIES, M.J.,  & EVANS, J.G.  (1980) Tissue content  of
mercury  in  rats given  methylmercuric  chloride orally:  influence of
intestinal flora.  Arch. environ. Health, 35: 155-160.

(1983)  Are  developmental  changes  in  methylmercury  metabolism  and
excretion  mediated by the  intestinal microflora? In:  Clarkson, T.W.,
Nordberg,  G.F.,  & Sager,  P.R.,  ed. Reproductive  and  developmental
toxicity of metals, New York, London, Plenum Press, pp. 745-758.

ROWLAND, I.R., ROBINSON, R.D., & DOHERTY, R.A. (1984) Effects  of  diet
on mercury metabolism and excretion in mice given  methylmercury:  role
of gut flora. Arch. environ. Health, 39: 401-418.

(1986) The effect of various dietary fibres on tissue concentration and
chemical  form of mercury after  methylmercury exposure in mice.  Arch.
Toxicol., 59:  94-98.

RUDD,   J.W.M.,   FURUTANI,  A.,   &   TURNER,  M.A.   (1980)   Mercury
methylation by fish intestinal contents. Appl. environ. Microbiol., 40:

RUSTAM,  H.,  VON  BURG, R.,  AMIN-ZAKI,  L.,  & ELHASSANI,  S.  (1975)
Evidence  for  a  neuromuscular disorder  in  methylmercury  poisoning.
Arch. environ. Health, 30: 190-195.

SAGER,   P.R.  (1988)  Selectivity   of  methyl  mercury   effects   on
cytoskeleton and mitotic progression in cultured cells.  Toxicol  appl.
Pharmacol., 94: 473-486.

SAGER, P.R. & MATHESON, D. (1988) Mechanisms of  neurotoxicity  related
to  selective  disruption  of microtubules  and intermediate filaments.
Toxicology, 49(2-3): 479-492.

SAGER,  P.R., DOHERTY, R.A.,  & OLMSTEAD, J.B.  (1981a) Interaction  of
methylmercury with microtubules. Toxicologist, 1: 118-119.

SAGER,  P.R., DOHERTY, R.A., &  OLMSTEAD, J.B. (1981b) Interactions  of
methylmercury with microtubules. J. cell Biol., 91: 330a.

SAGER,   P.R.,  DOHERTY,  R.A.,  &  RODIER,  P.M.  (1982)  Morphometric
analysis  of the effect of methylmercury on developing mouse cerebellar
cortex.  Toxicologist, 2: 116.

SAGER,  P.R., DOHERTY,  R.A., &  OLMSTEAD, J.B.  (1983) Interaction  of
methylmercury  with microtubules in cultured  cells and in vitro.  Exp.
cell Res., 146: 127-137.

SAGER,  P.R., ASHNER, M., & RODIER, P.M. (1984) Persistent differential
alterations  in developing cerebellar  cortex of male  and female  mice
after methylmercury exposure. Brain Res., 12: 1-11.

SARAFIAN,  T.  &  VERITY, M.A.  (1985)  Inhibition  of RNA  and protein
synthesis  in isolated cerebellar cells by in vitro and in vivo methyl-
mercury. Neurochem. Pathol., 3(1): 27-39.

SARAFIAN,  T. & VERITY, M.A. (1986) Mechanism of apparent transcription
inhibition  by  methylmercury  in cerebellar  neurons.  J.  Neurochem.,
47(2):  625-631.

SARAFIAN,   T.A.,   CHEUNG,  M.K.,  &  VERITY,  M.A.  (1984)  In  vitro
methylmercury  inhibition of protein  synthesis in neonatal  cerebellar
perikarya. Neuropathol. appl. Neurobiol., 10: 85-100.

SATOH, H., YASUDA, N., & SHIMAI, S. (1985) Development of  reflexes  in
neonatal  mice  prenatally  exposed  to  methylmercury  and   selenite.
Toxicol.  Lett., 25: 199-203.

SCHROEDER,  W.H.  &  JACKSON, R.A.  (1987)  Environmental  measurements
with  an  atmospheric  mercury  monitor  having  specific  capabilties.
Chemosphere, 16:  183-199.

SECO,  J.M. (1987) Big mercury deposit found in Spain. Financial Times,
30 October 1987.

SHAMOO,    A.E.,   MACLENNAN,   D.H.,   &    ELDEFRAWI,   M.E.   (1976)
Differential  effects  of  mercurial compounds  on  excitable  tissues.
Chem.-biol.  Interact., 12: 41-52.

SHERLOCK,   J.C.,  LINDSAY,  D.G.,   HISLOP,  J.E.,  EVANS,   W.H.,   &
COLLIER, T.R. (1982) Duplication diet study on mercury intake  by  fish
consumption in the United Kingdom. Arch. environ. Health, 37: 271-278.

SHERLOCK,  J.C.  & QUINN,  M.  (1988) Underestimation  of dose-response
relationship  with particular reference to the relationship between the
dietary  intake  of  mercury  and  its  concentration  in  blood.  Hum.
Toxicol.  7: 129-132.

(1984)  Elevation of  mercury in  human blood  from controlled  chronic
ingestion of methylmercury in fish. Hum. Toxicol., 3: 117-131.

SHIMAI, S. & SATOH, H. (1985) Behavioral teratology  of  methylmercury.
J. toxicol. Sci., 10: 199-216.

SHIMOJO,  N.,  YAMAGUCHI,  S.,  &  SANO-KENICHI  (1976)   Methylmercury
derivatives  in engine exhausts and its synthesis. Jpn. J. ind. Health,
18: 36-37.

SIDMAN,  R.L.  &  RAKIC, P.  (1973)  Neuronal  migration, with  special
reference to developing human brain: a review. Brain Res., 63: 1-35.

(1986)  Mercury in neonatal scalp hair. Sci. total Environ.,  57:  105-

SILVER,  S. (1984) Bacterial transformations of and resistance to heavy
metals. In: Nriagu, J.O., ed. Changing metal cycles and  human  health,
Berlin, Heidelberg, New York, Springer-Verlag, pp. 199-225.

SKERFVING,  S. (1974) Methylmercury  exposure, mercury levels  in blood
and  hair, and  health status  in Swedes  consuming contaminated  fish.
Toxicology, 2: 3-23.

SLOTKIN,    T.A.,   KAVLOCK,   R.J.,    COWDERY,   T.,   ORBAND,    L.,
(1986)  Functional  consequences  of prenatal  methylmercury  exposure:
effects  on renal and hepatic repsonses to trophic stimuli and on renal
excretory mechanisms.  Toxicol. Lett., 34: 231-245.

(1985)  Effects of neonatal  methylmercury exposure on  development  of
nucleic acids and  proteins in rat brain: regional  specificity.  Brain
Res.  Bull., 14: 397-400.

(1983) The effect of prenatal methylmercury administration on postnatal
renal functional development. Environ. Res., 30: 63-71.

SMITH,  R.G.,  VORWALD,  A.J.,  PATIL,  L.S.,  &  MOONEY,  T.F.  (1970)
Effects of exposure to mercury in the manufacture of chlorine. Am. Ind.
Hyg.  Assoc.  J., 31: 687-700.

SPUHLER, K. & PRASAD, K.N. (1980) Inhibition by methylmercuric chloride
of  prostaglandin E1-sensitive adenylate cyclase activity in glioma but
not  in neuroblastoma cells in  culture. Biochem. Pharmacol., 29:  201-

SPYKER,   J.M.,  SPARBER,  S.B.,   &  GOLDBERG,  A.M.   (1972)   Subtle
consequences  of  methylmercury  exposure:  behavioural  deviations  in
offspring of treated mothers. Science, 177: 621-623.

STEIN,  A.,  GREGUS, Z.,  & KLAASSEN, C.  (1988) Species variations  in
biliary  excretion  of  glutathione-related thiols  and  methylmercury.
Toxicol. appl. Pharmacol., 93: 351-359.

STOKES,  P.M. & WREN, C.D. (1987) Bioaccumulation of mercury by aquatic
biota  in  hydroelectric reservoirs:  a  review and  consideration   of
mechanisms.  In: Hutchinson,  T.W. &  Meema, K.M.,  ed. Lead,  mercury,
cadmium and arsenic in the environment, New York, Chichester, Brisbane,
Toronto, John Wiley & Sons, pp. 255-277.

SUDA,  I. & TAKAHASHI, H.  (1986) Enhanced and inhibited  bio-transfor-
mation  of methylmercury in the rat spleen. Toxicol. appl.  Pharmacol.,
82: 45-52.

SUGIURA,  Y., TAMI, Y., & TANAKA, H. (1978) Selenium protection against
mercury toxicity: high binding affinity of methylmercury  by  selenium-
containing   ligands  in  comparison  with  sulfur-containing  ligands.
Bioinorg. Chem. 9(2): 167-180.

SUZUKI,   T.,   SHISHIDO,  S.,  &  URUSHIYAMA,  K.  (1976)  Mercury  in
cigarettes.  Tohoku J. exp. Med., 119: 353-356.

SUZUKI,  T.,  HONGO, T.,  & YAMAMOTO, R.A  (1984a) Hair mercury  levels
of Japanese women during the period 1881-1968. J. appl. Toxicol. 4:101-

KIGAWA, T. (1984b) Normal organic and inorganic mercury levels  in  the
human feto-placental system. J. appl. Toxicol., 4: 249-252.

OHTSUKA,  R., & AKIMICHI, T. (1988) Mercury in scalp hair of Papuans in
the  Fly Estuary, Papua New  Guinea. Asia-Pacific J. public  Health, 2:

Occurrence  and  turnover of  mercury  in the  environment,  Stockholm,
National Environmental Protection Board (Mercury Report No. 3).

SWEDISH  EXPERT GROUP (1971)  Methylmercury in fish.  A  toxicological-
epidemiological  evaluation  of  risks. Nord.  Hyg. Tidskr., 4(Suppl.):

SYVERSEN,  T.L.M. (1982) Changes  in protein and  RNA synthesis in  rat
brain neurons after a single dose of methylmercury. Toxicol. Lett., 10:

SZPRENGIER-JUSZKIEWICZ,  T.  (1988)  [Evaluation  of  daily  intake  of
mercury  with food stuffs  in Poland.] Bromatol.  Chem. Toksykol.,  21:
228-232 (in Polish).

SZUCKI, B. & KURYS, H. (1982) [Mercury levels in the blood and hairs in
the general population.] Rocz. PZH, 33(3): 143-148 (in Polish).

TAKEUCHI,  T. (1977) Pathology of fetal Minamata disease. The effect of
methylmercury  on intrauterine life  of human being.  Pediatrician,  6:

TAKEUCHI, T. & ETO, K. (1975) Minamata disease. Chronic occurrence from
pathological  viewpoints.  In:  Studies  on  the  health   effects   of
alkylmercury in Japan, Tokyo, Japan Environment Agency, pp. 28-62.

TAMASHIRO,   H.,   AKAGI,   H.,   ARAKAKI,   M.,   FUTATSUKA,   M.,   &
ROHT,  L.H.  (1984) Causes  of death in  Minamata disease: analysis  of
death certificates. Int. Arch. occup. environ. Health, 54: 135-146.

TAMASHIRO,   H.,  ARAKAKI,  M.,  FUTATSUKA,   M.,  &  LEE,  S.   (1986)
Methylmercury exposure and mortality in southern Japan: a close look at
causes of death. J. Epidemiol. community Health, 40: 181-185.

TAMASHIRO,   H.,  FUKUTOMI,  K.,   &  LEE,  E.   (1987)   Methylmercury
exposure  and mortality in Japan: A life table analysis. Arch. environ.
Health, 42: 100-107.

TAYARANI,  I., LEFAUCONNIER,  J., &  BOURRE, J.  (1988) The  effect  of
mercurials  on amino acid transport and rubidium uptake by isolated rat
brain microvessels. Neurotoxicology, 8(4): 543-552.

Taylor A, Marks V (1973) Measurement of urinary mercury excretion by atomic absorption
in health and disease. Br J Ind Med 30: 293-296.

THOMAS,  D.J. & SMITH, J.C.  (1979) Partial characterization of  a low-
molecular  weight methylmercury complex in rat cerebrum. Toxicol. appl.
Pharmacol., 47: 547-556.

THOMAS,  D.J. &  SMITH, J.C.  (1982) Effects  of  co-administered  low-
molecular-weight  thiol compounds on short-term distribution of methyl-
mercury in the rat. Toxicol. appl. Pharmacol., 62: 104-110.

THOMAS,  D.J. & SMITH,  J.C. (1984) Effects  of co-administered  sodium
selenite  on  short-term  distribution  of  methylmercury  in  the rat.
Environ. Res., 34: 287-294.

P.,  &  HALL, L.L.  (1986) Sexual differences  in the distribution  and
retention  of  organic  and inorganic  mercury in methylmercury-treated
rats.  Environ.  Res., 41: 219-234.

THROWER,  S.J.  &  ANDREWARTHA,  K.A.  (1981)  Glutathione   peroxidase
response  in  tissues  of  rats  fed  diets  containing  fish   protein
concentrate  prepared from shark  flesh of known  mercury and  selenium
content. Bull.  environ.  Contam. Toxicol., 26: 77-84.

TOLLEFSON,  L. & CORDLE, F.  (1986) Methylmercury in fish:  a review of
residue  levels, fish consumption and  regulatory action in the  United
States. Environ. Health Perspect., 68: 203-208.

TSUBAKI,  T. & IRUKAYAMA, K.,  ed. (1977) Minamata disease,  Amsterdam,
Oxford, New York, Elsevier Science Publishers.

TSUBAKI,  T. & TAKAHASHI, H. (1986) Recent advances in Minamata disease
studies, Tokyo, Kodansha.

(1978)   Clinical,   epidemiological   and  toxicological   studies  on
methylmercury  poisoning.  In:  Plaa,  G.L.  &  Duncan,   W.A.M.,   ed.
Proceedings  of  the First  International  Congress on  Toxicology, New
York, London, San Francisco, Academic Press, pp. 339-357.

TURNER,  C.J.,  BHATNAGER,  M.K.,  &  YAMASHIRO,  S.   (1981)   Ethanol
potentiation  of  methyl mercury  toxicity:  a preliminary  report.  J.
Toxicol. environ. Health, 7: 665-668.

TURNER, M.A. & RUDD, J.W.M. (1983) The English-Wabigoon  river  system.
III. Selenium in lake enclosures: its geochemistry, bioaccumulation and
ability  to reduce mercury bioaccumulation. Can. J. Fish. aquat.  Sci.,
40:  2228-2250.

TURNER,   M.D.,   KILPPER,   R.W.,   SMITH,   J.C.,   MARSH,   D.O.,  &
CLARKSON, T.W.  (1975) Studies on volunteers consuming methylmercury in
tuna fish.  Clin.  Res., 23: 2.

J.B.,   RUBINO,  E.C.,  CHIRIBOGA,   J.,  &  CHIRIBOGA,   C.C.   (1980)
Methylmercury  in populations eating  large quantities of  marine fish.
Arch. environ.  Health, 35: 367-378.

URANO,   T.,   NAGANUMA,  A.,   &   IMURA,  N.   (1988)  Methylmercury-
cysteinylglycine  constitutes  the main  form  of methylmercury  in rat
bile.  Res. Commun. chem. Pathol. Pharmacol., 60: 197-210.

US  DEPARTMENT  OF  COMMERCE  (1978)  Report  on  the  chance   of   US
seafood  consumers exceeding the  current acceptable daily  intake  for
mercury  and  on recommended  regulatory  controls, Washington,  DC, US
Department    of    Commerce,   National    Oceanic   and   Atmospheric
Administration, National Marine Fisheries Service, pp. 1-198.

US EPA (1980) Ambient water quality criteria for  mercury,  Washington,
DC, US Environmental Protection Agency, Criteria and Standards Division

US EPA (1984) Mercury health effects update: health  issue  assessment,
Washington,  DC,  US  Environmental  Protection  Agency  (EPA-600/8-84-

(1986)   Neurobehavioural assessment of Mohawk Indians for sub-clinical
indications of methyl mercury neurotoxicity. Arch. environ. Health, 41:

VERSCHAEVE,  L.  & LEONARD,  A. (1984) Dominant  lethal test in  female
mice treated with methylmercury chloride. Mutat. Res., 136: 131-136.

VERSCHAEVE,    L.,   KIRSCH-VOLDERS,   M.,   &   SUSANNE,   C.   (1983)
Mercury chloride- and methyl mercury chloride-induced inhibition of NOR
activity.  Teratog. Carcinog. Mutagen., 3: 447-456.

VOGEL,  D.G., MARGOLIS,  R.L., &  MOTTET, N.K.  (1985) The  effects  of
methylmercury  binding to microtubules. Toxicol.  appl. Pharmacol., 80:

VOGEL,    D.G.,    RABINOVITCH,    P.S.,   &    MOTTET,   N.K.   (1986)
Methyl-mercury  effects on cell cycle kinetics. Cell Tissue Kinet., 19:

VON  BURG, R. & LANDRY, T. (1976) Methylmercury and the skeletal muscle
receptor. J. Pharm. Pharmacol., 28: 548-551.

VON  BURG,  R.,  FARRIS, F.,  &  SMITH,  J.C. (1974)  Determinations of
methylmercury in blood by gas chromatography. J. Chromatogr.,  97:  65-

WALSH,  C.T.  (1982)  The influence  of  age  on  the  gastrointestinal
absorption  of mercuric chloride and methylmercury chloride in the rat.
Environ. Res., 27: 412-420.

WASSICK, K.H. & YONOVITZ, A. (1985) Methylmercury ototoxicity  in  mice
determined   by   auditory   brain  stem   responses.  Acta otolarynol.
(Stockholm), 99: 35-45.

WATANABE,  H.,  SHIMOJO,  N., SANO,  K.,  &  YAMAGUCHI, S.  (1988)  The
distribution   of   total  mercury  in  the  brian  after  the  lateral
ventricular  single injection of  methylmercury and glutathione.   Res.
Commun. chem.  Pathol. Pharmacol. 60(1): 57-69.

WATANABE,  T.,  SHIMADA,  T., &  ENDO,  A.  (1982) Effects  of  mercury
compounds  on ovulation and meiotic  and mitotic chromosomes in  female
golden hamsters. Teratology, 25: 381-384.

WELSH,  S.O.  (1979)  The protective  effect  of  vitamin E  and  N,N'-
diphenyl-p-phenylenediamine  (DPPD) against methyl mercury  toxicity in
the rat.  J. Nutr., 109: 1673-1681.

WESTOO, G. (1968) Determination of methylmercury salts in various kinds
of biological material. Acta chem. Scand. 22: 2277-2280.

WGMF  (1980) Report  on mercury  in fish  and fish  products.  Canberra
Working Group on Mercury in Fish, Department  of Primary  Industry,  p.

WHEATLEY,  B. (1979) Methylmercury  in Canada: exposure  of Indian  and
Inuit residents to methylmercury in the Canadian  environment,  Ottawa,
Department  of National Health and Welfare, Medical Services Branch, p.

WHEATLEY,  B.,  BARBEAU,  A.,  CLARKSON,  T.W.,  &  LAPHAM,  L.  (1979)
Methylmercury  poisoning in Canadian  Indians - the  elusive diagnosis.
Can.  J. neurol. Sci., 6(4): 417-422.

WHO  (1976a)  Conference  on intoxication  due  to alkylmercury-treated
seed,  Baghdad, Iraq, 9-13 September  1974, Bull. World Health  Organ.,
53(Suppl.): 105-112.

WHO  (1976b) Environmental Health  Criteria 1: Mercury,  Geneva,  World
Health Organization, 132 pp.

WHO  (1978) WHO Technical Report Series, No. 631 (Evaluation of certain
food  additives  and contaminants.  Twenty-second  report of  the Joint
FAO/WHO Expert Committee on Food Additives).

WHO  (1980)  Consultation to  re-examine  the WHO  Environmental Health
Criteria  for mercury, Geneva, 21-25  April 1980, Geneva, World  Health
Organization (Unpublished report EHE/EHC/80.22).

WHO (1989a) Environmental Health Criteria 86: Mercury  -  Environmental
aspects, Geneva, World Health Organization, 150 pp.

WHO  (1989b)  Evaluation of  certain  food additives  and contaminants.
Thirty-third  report of  the Joint  FAO/WHO Expert  Committee  on  Food
Additives,  Geneva,  World  Health Organization  (WHO  Technical Report
Series 776).

WIENER,  J.G. (1987) Metal  contamination of fish  in low-pH lakes  and
potential  implications  for  piscivorous wildlife.  Trans.  North  Am.
Wildl.  Natl. Resour. Conf., 52: 645-657.

WIGFIELD,  D.C., CROTEAU, S.M., &  PERKINS, S.L. (1981) Elimination  of
the  matrix effect  in the  cold-vapor atomic  absorption  analysis  of
mercury in human hair samples. J. anal. Toxicol., 5: 52-55.

WOOD,  J.M. & WANG, H.K.  (1983) Microbial resistance to  heavy metals.
Environ. Sci. Technol., 17: 82a-90a.

WULF,    H.C.,    KROMANN,    N.,   KOUSGAARD,    N.,   HANSEN,   J.C.,
NIEBUHR,  E., & ALBOGE,  K. (1986) Sister  chromatid exchange (SCE)  in
Greenlandic  Eskimos.  Dose-respone relationship between   SCE and seal
diet,  smoking and blood cadmium and mercury concentrations. Sci. total
Environ., 48:  81-94.

XUN, L. & CAMPBELL, N.E.R. (1987) Measurements of specific rates of net
methyl  mercury production in the water column and surface sediments of
acidified and circumneutral lakes. Can. J. Fish. aquat.  Sci., 44: 750-

MORI,  Y.,  PHAS, B.,  & SANO, K.  (1977) A background  of geographical
pathology on mercury in the east Pacific area. J. occup. Med., 19: 502-

YAMAMOTO,  R.,  SUZUKI, T.,  SATOH, H., &  KAWAI, K. (1986)  Generation
and  dose as  modifying factors  of inorganic  mercury accumulation  in
brain,  liver and kidneys of rats fed methylmercury. Environ. Res., 41:

YAMINI, B. & SLEIGHT, S.D. (1984) Effects of ascorbic  acid  deficiency
on  methylmercury dicyandiamide toxicosis  in guinea pigs.  J. environ.
Pathol.  Toxicol. Oncol., 5: 139-150.

YOSHINO, Y., MOZAI, T., & NAKAO, K. (1966) Biochemical changes  in  the
brain  in rats poisoned  with an alkyl  mercury compound, with  special
reference  to  the  inhibition of  protein  synthesis  in brain  cortex
slices.  J. Neurochem., 13: 1223-1230.

ZELENKO,  V.  &  KOSTA, L.  (1973) A  new method  for the  isolation of
methylmercury  from  biological tissue  and  its determination  at  the
parts-per-million level by gas chromatography. Talanta, 20: 115-123.

ZIMMER,  L.,  JOHNSON,  P.C., &  CARTER,  D.E.  (1980) A  comparison of
biochemical, pathological or behavioral methods for the  assessment  of
the  effectiveness of treatment  for methylmercury poisoning  in  rats.
Neurobehav. Toxicol., 2: 323-330.

Comparison between maximum hair levels of mercury during pregnancy and
symptoms and signs in the mother and her offspringa
              Mother                                      Child
         -------------------------   ----------------------------------------------------------
              Symptoms                                                  Symptoms
         -----------------------                                -------------------------------
Mother-  Paraes-  Other  Mercury     Sex      Walked   Talked   Mental  Seizures  Neurological
infant   thesia          level                (month)  (month)                    score
number                   (mg/kg)

2        0        0      1           female   12       24       0       0         2
3        0        0      1           male     -        -        0       0         2
5        0        0      1           male     14       12       0       0         0
6        0        0      1           male     18       18       0       0         0
7        0        0      1           male     18       24       0       0         3
9        0        0      1           male     13       26       +       0         3
13       0        1      1           female   12       12       0       0         4
14       0        0      1           female   18       26       0       0         2
18       0        0      1           female   16       18       0       0         0
19       0        0      1           male     12       12       0       0         0
26       0        0      1           male     12       14       0       0         0
31       0        0      1           male     11       12       0       0         1
33       0        0      1           female   12       20       0       0         2
39       0        0      1           female   -        -        0       0         4
41       0        0      1           male     11       18       0       0         3
69       0        0      1           male     18       20       0       0         4
4        0        0      2           male     18        -       0       0         0
8        0        0      2           female   13       18       0       0         0
10       0        0      2           male     16       18       0       0         3
11       0        0      2           male     12       24       0       0         3
12       0        0      2           male     18       18       0       0         3
16       0        0      2           female   18       18       0       0         2
27       0        0      2           male     12       10       0       0         0
32       0        0      2           male     14        -       0       0         0
47       0        0      2           male     18       24       0       0         3
1        0        0      3           female   14       18       0       0         0
21       0        0      3           male     18        -       0       0         1
23       0        0      5           male     12       12       0       0         1
34       0        0      6           male     12       10       0       0         0
38       0        0      6           female   18       10       0       0         2
35       0        0      7           male     12       18       0       0         0
29       0        0      8           male     18       19       0       0         0
40       0        0      9           female   12        -       0       0         0
20       0        0      10          male     12       12       0       0         2
24       0        +      10          male     14       -        0       0         3
22       0        0      12          male     18       14       0       0         1
28       0        0      12          female   14       18       0       0         2
17       +        +      14          female   20b      18       0       0         1
Appendix (contd).
              Mother                                      Child
         ------------------------    --------------------------------------------------
              Symptoms                                                  Symptoms
         ------------------------                               -------------------------------
Mother-  Paraes-  Other  Mercury     Sex      Walked   Talked   Mental  Seizures  Neurological
infant   thesia          level                (month)  (month)                    score
number                   (mg/kg)

36       0        0      16          male     18       16       0       0         5
42       0        0      18          female   36b      30b      0       0         0
25       0        0      19          male     12       18       0       0         2
30       +        +      23          female   12       12       0       0         1
37       0        0      26          male     12       12       0       0         1
15       0        0      38          male     20b      18       0       0         6
49       0        0      45          male      -        -       0       0         4
59       0        0      46          male     12       12       0       0         2
53       0        0      52          female   18       18       0       0         1
48       +        +      59          female   18       26b      0       0         0
43       0        0      60          male     20b      18       0       0         5
44       0        0      62          male     18       24       0       0         0
54       +        +      74          male     18       26b      0       0         2
46       +        0      75          female   12       12       0       0         0
52       +        0      78          female   14       28b      +       +         4
50       0        0      86          male     11       26b      0       0         6
58       0        +      98          female   12       12       0       0         2
57       0        0      104         female   15       18       0       0         4
72       0        0      114         male     14       48b      +       0         0
64       0        0      118         female   18       18       0       0         0
51       +        +      154         male     24b      36b      0       +         3
76       0        0      196         male     12       15       0       0         0
77       0        0      202         male     24b      20       0       0         3
61       0        +      242         female   15       18       +       0         0
74       0        0      263         female   18       18       0       0         5
66       0        0      269         male     12       12       0       0         1
63       +        0      294         male     20b      34b      +       +         0
62       +        +      336         male     24b      36b      0       +         0
67       +        0      339         female   20b      26b      0       0         4
60       +        0      357         female   20b      30b      0       0         2
65       +        0      362         male     14       16       0       0         4
71       +        +      376         female   20b      30b      0       +         2
75       0        0      399         male     15       24       0       0         3
56       +        +      404         male     60b      60b      +       +         11
70       +        0      405         female   60b      36b      +       0         11
68       0        0      418         male     72b      72b      +       +         11
45       0        0      443         male     36b      30b      +       0         11
73       0        0      468         female   14       20       0       0         6

Appendix (contd).
              Mother                                      Child
         -----------------------     ----------------------------------------------
              Symptoms                                                  Symptoms
         -----------------------                                -------------------------------
Mother-  Paraes-  Other  Mercury     Sex      Walked   Talked   Mental  Seizures  Neurological
infant   thesia          level                (month)  (month)                    score
number                   (mg/kg)

80       0        +      557         female   22b      22b      0       0         2
79       0        0      568         female   20b      26b      0       0         4
78       0        0      598         male     24b      23       0       0         7
81       +        +      674         male     24b      26b      0       0         2
a From: Marsh et al. (1987)
   o = absence of abnormality.
   + = presence of abnormality.
   - = no observations were made.
b Abnormal value.
   For further details, see section

    See Also:
       Toxicological Abbreviations
       Methylmercury (WHO Food Additives Series 52)
       Methylmercury (WHO Food Additives Series 24)
       Methylmercury (WHO Food Additives Series 44)
       METHYLMERCURY (JECFA Evaluation)