Methylmercury (EHC 101, 1990)

INTERNATIONAL PROGRAMME ON CHEMICAL SAFETY

ENVIRONMENTAL HEALTH CRITERIA 101

METHYLMERCURY

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

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WHO Library Cataloguing in Publication Data

Methylmercury.

(Environmental health criteria ; 101)

1.Methylmercury compounds 2. Mercury poisoning
I.Series

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

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CONTENTS

ENVIRONMENTAL HEALTH CRITERIA FOR METHYLMERCURY

1. SUMMARY AND CONCLUSIONS

1.1. Identity, physical and chemical properties, analytical
methods
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. IDENTITY, PHYSICAL AND CHEMICAL PROPERTIES, ANALYTICAL METHODS

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. SOURCES OF HUMAN AND ENVIRONMENTAL EXPOSURE

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

4. ENVIRONMENTAL TRANSPORT, DISTRIBUTION, AND TRANSFORMATION

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

5. ENVIRONMENTAL LEVELS AND HUMAN EXPOSURE

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. KINETICS AND METABOLISM

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

7. EFFECTS ON ORGANISMS IN THE ENVIRONMENT

8. EFFECTS ON EXPERIMENTAL ANIMALS AND IN VITRO TEST SYSTEMS

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. EFFECTS ON MAN

9.1. General population exposure
9.1.1. Effects on adults
9.1.1.1 Effects on the nervous system
9.1.1.2 Effects on non-nervous tissue
9.1.2. Effects on developing tissues
9.1.2.1 Effects on the nervous system
9.2. Occupational exposure
9.3. Mechanisms of toxicity
9.3.1. The mature organism
9.3.1.1 Mechanism of selective damage
9.3.1.2 The latent period
9.3.1.3 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
9.4.1.1 The Minamata and Niigata outbreaks
9.4.1.2 The Iraqi outbreak
9.4.1.3 Exposed populations in Canada
9.4.1.4 Other fish-eating populations
9.4.1.5 Special groups
9.4.1.6 Summary
9.4.2. Prenatal exposure
9.4.2.1 Iraq
9.4.2.2 Canada
9.4.2.3 New Zealand
9.4.2.4 Summary

10. EVALUATION OF HUMAN HEALTH RISKS

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

11. RECOMMENDATIONS

11.1. Gaps in knowledge
11.2. Preventive measures

12. PREVIOUS EVALUATIONS BY INTERNATIONAL BODIES

REFERENCES

APPENDIX

WHO TASK GROUP ON ENVIRONMENTAL HEALTH CRITERIA FOR METHYLMERCURY

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

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 York^a

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 Seychelles^a

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 )

Observers

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,
Japan^a

Professor C. Maltoni, Institute of Oncology, Bologna,
Italy

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

Secretariat

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.

NOTE TO READERS OF THE CRITERIA DOCUMENTS

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).

ENVIRONMENTAL HEALTH CRITERIA FOR METHYLMERCURY

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,
respectively.

* * *

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.

1. SUMMARY AND CONCLUSIONS

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
groups.

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-
voirs.

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 µg mercury/kg fresh
weight). However, fish and fish products are the dominant
source of methylmercury in the diet, and levels greater
than 1200 µg/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 µg methylmercury from all sources, and a
daily uptake of approximately 2.3 µg. The total daily
intake of all forms of mercury from all sources has been
estimated to be 6.7 µg, with an added burden of 3.8 to
21 µg 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 µg mercury/kg will result
in the intake of 100 µg 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 µg/litre; hair,
2 µg/g; urine, 4 µg/litre, and placenta, 10 µg/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 µg mercury/day from
fish, blood mercury levels are approximately 200 µg/litre
and corresponding hair levels about 250 times higher
(50 µg/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 µg/kg per day before and during pregnancy). It
also affects spermatogenesis in mice (1 mg mercury/kg as
methylmercury).

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
relationships.

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 µg/kg body weight (hair
mercury concentrations of approximately 50-125 µg/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 µg/g in the Iraqi outbreak and the
highest no-observed-effect level for severe effects was
399 µg/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 µg/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 µg/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 µg/g (the second highest value

was 19.6 µg/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 µg/litre, corresponding to 50 µg/g of hair)
associated with a low (5%) risk of neurological damage to
adults.

The fetus is at particular risk. Recent evidence shows
that at peak maternal hair mercury levels above 70 µg/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 µg/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 µg/g,
in order to screen for those effects only detectable by
available psychological and behavioural tests.

2. IDENTITY, PHYSICAL AND CHEMICAL PROPERTIES, ANALYTICAL METHODS

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 µg/g = 1 ng/mg
1 ppb = 1 µg/kg = 1 ng/g
1 µmol mercury • 1 µmol methylmercury • 200 µg
mercury

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-
sidered.

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
collection.

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
breakage.

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 µg 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-
sorption).

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

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
(1978)

All media total mercury neutron activation 0.1 reference method Kosta & Byrne
(1969)
Byrne & Kosta
(1974)
---------------------------------------------------------------------------------------------------------------------------------------------
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. SOURCES OF HUMAN AND ENVIRONMENTAL EXPOSURE

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
(200).

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. ENVIRONMENTAL TRANSPORT, DISTRIBUTION, AND TRANSFORMATION

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 cycle^a
----------------------------------------------------------
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
considered:

- 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
trapped;

- 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
include:

- 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
soils;

- 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.,
1986);

- 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 fish^a,b
----------------------------------------------------------------------------------
Species Atlantic Pacific Indian Mediterranean
Ocean Ocean Ocean Sea
----------------------------------------------------------------------------------

Non-predators

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

Predators

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⁺⁺ (K_s = l0^-52).

The solubility product of mercury selenide, HgSe, is
even lower (K_s = 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 (Björnberg
et al., 1988). In these studies the selenium level was
raised artificially from 0.4 to 2.4 µg/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
standards.

5. ENVIRONMENTAL LEVELS AND HUMAN EXPOSURE

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 µg/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 µg/kg, whereas anchovies and
smelt have average values below 85 µg/kg. Most other
foodstuffs have average values below 20 µg/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 µg/day, compared with an
intake from fish alone of 2.9 µg/day (Fouassin & Fondu,
1978). Also in Belgium, Buchet et al. (1983) measured a
daily intake from all foodstuffs of 6.5 µg mercury.

The intake of total dietary mercury (µg/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 µg/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 µg/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 mercury^a
--------------------------------------------------------------------------
Exposure Elemental Inorganic mercury Methylmercury
mercury vapour compounds
--------------------------------------------------------------------------
Air 0.030 (0.024) 0.002 (0.001) 0.008 (0.0064)

Food

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
figures.

In Poland, the average daily dietary intake of mercury
(estimated in 2134 duplicate portions) was 5.08 µg/day in
the age group l-6 years, 5.43 µg/day in the age group
6-18 years, and 15.8 µg/day in adults (Szprengier-
Juszkiewicz, 1988). Owing to the low fish consumption
(6.76 kg/year) and low mercury concentration in market
fish (65 µg/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 µg/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 µg and that 20% of this is in
the form of inorganic mercury compounds (i.e., 0.6 µg/day)
and 80% is methylmercury (i.e., 2.4 µg/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 µg/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 µg. 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 µg/day. By subtracting from this
figure the intake of methylmercury from fish (2.4 µg/day),
the estimated total dietary intake of inorganic mercury is
4.2 µg/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 µg/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 µg 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 µg/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 µg 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 µg
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 consumption^a
------------------------------------------------
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
1000^c 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.

6. KINETICS AND METABOLISM

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-
priate.

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
(µg/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.
(1974)
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 µg/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,
1983).

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.,
1988).

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)
daily
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
expression:

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 µg/litre is related to the average daily dietary
intake (in µg 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 (µg/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 µg/litre, in hair about
2 µg/g, in urine 4 µg/litre, and in the placenta about
10 µg/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 (µg of ----------------------------
subjects mercury doses Whole body Blood
/kg) ----------------------------
f T´ f T´
(days) (days)
----------------------------------------------------------------------------

3 adult tracer 1 0.95 72 - - WHO
(1976b)
15 adult tracer 0.94 76 0.07 50 WHO
(1976b)
5 adult 20 1 - - 0.05^a 52 Kershaw
et al.
(1980)
5 adult 3.3 100 - - 0.05^a 53 Sherlock
et al.
(1984)
5 adult 1.5 100 - - 0.055^a 51 Sherlock
et al.
(1984)
4 adult 100 100 - - 0.057^a 48 Sherlock
et al.
(1984)
5 adult 0.6 100 - - 0.064^a 46 Sherlock
et al.
(1984)
----------------------------------------------------------------------------
^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 populations^a
-----------------------------------------------------------------------------------------
Country Indicator No. of Mercury concentration^b Reference
media Subjects Mean Range
-----------------------------------------------------------------------------------------
Belgium placenta 474 15 1.1 - 103 Roels et al. (1978)^c
whole blood 497 13^d 0.1 - 47^d 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 4^d 0.6 - 24^d Lie et al. (1982)

Poland whole blood 270 11.3^d 2.5 - 24^d 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)

Sweden^e hair 18 0.4 Ohlander et al. (1985)
hair 41 0.53 Forhammer et al. (1984)

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

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

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

Northern hair 312 3.1 0 - 9 Airey (1983)
hemisphere^k

Northern hair 4603 2.3 0 - 5 Airey (1983)
hemisphere

Southern hair 1449 1.7 0.8 - 2.5 Airey (1983)
hemisphere
-----------------------------------------------------------------------------------------
^a No known occupational exposure; fish consumption usually less than one meal per week.
^b The units for mercury concentrations are: µg/kg for placenta, mg/kg for hair, and
µg/kg for blood and urine, unless otherwise stated. ND = not detectable.
^c This reference contains data on levels published prior to 1976.
^d µg/litre
^e Pregnant women.
^f Values are for adults
^g µg/g creatinine
^h Values after exclusion of 9 samples >50µg/kg as outliers; without the exclusion
the mean was 14.2 and range 0-298 µg/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 µg mercury/day will have blood levels in the range
of 200 µg 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 µg/g; once every 2
weeks, 1.9 µg/g; once a week, 2.5 µg/g; and once or
more a day, 11.6 µg/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 µg/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.,
1988b).

7. EFFECTS ON ORGANISMS IN THE ENVIRONMENT

Data concerning the effects of methylmercury on organ-
isms in the environment are discussed in Environmental
Health Criteria 86: Mercury - Environmental Aspects (WHO,
1989a).

8. EFFECTS ON EXPERIMENTAL ANIMALS AND IN VITRO TEST SYSTEMS

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 9.3.1.3.

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 µg 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 µg/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 µg/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.,
1986).

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 µg/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 µg/litre, with maximum values within the range
of 1510-1840 µg/litre. The mean blood levels of the
offspring at birth were 1690 µg/litre (range, 880-
2460 µg/litre). When tested 190 days post-conception, the
mean blood levels had fallen to 1040 µg/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 µg/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 µg/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-
ine.

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 µmol/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 meth