Critical Reviews in Toxicology, 25( 1):1-24 (1995)

Minamata Disease: Methylmercury Poisoning in

Japan Caused by Environmental Pollution
Masazumi Harada
Department of Epidemiology, Institute for Medical Genetics, Kumamoto University Medical School,
Japan

ABSTRACT: Minamata disease (M. d.) is methylmercury (MeHg) poisoning that occurred in humans who
ingested fish and shellfish contaminated by MeHg discharged in waste water from a chemical plant (Chisso Co.
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Ltd.). It was in May 1956, that M. d. was first officially “discovered” in Minamata City, south-west region of
Japan’s Kyushu Island. The marine products in Minamata Bay displayed high levels of Hg contamination (5.61
to 35.7ppm). The Hg content in hair of patients, their family and inhabitants of the Shiranui Sea coastline were
also detected at high levels of Hg ( m a . 705 ppm).
Typical symptoms of M. d. are as follows: sensory disturbances (glove and stocking type), ataxia, dysarthria,
constriction of the visual field, auditory disturbances and tremor were also seen.
Further, the fetus was poisoned by MeHg when their mothers ingested contaminated marine l i e (named
congenital M. d.). The symptom of patients were serious, and extensive lesions of the brain were observed.
While the number of grave cases with acute M. d. in the initial stage was decreasing, the numbers of chronic
M. d. patients who manifested symptoms gradually over an extended period of time was on the increase.
For the past 36 years, of the 2252 patients who have been officially recognized as having M. d., 1043 have
died.
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This paper also discusses the recent remaining problems.

KEY WORDS: Methylmercury (MeHg), Minamata disease (M. d.), congenital Minamata disease, chronic
Minamata disease, mercury levels, mercury contents in hair, preserving umbilical cord, grove and stocking type’s
sensory disturbance.

I. INTRODUCTION points that have been elucidated and the problems

Minamata disease (M. d.) is one of the first
and most serious cases of diseases resulting
from environmental contamination caused by
waste water discharge from an industrial plant.
Methylmercury (MeHg) contained in the plant’s
waste water contaminated marine life in the
surrounding waters and was, in effect, poison-
ing those who ingested the affected fish and
seafood.
Matters pertaining to MeHg toxicity, symp-
toms, pathology, and the onset mechanism of the
disease have already been clarified and settled to
a considerable extent.lV2 However, many matters,
such as the appropriateness of conventional safety
standards regarding fetuses, remain u n ~ e t t l e d . ~ ? ~ (Figure 1).
Thirty-five years after the official discovery
of Minamata disease, it is useful to review the
1040-8444/95/$.50
0 1995 by CRC Press, Inc.
that continue to remain unsolved today.
II. OUTBREAK OF THE DISEASE AND
BACKGROUND
The MeHg-contaminated Shiranui Sea is a
quiet inland sea situated in the southwest region
of Japan’s Kyushu Island. It is approximately
60 km in length and 20 km in breadth, covering
an area of 1200 km2.At the time of the outbreak
of the disease, approximately 200,000 people in-
habited the coast of the sea and its associated
islands, most of whom were primarily engaged in
the fishing industry and other related industries
Minamata disease was officially discovered
in May 1956. The discovery was triggered by
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A Where Minamata Disease cats A Where lish were lound lloating

were Oiscouered

* Figures in ( ) are population of 1960.

FIGURE 1. M a p of the Shiranui Sea.

public concern over two daughters of a ship car-
penter (aged three and five respectively) who
suffered from symptoms similar to encephalitis
(inflammation of the brain or brain-damage symp-
toms). As rumors of an epidemic grew, an inves-
tigation into the matter was undertaken by the
Public Health Departments, the Chisso factory
hospital, the Minamata City hospital, and the lo-
cal medical association. The investigationrevealed
two main findings:
1. The disease affected adults as well as chil-
dren.
2. The first case was reported as early as 19535
(it has since become clear that there were
patients even before this date).

2
 As the cause of the disease was unknown, it
came to be called “Minamata disease”, named
after the place where it was first observed.
The Minamata Disease Research Group,
mainly consisting of members of the Kumamoto
University School of Medicine, were first to es-
tablish that the disease was a form of poisoning
that occurred with the ingestion of marine life
taken from the area, and that it was not in itself
contagious.
Minamata City was the only industrialized
city in the area where Chisso Co. Ltd. operated a
chemical plant. Given that it was never doubted
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that the cause of the disease was water contami-
nation, it was obvious that the source could only
have been the Chisso chemical plant. However,
the plant accepted no responsibility and took no
measures whatsoever to prevent further contami-
nation, claiming that the cause of the disease was
unknown. Chisso also refused to cooperate with
investigations on the grounds that doing so would
reveal confidential corporate information.6
Further, an effective community strategy was
left unconsidered due to inaction and similar claims
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of unknown cause by both the national and pre-
fectural governments. Even fishing was not banned
in Minamata Bay itself.
During the 1950s, people began to witness
strange phenomena in and around Minamata Bay.
For no apparent reason, fish rotated continu-
ously and floated belly-up to the surface, shell-
fish opened and decomposed, and birds fell while
in flight.
The most shocking of all incidents was the
frenzied death of cats. Cats suffered from exces-
sive salivation and manifested general convul-
sions or violent rotational movements, were un-
able to walk straight, and often collapsed dead.
Many jumped into the sea to drown, and eventu-
ally cats were no longer seen in the area.5,7
Cats played an important role in helping to
elucidate the etiology of the disease. In February
1957, cats were brought to Minamata from
Kumamoto City, located 100km from Minamata.
All developed similar symptoms within 32 to 65 d
of arrival.* Tests showed that the degree of con-
tamination was effectively equivalent to ad-
ministering MeHg at 1 mg/kg of a cat’s body
weight. Later, Hg (total) was detected in high
concentrations in their brains (18.6 ppm max),
livers (145.5 ppm max), kidneys (36.1 ppm max),
and hair (134.0 ppm max).’
111. RESEARCH ON THE CAUSE OF
MINAMATA DISEASE
When the etiology of a disease is unknown,
delineation of clinical pictures of the disease is a
first requirement. By the summer of 1959, the
disease’s clinical and pathological pictures be-
came ~ l e a r . ~ , ~ . ’ ~
A. Early Patients
Those patients who were first detected are
considered to have been cases of acute and sub-
acute poisoning. Of the 34 patients diagnosed as
having Minamata disease, 16 died within 3 months
from the onset of the disease. Within 6 months of
the onset, an additional four patients died, which
demonstrated that the disease advances rapidly ?,6J1
All these patients were reported to have com-
mon symptoms (Figure 2),1.9including constric-
tion of the visual field, sensory disturbances,
ataxia, dysarthria, auditory disturbances, and
tremor. However, some bias in early diagnosis
may have been due to the fact that only serious
cases manifesting all and only these symptoms
were diagnosed as having the disease.
Pathological findings were also marked with
common features (Takeuchi et al.): damage to the
central nervous system, particularly the cerebral
cortex and cerebellar cortex, was notable. In ad-
dition, the disease was further characterized by
notable damage to the calcarine region of the
occipital lobe (visual center) (Figure 3), the pre-
and postcentral cortex (motor and sensory cen-
ters), and temporal cortex (auditory center). In
relation to the cerebellar cortex, deciduation of
granular cells was remarkable while h k i n j e cells
were relatively well retained, showing a granular
cell-type cerebellar atrophy (Figure 4).1J0As for
the peripheral nerve system, destruction and de-
myelination of dorsal roots or sensory nerve fi-
bers were characteristically notable.’@-I2
Efforts were made worldwide to locate and
determine a disease with the above characteris-
tics. The symptoms were found to coincide with
3
 50 %
Constriction o f the visual field
superficial
Sensory disturbance
deep
adiadochokinesis

1
in writing
Ataxia in buttoning
in finger-finger,
finger-nose tests
Romberg's sign
Dysarthria
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Auditory disturbance
Disturbance o f gait
Tremor
Muscular rigidity
Ballism

Chorea
Athetosis
Cont rac t u r e
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exaggerated
Tendon reflex
weak
Pathologic reflexes
Hemiplegia
Hypersaliva tion

Sweating
Ment a I disturbance

FIGURE 2. Frequency of symptom in Minamata disease. (From Tokuomi, H., Psychiatry Neurol. Jpn.,
62, 1816, 1960. With permission.)

a case of organic mercury poisoning reported in
1940 at a chemical fertilizer plant (using MeHg)
in England.13,*4This served as a most useful clue
for elucidating the cause.'
B. The Chisso Plant
In 1965, about 3700 people were employed at
the Chisso Minamata industrial plant, one of the
biggest and most modem chemical plants in Ja-
pan. It was then producing chemical fertilizers,
syntheticresins, plasticizers, and industrial chemi-
cals. The plant used a variety of chemical sub-
stances in large quantities and discharged the waste
water directly into Minamata Bay. Despite the
plant's unmonitored and irresponsible practices,
it made no efforts to initiate any environmental
research in relation to the contaminations.
There was evidence of contamination of ma-
rine life close to the plant as early as 1925. Chisso
Co. Ltd. had paid compensationto the Fishermen's
Union whenever complaints were lodged, but took
no countermeasures whatsoever against contami-

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FIGURE 3. Severe cortical disintegration in calcarine region

in female infant, aged 4 years, who died after 553 clinical days.
Atrophy and disintegration of the cortex is particularly striking
from the gyral wall to the valley of the dilated sulci. (Photo-
graph provided by T. Takeuchi.)

nation. The company’s policy in this regard was
reflected by an official’s comment that the “chemi-
cal industry is essential to Japan today and some
damage to marine life should be t~lerated.”~
C. Cause Determined and Reported
Concurrently conducted experiments of feed-
ing MeHg and affected marine life to cats re-
vealed that Minamata disease was induced and
caused by MeHg poisoning.’ In November 1959,
the Minamata Disease Research Group of
Kumamoto University reported to the Japanese
Ministry of Health and Welfare that “Minamata
disease was poisoning by MeHg contained in the
waste water from the plant.”
Mr. L. T. Kurland of the U.S. was one of the
first foreigners to visit Minamata and conduct
experiments. In 1960, Kurland published a paper
supporting the conclusion of the Minamata Dis-
ease Research Group in the journal World Neu-
rology. At the same time, he submitted the recom-
mendations outlined t~el0w.l~
1. Fishing should be banned until the safety of
fish and shellfish is demonstrated by animal
experiments.

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FIGURE 4. Cerebellum of a female infant, aged 4 years, who died after a clinical course of 1.6 years. A
moderate cerebellar atrophy of the granular cell layer is seen, showing a central type. Disappearanceof the
granular cell is more striking in the central, deeper region of the hemisphere, where intense atrophy of the
gyn occurs. Dentate nucleus is well preserved. (Photograph provided by T. Takeuchi.)

2. Ecological studies of fish and shellfish should
be conducted.
3. Methods for the removal of mercury from
the sludge in Minamata Bay should be
studied.
4. Recycling or decreasing the amount of
mercury should be studied in order to
decrease the discharge of mercury during
production steps in industrial plants.
5. Extensive follow-up studies on the health of
people living in contaminated areas should
be conducted.
If his recammendatians had k e n fsllswed,
damage would have been kept to a minimum and,
indeed, the history of Minamata disease may have
taken a different course. In particular, if the fol-
low-up studies on the health of the inhabitants
and memuy in hair samples had been conducted
after 1961, it would have at least made it clear that
contamination and the Occurrence of Minamata
disease was continuing.
IV. MERCURY LEVELS
Mercury at 2010 ppm in wet weight was
detected from sludge near the drainage channel
of the Chisso industrial plant in 1960. The sludge
mercury level decreased proportionately with the
distance from the channel, but mercury was de-
tected in an extensive area beyond Minamata
Bay (Figure 5).l The marine life in Minamata
Bay also displayed high levels nf mercury con
tamination: hormomya nutabilis - 11.4 to
39.0ppm; oysters - 5.61 ppm; crabs - 35.7
ppm; and scidena schlegelii - 14.9 ppm.' Mer-
cury was also present in high levels in the organs
of the patients who died from the disease (livers
ranging from 22.0 to 70.5 ppm, brains at 2.6 to
 SHlRANUl SEA
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Minamata
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FIGURE 5. Minamata Bay and mercury content of sludge at the bottom of the
bay. (From Minamata Disease Research Group, Minamata Disease, Medical
School of Kumamoto University, Kumamoto, Japan, 1968. With permission.)
24.8 ppm, and kidneys at 21.2 to 140.0 ppm
[1959 test results]).
In 1958, Chisso rebuilt the waste water drain-
age channel, diverting the waste water directly
into the Minamata River. As a result, the contami-
nation spread throughout the entire Shiranui Sea.
In 1959, cats developed the disease in villages
outside Minamata City'J6 (see Figures 1 and 5).
Further, mercury levels at the estuary rose to
20.0ppm in shortneck clams, 24.1 pprn in sea
bream, and 10.6 ppm in grey mullet.16
A. Hair Samples
Analysis of human hair was not used to ascer-
tainlevels of mercury contamination prior to 1960
primarily due to the cause of the disease being
officially unknown. The time lag between the
onset of the disease and the analysis of mercury in
hair samples, together with the failure to analyze
0 Hg=pprn wet weight
(Kitarnura. 1959)
0 Hg=pprn wet weight
(Irukayarna. 1963)
mercury using this method in a systematic and
organized way, meant that many problems were
allowed to surface in later years. However, the Hg
content of patients, even 4 to 5 years after their
onset, ranged from 2.46 ppm (min) to 705 ppm
(max).'
Analysis of hair samples of those inhabitants
of the heavily affected areas who believed them-
selves to be unaffected by the disease revealed
high levels of mercury, with the highest level
recorded at 191 ppm.' These people subsequently
developed chronic Minamata disease (explained
below). Despite the fact that patients began re-
fraining from ingesting the local seafood as early
as 1956, the maximum value of mercury in the
hair samples of the inhabitants was measured at
705 ppm.
Further, the mercury content in the hair
samples of inhabitants of the Shiranui Sea coast-
line were also detected at high levels. The con-
7
 tamination ultimately spread as far as Goshonoura
on the other side of the Shiranui Sea (Table l).6,9
V. CONGENITAL MINAMATA DISEASE
A. Group Diagnosis
Soon after the official discovery of Minamata
disease, it became clear that a considerable num-
ber of children were born with congenital cerebral
palsy.17Although Minamata disease was suspected
as its probable cause, this was impossible to prove.
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group diagnosis or diagnosis in terms of epidemi-
ology is possible. The incidence of similar symp-
toms and causes among the patients was extraor-
dinarily high, and in the areas with the highest
Occurrence of Minamata disease, the Occurrence
of cerebral palsy was abnormally high. In a small
fishing village called Yudo, seven cases of cere-
bral palsy and ten cases of infantile Minamata
disease were found in a total of 50 households
(Figure 6). Between 1955 and 1958, there were
188 births in three small fishing villages of Yudo,
Tsukinowa, and Modo with a 9.0% incidence of
cerebral palsy during this early period, while the

However, these patients had common symptoms
and were diagnosed to have the same disease due
to the same cause. Symptoms included mental
retardation (loo%), primitive reflex (loo%),cer-
ebellar ataxia (loo%), disturbances in physical
development and nutrition (loo%), dysarthria
(loo%), deformity of the limbs (loo%),hyper-
kinesia (95%), hypersalivation (95%), paroxys-
mal symptoms (82%), strabismus (77%), and py-
ramidal symptoms (pathologicalreflex) (75%)18J9
(Table 2).
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overall national incidence ranges between 0.2 to
2.3%.19
B. Tests on Mothers
There was a high incidence of Minamata dis-
ease patients among the family members of those
with cerebral palsy. While mothers were at first
accused of being asymptomatic, subsequent de-
tailed examinations revealed a high incidence of
mild symptoms of Minamata disease among them.

Such extensive damage to the brain is, of These mothers suffered from sensory disturbances
course, not limited to the symptoms of Minamata (loo%),focal cramps (loo%), mild ataxia (79%),
disease. Without data on mercury contamination, auditory disturbances (75%), pain in the limbs
individual diagnosis is often near impossible, but (64%), constriction of visual field (57%),

TABLE 1
Mercury Content in Hair of Healthy Fishermen, 1960

PPm -1 1-10 10-50 50-100 100-150 150-200 200-300 300- Total

Minamata 7 31 100 49 11 1 199

Tsunagi 12 61 23 4 2 102
Yunoura 14 9 1 24
Ashikita 1 19 19 1 40
Tanoura 6 15 11 33
Ryugatake 2 22 57 5 1 87
Goshonoura 6 53 334 75 11 1 2 (357) 482
(920)

-20 20-50 50-1 00 100-200 200-300 300

Komenotsu 185 117 105 37 5 1 (624) 445

Akune 26 4 1 3 1 (338) 33
Takaono 2 3 5 10
Higashi Town 18 32 23 2 (142) 75
Kumamoto
City (control) 4 18 9 0 0 0 0 0 31
( ) = PPm

8
 TABLE 2
Frequent Symptoms in Congenital Minamata Disease

1962 1971 1974 1981

Mental retardation 100(0/0) 1 OO(Y0) 1 OOP?) 1 OO(Y0)

(severe cases) (100) (72) (72) (66)
Dysarthria 100 96 92 93
Chorea, athetose 95 92 92 66
Ataxia 100 76 78 60
Deformities of limbs 100 84 62 51
Primitive reflexes 100 72 67 51
Strabismus 77 72 67 60
Hypersalivation 100 72 72 45
Paroxysmal symptom 82 36 35 27
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Pathological reflex 75 48 45 39
Inhibited bodily growth 100 68 59 33
Number of cases 17 25 37 33
Death 1 3 3 7

*;q
..
.-
Congenital M d ..
Infantile M.d.
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Route 3

FIGURE 6. Distribution of congenital-infantile Minamata disease patients.

dysarthria (43%), tremor (39%)’ etc.ls However,
the degrees of their symptoms were milder than
those of congenital patients. Similar observations
were also made in the MeHg contamination inci-
dents of New Mexico and Niigata.20
As stated earlier, mercury contents in the hair
and blood samples of patients were not analyzed
until 1959. This was primarily, but only partially,
due to the causes of Minamata disease being un-
known. Another contributing factor for this tardi-
ness was that the symptoms of Minamata disease
did not reveal themselves until an extended pe-
riod of time had elapsed after birth. As a result,
mothers’ hair samples were only analyzed 5 to 8
years after giving birth. Even after this time had
elapsed, analyses revealed that the mercury con-
tent in hair samples of mothers ranged from
1.82 ppm (min) to 191 ppm (max), while that of

9
 congenital patients ranged from 5.25 ppm (min)
to 110 ppm (max).lJ5
In the MeHg contamination incident in
Niigata, the mercury content of a mother's hair
immediately after giving birth to a congenital
patient was 293 ppm. However, her symptoms
were mild, with sensory disturbances and a num-
ber of Minamata disease symptoms. In New
Mexico, a mother had a mercury value of 2.91
ppm in her blood, with her affected baby having
2.77 ppm in its ~ r i n e . *In~Niigata,
. ~ ~ there is only
one official congenital Minamata disease patient,
primarily due to the fact that the incident occurred
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C. Infantile Diagnosis
Generally, infantile cerebral palsy is noted or
diagnosed only after an extended time has elapsed
after birth. This was also true of congenital
Minamata disease, with diagnosis first taking place
in Minamata in 1962. Therefore, no data exist on
the mercury contents in mothers or children at the
time of birth.
Fortunately, people in Japan (from the Ainus
in Hokkaido in the north to the inhabitants of
Okinawa, the southernmost island) have the cus-
tom of preserving umbilical cords of the new-

in 1965, 5 years after the cause of Minimata dis-
ease became clear, and, as a result, women whose
mercury content in their hair was measured at
50ppm or above were advised not to become
pregnant. Properly speaking, the obligation of gov-
ernment was to take measures to prevent Minamata
disease from occurring again. However, after
outbreaks of Minamata disease in Niigata, the
prefectural government advised the people not to
ingest the local seafood and the women not to get
pregnant.
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born. (This custom also prevails in Indonesia
and Malaysia.) This provided an opportunity to
analyze mercury levels of infants at the time of
birth.
Analyses of MeHg in the umbilical cords of
infants born in the Minamata area revealed high
levels, particularly when the incidence of acute
and fulminant cases was highest. Correlation
also existed between the production of acetalde-
hyde from the Chisso plant and the MeHg levels
in umbilical cords21 (Figure 7). MeHg levels

.+
5.28
. 1

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C
0
c

4,000 $

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9
m
al

c
al
0
m
3,000 'i;
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0
3

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2,000 g
->.
5

t -/ -. 0 , 1,000
E
8
I

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al
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2

year 1935 1940 1945 1950 1955 1960 1965 1970

I Average monthly production of acetaldehyde (ton)
0 Month of childbinh and methyl mercury content (ppm) dry weight

FIGURE 7. Comparative chart of acetaldehyde production rate and methylmercury in umbilical

cords. (From Nishigaki, S. and Harada, M., Nature (London),258, 324, 1975. With permission.)

10
 were also high in the preserved umbilical cords
of those diagnosed as suffering from congenital
Minamata disease and those manifesting clinical
symptoms.
In most cases, those whose MeHg content
was 1.0 ppm or higher suffered from congenital
Minamata disease. However, the data are not con-
sistent and some with less than 1.0 ppm were
congenital patients, while others without symp-
toms contained higher levels. As could be ex-
pected, high MeHg levels were also detected from
the umbilical cord of acute infantile Minamata
disease patients.22
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These findings show that Minamata disease
is caused by MeHg poisoning due to continued
environmental contamination and that the dis-
ease was already present in the fetal stage, with
higher concentration exposure during infancy
triggering the onset of acute cases. This differ-
entiates Minamata disease from poisonings that
occurred in Iraq233and New MeXico.20,25 In those
cases, only relatively limited periods (3 months
or so) of extremely high levels of mercury expo-
sure were experienced, whereas in Minamata
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and Niigata, an initial, relatively short period
(7 to 8 years) of high-level contamination was
followed by a very long period of relatively low-
level contamination. Therefore, infants often
contracted the disease as a result of exposure to
MeHg during infancy in addition to exposure in
the womb.
As preserved umbilical cords can be analyzed
for substances other than MeHg, the author has
tested them for selenium, manganese, zinc, cop-
per, and other metals.21y2226However, the full
meaning of the test results is yet to be understood
because the control for these substances has not
been determined.
D. Pathological Findings
The pathological findings of congenital
Minamata disease are general atrophy and hypo-
plasia of the brain cortex and abnormality of the
cytoarchitecture, remaining matrix cells, hypo-
plasia of the corpus callosum, intramedullarypres-
ervation of the nerve cells, and dysmyelination of
the pyramidal tract. In the cerebellum,hypoplasia
of the granular cell layer and other layers as well
as degeneration of granular cells (characteristic of
Minamata disease) were also observed.*.27
Naturally, outbreaks of congenital Minamata
disease had both a geographic and a chronologi-
cal correspondence with the acute adult cases of
Minamata disease (Figure 8). The findings of our
follow-up study revealed that some patients who
first experienced mild symptoms had some symp-
toms alleviated (Table 2):= paroxysmal symp-
toms (attacks) decreased from 82 to 27%, saliva-
tion from 100 to 45%, primitive reflexes and
abnormal limb posture from 100 to 51%, and
incoordination (ataxia) from 100 to 60%.How-
ever, dysarthria and intelligence disturbancewere
left unimproved, and subjective signs that had not
been previously observed and noted before such
as headache, insomnia, arthralgia, numbness, diz-
ziness, and anorexia increased.
Observing this over time, it was ascertained
that patients who exhibited the same symptoms
at first developed an incomplete form of the
disease with varying symptoms. Assuming this
to be the case, it is possible that, as with con-
genital Minamata disease, the disease developed
in an incomplete or nonacute form from the
outset.
The exact number of congenital Minamata
disease patients is not known, as some undiag-
nosed patients were already deceased. At present,
of the 64 patients for whom diagnosis was con-
firmed by the author, serious cases are discussed
(see Table 2). These sufferers are unable to func-
tion and perform as ordinary citizens of the com-
munity; only three are earning salaries and an-
other three are helping to fish.28
VI. CHRONIC MINAMATA DISEASE
For the past 35 years, many thousands of
patients have spent their lives in and out of hos-
pitals. Officially, there are approximately 2200
Minamata disease sufferers. However, it is sub-
mitted and generally accepted that there are many
"unofficial" sufferers who have not been offi-
cially diagnosed due to the problems associated
with the appropriateness of examination guide-
lines.
The incidence of acute and subacute Minamata
disease showed signs of decreasing in 1960. This
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0 congenital patient
FIGURE 8. New distribution of congenital Minamata disease patients.
was essentially due to the fact that people ceased
ingesting the local seafood out of fear of being
affected, and not due to any special measures
taken by the Chisso plant or national government.
On the contrary, acetaldehyde production in-
creased around this time to 3000 Vmonth, as is
reflected in the high mercury level readings of
shortneck clams (at 40 ppm) in Minamata Bay
(Figure 9). Thus, contamination of Minamata Bay
and the Shiranui Sea continued and worsened. Up
12
to 1965, data show that the plant must have con-
tinued the discharge without taking any precau-
tionary measures.
Only after the discovery of a second case of
MeHg contamination in Niigata in 196529(known
as the “Second Minamata”) did Chisso install a
closed circulatory waste water system, after being
ordered to do so by the Ministry of International
Trade and Industry (MITI). Thereafter, levels of
contamination decreased slightly. At Minamata,
 it was only after May 1968that the mercury levels
in the marine life in the Bay substantially de-
clined with the closing of the acetaldehyde plant
(Figure 9).6,30
Sludge in the Bay continued to contain very
high concentrations of mercury up to 1978 (250
to 7000 ppm), requiring a decade's work to seal
the contaminated sludge. With or without the
knowledge of this contamination, the Fishermen's
Union issued a statement declaring that the fish-
ing ground in Minamata Bay was fully recovered
and fishable as early as 1964.6
A. Atypical Cases
After a period of 10 years (of initial diagnosis
of early cases of Minamata disease) had elapsed,
the author conducted follow-up studies of the
acute and typical patients. These studies revealed

3766
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3000
1 3066

80-
----- Total Hg in shellfish
E0,
'-
70-
g
t
2000 60- '0
For personal use only.

5
50-
-Em
40- 'j
I-

30-

20-

10-

4
year 50 55 60 65 70

(1962) 1 3 6 37 2 3 1 3
Acute or subacute patients (black bar)
Number
(1972) 3 313121066 12144125122381411116 ' of
Additional patients discovered by the Second Minamata Disease Research patients
Group (white bar)

Note: These patients are those limited to the Tsukinoura. Detsuki and Yudo areas [Harada. 1975).
Shellfish are Venus japonica of Koiji Island (Fujiki. 1972).
( I ) Oficial discovery of patients
(2) Cause proven to be methyl mercury
(3) A year long labor dispute
( 4 ) Circulatory waste water system installed
( 5 ) Stoppage of production

FIGURE 9. Comparative chart of acetaldehyde production rate, onset of Minamata disease, and
mercury content in the shellfish of Minamata Bay. (From Harada, M., Minamata Disease, Holt,
Reinhardt and Winston, New York, 1975. With permission.)

13
 that symptoms had gradually become atypical:
speech disabilities, constriction of the visual field,
i d sensory disturbances remained unchanged,
but hearing ability worsened. Certain symptoms
alleviated in some patients, while other cases,
such as congenital cases, worsened.31Thus, judg-
ing from the variety of findings, it is highly prob-
able that atypical cases of Minamata disease have
existed from the outset. Due to the fact that only
very serious and typical cases were diagnosed as
Minamata disease in the early years? it can fairly
be said that atypical cases, mild cases, and incom-
plete cases essentially were overlooked. Where
Critical Reviews in Toxicology Downloaded from informahealthcare.com by McGill University on 08/06/12
gradually advancing. Research findings point to
the existence of three types of patients who be-
long to this group pipe 10):
1. Gradually progressive type
2. Delayed onset type
3. Escalator progressive type with aging or
other factors (Figure 10)
Authors labeled these patients as “chronic”
Minamata disease patients. As we extended our
investigation from patients’ immediate family
members to the general inhabitants of contami-

the onset of the disease was gradual, even patients
with typical symptoms were overlooked.
While conducting clinical follow-up studies
of family members of acute and seriously ill pa-
tients and mothers of congenital Minamata dis-
ease patients, researchers discovered a great num-
ber of patients with atypical, incomplete, or slight
symptoms (Table 3)” whose conditions were
nated areas, it was further discovered after 1970
that many people were suffering from chronic
Minamata disease despite the fact that the mer-
cury content in hair samples was not necessarily
high, primarily due to diagnoses of these patients
occurring a considerable amount of time after
contracting the disease. However, a few patients
among these had their hair samples tested shortly

TABLE 3
For personal use only.

Neurological Symptoms Observed Among Family Members of Acute and Subacute

Minamata Disease Patients

No. of cases (% of total observed)

Symptom Family members (1972)ll Mothers (1972)18 Mothers (1974)*O
Sensory disturbance 115 (79) 21 (100) 28 (100)
Extremities 109 (75) 21 (100) 28 (100)
Perioral 44 (30) 4 (19) 6 (21)
Incoordination 94 (65) 16 (76) 22 (79)
Ataxic gait 47 (32) 10 (48) 12 (43)
Finger-nose test 69 (48) 11 (52) 16 (57)
Adiadochokinesia 90 (62) 16 (76) 22 (79)
Romberg’s sign 20 (14) 6 (29) 7 (25)
Dysarthria 65 (45) 9 (43) 12 (43)
Constriction of the visual field 53 (37) 10 (48) 16 (57)
Auditory disturbance 80 (55) 16 (76) 21 (75)
Tremor 51 (35) 6 (29) 1 1 (39)
Chorea and athetosis 2 (1) 0 0
Muscular weakness 37 (26) 7 (33) 1 1 (39)
Muscular rigidity or spasticity 43 (30) 7 (33) 10 (35)
Hyperreflexia 42 (30) 7 (33) 1 1 (39)
Pathologic reflexes 11 (8) 2 (10) 3 (11)
Muscular atrophy 16 (11) 0 0
Hypersalivation 8 (6) 0 0
Vegetative symptoms 43 (30) 12 (57) 26 (76)
Deformities of the extremities 27 (19) 1 (5) 4 (14)
Pain 52 (36) 8 (38) 18 (64)
Intelligencedisturbance 67 (46) 14 (67) 20 (71)
Total examined 145 (100) 21 (100) 28 (I 00)

14
 Death

Acute fulminant form (Tokuomi)

Acute-subacute type
Critical Reviews in Toxicology Downloaded from informahealthcare.com by McGill University on 08/06/12
For personal use only.

Chronic-delayed type

FIGURE 10. Course of Minamata disease.

after the onset of the disease, with low levels of
mercury content being recorded.
There are clinicians who do not believe in the
existence of such patients, particularly delayed
onset-type patients. It may be more accurate to
say that in the case of Minamata, contamination
had continued for such a protracted period that
symptoms were delayed in appearing; in both the
Niigata and Chinese incidents, symptoms appeared
up to 5 years after methylmercury intake had
~ e a s e d .We
~ ~have
, ~ ~seen obvious cases that can-
not be considered as aging, but, rather, as a genu-
ine worsening of symptoms. This is a fact, and
how one interprets this fact is another matter.

15
 The onset mechanism of chronic Minamata
disease was ascertained to be caused by one of the
f~llowing:~,~’
1. Remaining MeHg. The possibility of MeHg
remaining in the body’s system means that
symptoms may manifest themselves long
after exposure or intake.
2. Manifestation of symptoms by accumulation
of MeHg caused by a relatively low-level
exposure over long periods. It was calculated
that a fisherman eats an average of 333.6 g
of fish per day. Based on the current mercury
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Minamata disease, the level of MeHg is not so
high. A theory exists that a patient remains
asymptomaticregardless of the length of the MeHg
exposure period provided that the amount of MeHg
to which he is exposed is minimal. However, this
theory does not explain the chronic Minamata
disease patient because by the time the symptom
appears, the level readings are usually low. Ad-
mittedly, Minamata is not an example of a simple
long-term trace contamination given that exces-
sive contamination existed until 1960, followed
by more than 20 years of relatively low contami-
nation levels.

content in fish, he will have ingested

0.048 mg of total mercury or 0.028 mg of
MeHg per day.32 This is well over the
recommended safety standards.
3. Latent symptoms of Minamata disease
surfacing when complicated by other
diseases or aging. Exacerbated cases are
found more frequently among elderly
persons, with exacerbation occurring in
typical symptoms of Minamata disease such
as sensory disturbances of the limbs,
For personal use only.
C. Studies of Local Inhabitants
An investigation of local inhabitants suspected
to have contracted the disease (i.e., those who
inhabited heavily contaminatedareas with inflicted
family members) revealed a very high frequency
of sensory disturbances, presenting a typical pat-
tern of a “glove and stocking type”, occasionally
accompanied by perioral sensory disturbances

constriction of the visual field, and ataxia. (Table 4) (Figure 11). It is difficult for such sen-
sory disturbances to be observed with aging or
cervical spondylosis. This has been confirmed in
B. Threshold Calculations incidents occurring in Canada’s Indian reserves33
and in China.34
The thresholds calculated for the MeHg poi- There are many examples of mild cases in-
soning in Iraqz3 and Niigata29 were 25 mg of volving complaints primarily concerned with such
MeHg per 60 kg.* However, with chronic sensory disturbances. Such cases are found, for
instance, among mothers of congenital pa-
t i e n t ~ . ’ ~ ”Constriction
.~~ of the visual field, ataxia,
TABLE 4 and auditory disturbances are observed with rela-
Frequency of Main Neurological tively high frequencies (Table 4). Constriction of
Symptoms in Chronic Minamata Disease the visual field - namely, bilateral concentric
and Contaminated Inhabitants and peripheral depression with normal central
vision (the state of the eye could be described as
Symptoms N % a half-shut umbrella) -was detected in 16.7%of
the local inhabitants tested. In some cases, con-
Sensory disturbance
Glove and stocking type 1540 64.2 striction of the visual field began 2 to 3 years after
72.3 the discontinuation of ingesting fish and seafood.
Generalized type 184 7.7 Progressive or changeable constriction also was
Auditory disturbance 1173 49.2 observed.35
Incoordination 803 33.6 Ataxia in chronic Minamata disease is slight
Dysarthria 527 22.1 compared to those in acute and subacute patients.
Constriction of the visual field 398 16.7
Weakness 842 35.3 It may affect the lower limbs or emerge as inad-
Tremor 662 27.7 equate or very slow motions in daily life.
Total 2383 100.0 Neuroophthalmological examinations using an

16
 Glove E Stocking
Hemiplegic Irregular &
uncertain

I
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Perioral Generalized Vertebral

Number
1393
- 147
184 199 84 196

-
1540

58.4 6.1
% 7.7 8.3 3.5 8.2
64.2

* Some cases overlapped each other types.

For personal use only.

FIGURE 11. Types of sensory disturbance.

electrooculogram (EOG)are necessary for proper
diagnosis. The most common abnormal pattern of
EOG is staircase or cogwheel saccadation in
smooth-pursuit movement. The next abnormal
pattern is intermittent or constant defect in fast-
pursuit movement.36
Further, findings of the optokinetic nystag-
mus pattern (OW)are characteristic and useful
for the diagnosis of slight ataxia. For example,
notwithstanding that horizontal OKP is normal,
suppressed abnormal patterns usually were ob-
served in patients with Minamata disease in ver-
tical OKP (Figure 12).37
Auditory disturbances can occur by other
causes, but those attributed to Minamata disease
are characterized by a sensorineural type (corti-
cal). However, difficulty can again arise in distin-
guishing the nonsevere cases from aging. Disor-
ders in taste and smell are often overlooked.
Symptomsdisturbingpatients and preventing them
from returning to a normal lifestyle include
arthralgia, muscle pains, focal cramps, insomnia,
headache, and forgetfulness.
In the chronic stage, mercury and MeHg lev-
els in some organs are higher than in the con-
After performing both clinical check-ups
and autopsies on more than 100 infected patients
and comparing clinical symptoms, pathological
observations, and mercury content in internal or-
gans (viscera), inhabitants of the heavily con-
taminated area without typical symptoms of
Minamata disease showed higher values than the
control (Table 5).
Possible relationships to the disease are sus-
pected with hypertension, cerebral arteriosclero-
sis, hepatopathy, gastric disorders, disorder of
immunity, and thyroid disorders, but have yet to
be demonstrated clinically. Among Minamata
disease patients, particularly infant patients, in-
tense cases of cerebral arteriosclerosisdo e x i ~ t . ~ * ~ '

17
 (Jung's Type Durn : 1 . 2 ' / ~ e C ' ~ ~ 1 2 0 ' / s e ~ )

Horizontal-OKN Verrcal-OKN
Critical Reviews in Toxicology Downloaded from informahealthcare.com by McGill University on 08/06/12

FIGURE 12. OKN findings and Minamata disease. (Photograph provided by Prof. H. Ino.)

TABLE 5
For personal use only.

Total Mercury and Methylmercury in the Organs (1975.1982)

Contaminated inhabitants (N = 98) Control (N = 16)

Total Hg Me-Hg Total Hg MeHg

Cerebrum 0.13 f 0.15 0.025f 0.032 0.08 f 0.03a 0.009 f 0.01 Oa

Cerebellum 0.1 2 f 0.1 1 0.026 f 0.028 0.08 f 0.04a 0.009f 0.01 Oa
Liver 0.67 f 0.58 0.057 f 0.057 0.65 f 0.41 0.071 f 0.01 1
Kidney 2.52 f 3.59 0.022 f 0.022 1.02 f 0.9P 0.015 f 0.030a

a Statistically significant.

There are also reports on the high incidence of
liver disorders. These will be clarified only after
the completion of long-term follow-up studies to
be conducted in the future.
Carcinogenesis will also become an issue.
Causes of death among chronic Minamata disease
patients who died from 1975 to 1982 (100 con-
f i i e d by autopsy) were infections and cancers at
28%, cerebrovascular disorders at 16%,cardiac
failure at 9%, and hepatic disorders at 6%.Causes
of death nationally during the same period were
cerebrovascular disorders at 24.1%, cancer 21.6%,
cardiac failures 21.3%,infectious diseases 5.0%,
and deaths by accidents at 4.3%.This comparison
reveals a high number of deaths from infectious
diseases among chronic Minamata disease pa-
tients.
D. Pathological Findings of Chronic
Minamata Disease
While their degrees vary greatly, the symp-
toms of chronic Minamata disease are essentially
the same as those for acute and typical Minamata
disease. The pathological findings of chronic cases

18
 of Minamata disease are characterized by lesions
in the cerebral cortex, cerebellar cortex, and
changes in peripheral nerve fibers (Figures 13
and 14).387mMoreover, there are extreme varia-
tions in the degree of brain damage suffered, con-
sequently resulting in a great variety of clinical
symptoms of chronic Minamata disease.
There were inhabitants of the contaminated
areas and family members of the patients who
manifested one or more of the lesions, but not all
three. For instance, some suffered only from dis-
orders of peripheral nerve fibers,while others had
no lesions in the cerebral cortex. These findings
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are not pathologically determined as Minamata
disease, but should be regarded as important in
considering the total effects of environmental
contamination on human bodies.
VII. REMAINING PROBLEMS
A. Determination of Minimum Levels
Because the etiology of the disease was not
For personal use only.
known during the 1950s, the true conditions of
mercury contamination at that time are not known.
It was not possible to determine the minimum
-1 GRADES GRAMS
FIGURE 13. Changes of cerebral cortex in Minamata disease. (Photo-
graph provided by Dr. K. Eto and Prof. T. Takenchi.)
mercury amount that triggered the onset of
Minamata disease or to evaluate the initial symp
toms.
In Niigata, the minimum amount of mercury
required to trigger the onset of Minamata disease
was calculated as 25 md60 kg of mercury in an
adult or a 50-ppm mercury level reading in a hair
sample? The onset and basic symptoms were
considered to be sensory disturbances of the ex-
tremities.” Substantially similar values were used
in evaluating the mercury poisoning incident in
Iraq.2~~ However, subsequent clinical observa-
tions of chronic Minamata disease suggest that
the matter is more complicated. Even after the
ingestion of affected marine life was suspended,
the disease progressed in some, with some
asymptomatic patients later developing symptoms
during the period of high contamination as a re-
sult of long-term exposure to comparatively
smaller amounts of the substance. These cases
cannot be fully explained by the simple theory of
accumulation cited above.
Further, in the early stages of the disease,
authors concentrated solely on serious cases of
congenital Minamata disease.l8 Naturally, there
should also be cases with varying degrees of con-
genital Minamata disease.
GRADE4 GRADES
19
 CEREBELLUM
GRADE 8
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GRADE4
For personal use only.
GRADE 2
FIGURE 14. Changes of cerebellum in Minamata dis-
ease. (Photograph provided by Dr. K. Eto and Prof. T.
Takenchi.)
B. Mental Retardation
Many infants with mental retardation and
poor kinetic abilities inhabit the contaminated
areas. Mental retardation (excluding cases of
officially recognized congenital Minamata dis-
ease) totalled 29.1 % of all children born in the
heavily contaminated areas between 1955 and
1958, while 17.5% of all lower secondary school
pupils in the areas were affected. Furthermore,
clumsiness in movements of fingers and other
motor functions were observed in these
ca~es.~~,~~
In 1990, the International Programme on
Chemical Safety (IPCS) requested a study to
ascertain the possible effects of mercury in the
hair of fetuses when MeHg levels were recorded
at 50 ppm or 10wer.~Because fetuses are cer-
20
GRADE 6
GRADE 3
GRADE 1
tainly susceptible to such effects, it is reason-
able to set safety standards for them that are
different from adults. This assumption is based
on the results of untiring epidemic testing and
investigation by M a r ~ h , K ~ j~e l, l~~ ~t r O m , ~ ~ . ~ ~
McKeown-E~syn,4~ and others. All tests were
conducted under a long-term study of mental
and nerve development by comparing the mer-
cury content in hair before and after birth.
However, the IPCS request did not result in the
changing of standards.
C. Fetopathy vs. Embryopathy
As can be observed from congenital
Minamata disease cases, it was generally be-
lieved that organic mercury only caused fetopathy
 impairing brain development, but did not cause
embryopathy. For this reason, even the nonap-
pearance of congenital malformations became
an important diagnostic criterion for congenital
Minamata disease.
Professors T. Takeuchi4*and H. M ~ r i y a m a ~ ~ 2.42 ppm MeHg was detected in his umbilical
have already performed experiments offering
further evidence of fetopathy. However, other ex-
periments have given proof of embryopathy. Ex-
periments with animals strongly suggest embryo-
pathic effect^.^^.^^ In humans, therefore, why
should we expect the effects of organic mercury
to be only fetotoxic? Two possibilities exist as to
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why embryotoxic effects have not been consid-
ered:
1. At the embryotic stage, congenital malfor-
mations ultimately result in cases of miscar-
riages or stillbirths.
2. Infant patients with congenital malforma-
tions were simply excluded from diagnoses
of congenital Minamata disease.
Therefore, among congenital Minamata dis-
For personal use only.
ease patients, very few patients with congenital
malformations were diagnosed as such. This may
have led to the general, but perhaps misdirected,
belief that MeHg poisoning only caused
fetopathy.
In 1977, authors interviewed 89 mothers in
the most contaminated areas and found that in
272 pregnancies there had been 32 miscarriages,
9 stillbirths, 4 deaths within 1 week of birth, and
4 infants officially diagnosed with congenital
Minamata disease. Miscarriages and stillbirths
accounted for 15.0%28of all pregnancies. An-
other survey of a contaminated fishing village
showed that before the end of the second world
war, miscarriages and stillbirths accounted for
4.2%,but reached a high point of 42.9% of all
pregnancies in 1963.52
In addition, the author has discovered various
congenital malformations when looking for prob-
lems in the same way. Even among patients who
have already been diagnosed with congenital
Minamata disease, we have found polydactylia,
high palate, defective external acoustic meatus,
microcornea, and protrusion of the coccyx.
In a male born in March 1959, the author
found polydactylia, syndactyly, an undescended
right testis, and an enlarged in addition to
mental retardation. However, there were no re-
markable neurological symptoms without clumsi-
ness in movement. His parents were engaged in
fishing and suffered from Minamata disease, and
c0rd.5~However, this patient was diagnosed as an
official Minamata disease patient only after hav-
ing reached adulthood.
We should also note the health of children
born from chronic Minamata disease patients.
Among such children there are observed ortho-
static deregulation (24.6%) and disorders in
Bender’s gestalt test (14.2%)?8,54 Even though
these symptoms may not be the direct result of
MeHg poisoning, their mothers’ unhealthy state
must have affected the children in one way or
another.
VIII. ENVIRONMENTAL DAMAGE
It is impossible to reverse the environmental
damage? In Minamata Bay, 71,000 m2 of sludge
with high mercury content (above 100 ppm) was
covered with soil (reclamation area) and
1,539,000m2 of the waters area detected of mer-
cury at 25 ppm or higher on the sea floor was
dredged (dredging area) (Figure 15).55The work
required approximately 48.5 billion yen and 10
years. Chisso paid 63.5%of the expenses. There
is still marine life whose mercury content is higher
than the standard value, and fishing in the waters
enclosed by nets is still banned today.
There are no effective treatments for the dis-
ease, and only palliative therapy, rehabilitation
therapy, physiotherapy, acupuncture, and
moxibustion are being offered to patients.
As of March 1992,2252 patients have been
officially recognized as having Minamata dis-
ease, 1043 of whom have died. A total of 12,127
persons claiming to have the disease have not
been recognized as Minamata disease patients,
and 1968 persons are still awaiting the outcome
of examination by the Examining Board for the
Recognition of Minamata Disease Patients. Ap-
proximately 2000 persons not officially recog-
nized as patients are now in court. Minamata
disease has not ceased, and these people need
further assistance and help.
21
 0 in Mud
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.a*
, 0 Primary groundwater observation well
rkm
RGURE 15. Reclamation and dredging in Minamata Bay.
IX. LESSONS FOR THE WORLD
For personal use only.
The only way in which the Minamata vic-
tims can be fully repaid for their suffering is
for others to utilize the lessons learned. The
people of Minamata, Niigata,2956Iraq,u,24New
Mexico,20+25 and others have all fallen victims to
a disease somehow symbolic of modem devel-
opment. The people of the Ammonia in Brazil
now live with the concern that they, too, may
soon suffer from contamination e f f e ~ t s . De-
~,~~
veloping countries have a tendency to promote
short-term economic development at the expense
of future environmental implications. However,
these diseases and their grave social conse-
quences can be avoided with the implementation
of appropriate control measures. Dissemination
of the knowledge that the same problem has
already occurred elsewhere from the same basic
causes is also of vital importance. In this respect,
the exchange of views and experiences between
researchers and policy makers from different
countries can be a positive step toward avoiding
similar catastrophes in the future.58As one of the
first tragedies of its type, Minamata offers the
opportunity for the world to examine, learn, and
avoid.
22
0 Main surveillance point
0 Reserve surveillance point
8 Secondary groundwater observation well
ACKNOWLEDGMENT
The author wishes to acknowledge the sup-
port of the United Nations University in prepar-
ing this article.
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22. Harada, M., Fujino, T., and Kabashima, K., A
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