TR-509-75
PATHOLOGICAL, CLINICAL AND EPIDEMIOLOGICAL RESEARCH
ABOUT MINAMATA DISEASE, 10 YEARS AFTER. (2ND YEAR)
Kumamoto University,
Faculty of Medicine
Research Committee on Minamata Disease, after 10 years
Chairman Prof. Takeuchi
Parts I to V translated by
SCITRAN (Scientific Translation Service) of
Santa Barbara, California
for the U. S. Environmental Protection Agency
Parts VI to VIII translated by
Dr. Ryotaro Ishizaki
for Duke University, Durham, North Carolina
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TR-509-75
I. PREFACE
Tadao Takeuchi, Study Group Representative
It has been two years since this study o*f Minamata disease started, after
many incidents of the disease had been observed for more than 10 years. The
results of the first year's study were delineated in the study reports of
the last year. We attempted a rough analysis of the following: the
condition of mercury contamination of the Minamata district and its vicinity;
immunology of Minamata disease and its progress; detection of the outbreak
of the disease; general health hazard, etc. Clinical status of the Minamata
disease and its progress led to the finding of new symptoms and new methods
of treatment from the current viewpoints. They provide a valuable tool in
clinical diagnosis. Pathological fundamental knowledge on the dormancy of
Minamata disease, and Minamata disease which is difficult to diagnose, was
also provided by biopsies from victims of Minamata disease. Moreover,
fundamental methods of the prevention and the treatment of Minamata disease,
or methyl mercury poisoning, were attempted. Thus, during the first year,
attempts were made to study various medical problems relating to Minamata di-
sease. Moving toward a solution of these problems, the study moved on to
its second year.
We must report on the results of the second year here. When this study
originated, it was for three year's duration. However, in order to implement
the study, the prefecture authorities expressed their desire to complete
this study in two years. Thus, at the beginning of this year, the study plan
was changed for two years. Hence, efforts by study group members during this
year encompass two year's results, and the members have been constantly busy.
Also, regarding the accurate diagnoses of Minamata disease, we encountered
difficulties in communication between the area and the university medical
school researchers, in finding patients, and in examining everyone completely
concerning various non-medical problems. We had to resort occasionally to
11
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examining a limited number of people in a limited area. However, we believe
that we have achieved enough results, as described below in each item, for
this kind of study.
With this study, the concept of Minamata disease has been clarified.
Also, it has become easier to detect the symptoms of Minamata disease and
its diagnosis. With it, the distribution of organic mercury poisoning of
the Minamata district and its vicinity has been clarified. The relationships
between mercury contamination in the human body and the outbreak of Minamata
disease, the relationship between the contamination conditions and health
hazards caused by it, and light or chronic poison symptoms have become clear.
Fundamental knowledge has been formulated in analyzing the past conditions
of the outbreak of Minamata disease, present contamination conditions, and
future prospects.
On the other hand, there will be no end to the study. We had to conclude
our two-year study, with problems still remaining for the future. The remain-
ing problems include many in the area of medicine, such as how to handle the
contaminated areas not covered by the study, how to improve the treatment of
many Minamata disease patients, how to discover new methods of treatment, and
how to prevent an outbreak among people who are contaminated. Also, the in-
vestigation of health hazards due to micro-contamination and complex genes
remains a future problem. As far as the problems within the laboratory are
concerned, the discovery of internal organization of organic mercury poisoning
still remains a problem. We would like to continue this study in some form
with some assistance. What we most desire is for the results of this study
to be fully utilized.
111
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TABLE OF CONTENTS
I. PREFACE ii
II. EPIDEMIOLOGICAL STUDY OF MINAMATA DISEASE 1
1. Investigation on Mercury Contamination of Minamata
District and the Southern District of the Ariake Sea 1
2. Studies on Transformation of Inorganic Mercury Found
in Minama Bay Sediments into Methyl Mercury 20
3. Progress on Minamata Disease and Its Epidemiological
Study 32
III. CLINICAL STUDY OF THE MINAMATA DISEASE 95
4. A Study Concerning Effects of Consuming Fish Contaminated
by Organic Mercury on Residents Along the Shiranui Sea 95
5. Health Surveys in the Area of Pediatrics, Results of
Examinations of Minamata Disease-Stricken Children, and
Chromosomes of Congenital Minamata Disease Stricken
Children 187
6. Neuroophthalmological Study of Minamata Disease 197
7. Otolaryngological Studies Relative to Minamata Disease 212
8. Study on Prevention and Treatment of Minamata Disease
and Methyl Mercury Poisoning 249
Appendix. Trial Application of Computer Cards for Use in
Examinations for Minamata Disease 271
IV. GENERAL FINDINGS AS RESULT OF EXAMINATION 273
V. PATHOLOGICAL STUDY OF MINAMATA DISEASE 278
9. Pathological Research of Minamata Ten Years Later 278
10. Accumulation of Mercury in the Human Body and Its
Changes as Viewed from a Biopsy of Minamata Disease Cases 340
11. Clinical, Pathological Observations on Abnormalities and
Pathological Changes in the Areas of Mouth and Teeth of
Minamata Disease Patients, Particularly Abnormalities of
Fetal Development 360
IV
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12. Optical-Electron Microscopic Studies on Taste Bud
Disorders Caused by Methyl Mercury Chloride 387
VI. SUMMARY 414
VII. CLOSING REMARK 437
VIII. ACKNOWLEDGEMENT 438
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II. Epidemiological Stud^of Minamata Disease (Part 2)
1. INVESTIGATION ON MERCURY CONTAMINATION OF MINAMATA DISTRICT AND THE
SOUTHERN DISTRICT OF THE ARIAKE SEA
Mas ashi Fujiki, Group Member and Shizuko Tajima, Research Assistant
Kumamoto University Medical School Hygienics Department
I. INTRODUCTION
More than ten years have passed since the outbreak of Minamata disease.
As a result of the investigation of the health conditions of people who live
in the Minamata district and its vicinity, especially in the area which is
contaminated by mercury and the area where the mercury-contaminated fish
exist, it is suspected that persons who may exhibit Minamata disease-like
symptoms may extend to a fairly large range of areas [1]. It has become im-
portant to perform medical investigations to determine whether Minamata
disease-like symptoms are due to the methyl mercury contamination or not.
This study on environmental contamination by mercury has covered not
only the Yatsushiro Sea, but also wider areas. This study [2] has observed the
conditions of environmental contamination by measuring the amount of mercury
primarily in fish for the area not covered by the previous study.
II. INVESTIGATION METHOD
1. Marine Life
As illustrated in Figure 1, five specimens of marine life were collected
on November, 1972 from each of the following six places: outside of Minamata
Bay (around Awaji Island); offshore estuary of the Minamata river, fishing
grounds for scabbard fish off Minamata (in the Yatsushiro Sea); offshore
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Shimoda, Yushiraa, and the estuary of the Midori river (in the Ariake Sea).
Then, the amounts of methyl mercury and the total mercury contained in them
were measured. Also, for the purpose of comparison, the amounts of methyl
mercury and of the total mercury contained in ten frozen fish sold in the
market and caught in the sea of northern Okhotsh near Hokkaido were measured.
2. Hair
The amounts of methyl mercury and of the total mercury contained in the
hair of 34 persons from the Minamata district (measured on August, 1972),
and of 11 persons from the Goshoura district (measured on October, 1972) were
measured. They were selected from the people who complained about the oc-
currence of symptoms after 1966 and were considered to show Minamata disease-
like symptoms, after investigations of the health conditions of people living
in the Minamata and the Goshoura districts, performed by the Neuro-Psychiatry
Department ot Kumamoto University in 1971.
3. Analysis Method of Methyl Mercury
Approximately 50 g of the edible parts of fish and shellfish and approxi-
mately 1 g of hair were precisely measured and used as analysis subjects.
Each subject was soaked in hydrochloric acid for three days at room temper-
ature to decompose it. After collecting methyl mercury in the hydrochloric
acid layer, it was extracted by the standard method and measured by the gas
chromatograph method.
4. Analysis Method of Total Mercury
For hair, the remains after decomposition by hydrochloric acid and ex-
traction of methyl mercury were treated by heating for about 48 hours using
nitric acid, sulfuric acid and permanganic acid. Then, the mercury
in the dissolved liquid was measured by the flameless atomic absorption
photometry method [4]. This gives the amount of inorganic mercury, and the
total amount of mercury is obtained by adding the amount of methyl mercury to it.
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For fish and shellfish, approximately 5 g of the edible part were pre-
cisely measured. After drying, the mercury was collected by the quartz tube
heating absorption method [5], and then measured by the flameless atomic ab-
sorption photometry method.
III. RESULTS OF INVESTIGATION
1. Marine Life
As illustrated in Table 1, out of three places in the Minamata district
of the Yatsushiro Sea, the mercury density of fish outside of Minamata Bay
was the highest and contained 0.182-0.440 ppm of methyl mercury and 0.342-
0.530 ppm of total mercury. The fish which were offshore of the estuary
of the Minamata river contained 0.050-0.068 ppm of methyl mercury and 0.060-
0.210 ppm of total mercury. The fish in the fishing ground for scabbard fish
off Minamata contained 0.020-0.54 ppm of methyl mercury and 0.060-0.300 ppm
of total mercury.
For three places in the Ariake Sea, the fish in the offshore area of
Shimoda contained 0.018-0.080 ppm of methyl mercury and 0.58-0.320 ppm of
total mercury. The fish off Ushima contained 0.028-0.120 ppm of methyl mer-
cury and 0.45-0.205 of total mercury. The fish and shellfish which were off-
shore of the estuary of the Midori river contained 0.010-0.016 ppm of methyl
mercury and 0.022-0.085 ppm of total mercury.
The fish in the northern sea of Hokkaido contained 0.006-0.014 ppm of
methyl mercury and 0.020-1.904 ppm of total mercury.
The mercury concentration in hair is shown in Table 2. In the Minamata
district, it contained 1.35-11.37 ppm of methyl mercury and 2.10-14.82 ppm of
total mercury. In the Goshoura district, it contained 0.19-4.65 ppm of methyl
mercury and 0.39-5.15 ppm of total mercury.
IV. OBSERVATIONS
The fish in three places of the Minamata district contained 0.020-0.440
ppm of methyl mercury and 0.060-0.530 ppm of total mercury, which clearly
-------
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TABLE 1
AMOUNTS OF MERCURY IN FISH AND SHELLFISH COLLECTED IN THE YATSUSHIRO SEA,
ARIAKE SEA, AND THE NORTHERN SEA OF HOKKAIDO (COLLECTED NOVEMBER, 1972)
Collection place
Name of fish
or shellfish
Methyl mer- Total mer-
cury concen- cury concen-
tration (Hg tration (Hg
ppm/wet weight) ppm/wet weight)
a
0)
en
O
•H
JZ
to
3
en
4J
to
cfl
QJ
C/}
Q)
rt
•H
^
outside Minamata Bay
(around Awaji Island)
Offshore of the es-
tuary of the Mina-
mata River
Fishing ground for
scabbard fish off-
shore Minamata
Offshore Shimoda
Offshore Yushima
Offshore of the es-
tuary of the Midori
River
bera 1**
bera 2
bera 3
sillago
swellf ish
sillago 1
sillago 2
f lathead
bera
swellf ish
scabbard fish 1
scabbard fish 2
scabbard fish 3
scabbard fish 4
scabbard fish 5
Kawahagi 1 **
Kawahagi 2
horse mackerel 1
horse mackerel 2
Kitsukori **
Sea bream 1
Sea bream 2
swellfish
bera
garakabu **
gray mullet 1
tray mullet 2
clam
short-necked clam
shrimp
0 402
o 182
0 . 255
o. 1 10
o 21 '1
0 0,,0
0.065
o o(;o
0 i tt->8
o 0;.8
( i (15 |
o 022
0 020
0 021
0 050
0 02<">
0 018
0 080
o os">
0 028
0 060
0 030
0.120
0.010
0 0]4 '
(;'()75* :
0.0^0*
0 014
0.312
0 !7'x>
( 1 . 528
0 ",30
O.Oi.O
0.110
0.085
0.210
0 130
0 300
0.210
0. ' 10
n '!(,0
0 'Jo 1
0 058
0.155
O -i'!O
0.080
0.1'. '8
0 . IMS
0.115
0.072
0.015
0 . 205
"
0 . 022
0.040
0 220*
0 2 10*
0 . 08 5
-------
Collection place
TABLE 1. (Continued)
Name of fish
or shellfish
Methyl mer-
cury concen-
tration (Hg
Total mer-
cury concen-
tration (Hg
ppm/wet weight) ppm/wet weight)
c Northern Sea of
£ Hokkaido
•H
(0
6
o
0
M
O
111
tfl
cu
•*
bream 1
bream 2
bream 3
bream 4
horse mackerel 1
horse mackerel 2
turbot 1
turbot 2
turbot 3
turbot 4
0 014
0.011
o.oos
0 007
o.oio
0.012
0 007
0 006
( i 007
0 007
0.145
O.OSO
0 053
0 .M4
1.904
0.247
0 021
0.020
0.022
0.020
* Concentration per dry weight.
** Some Japanese fish names have been romanized.
TABLE 2. AMOUNTS OF MERCURY IN HAIR
Persons in Minamata district: collecte
in August, 1972
Subject No.
-
13
i.".
2i
23
i t
' n
ii )
''!
*"*! '
IK'
u-. j
;u5
!e>7
!S5
i ^^
j '^i1
Sex
female
male
female
male
female
male
male
male
male
female
female
male
male
female
female
female
male
male
female
male
male
Age
71
37
-/(>
52
b'i
65
32
54
69
61
-Q
7.-,
49
r>6
Tt
'"
4.,
!-
,',3
.d Methyl mercury
concentration
(Hg ppm)
, _.,
Ill (s
2 2H
) S2
5.<-»l
i! •! 5
.1.93
1.30
•>. !°
i / i
5 ! i
4.60
Total mercury
concentration
(Hg ppm)
:
-------
TABLE 2. (Continued)
Persons in Minamata district: collectec
in August, 1972
Subject No.
201
219
2*4
219
2'_ * '»
4.!"
l.-il
Total mercury
concentration
(Hg ppm)
r.70
^
4.78
J":il
•I.C.I
. .M
U. 5 1
i | \f.
2.11
People in the Goshoura district: col-
lected in October, 1972
Subject No.
W4
505
<;>
516
521
^47
550
,
599
,23
Sex
female
female
female
male
female
female
female
male
male
male
female
Age
3n
OS
-Q
45
44
57
42
tin
" '
Methyl mercury
concentration
(Hg ppm)
0 39
(I.J4
1 f!')
o.:<>
0 24
4.65
I. 1Q
D.64
1 . i "•
1 35
Total mercury
concentration
(Hg ppm)
f i . 7 3
0 . 89
(!..-')
2.92
II 00
o.so
5.15
' > . 70
1.36
1.31
1 73
fish in Yushima is high, compared with those in the area of comparison. How-
ever, this methyl mercury concentration is equivalent to about 1/10 of 0.5 ppm
methyl mercury concentration of tuna fish in the Pacific Ocean or Indian
Ocean [8], and it does not reach a poisonous level [15] under normal consumption.
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xShimabara
'Peninsula
Uji Peninsula
< -^ /
, Mikaku .4
' Yatsushiro
Ue j ima -> v i /H1/
* • i
': Yonenntou
- ^2ni layer
-10m layer
Figure 2. Normal current of the Yatu
shiro Sea.
.Shimabara]
'Peninsula'
Peninsula
/ ^-
Mikaku
-V -X
/-..-;"•'7: *; V
} ' )Hinaku
'; / ' /
Uej ima 6> I * /
^''/>";->'"/' * / ".^Ashikita
/ „ M A / x , v^
Shitajima „ M V/ ,
^^ Minamoto
Yonenotsu
Figure 3. Lowest tide of the Yatsu-
shiro Sea.
Among the specimens from offshore of the estuary of the Midori River,
gray mullets were the only fish selected. Since the cumulative amount of
mercury differs considerably from one type of fish to another, this mercury
concentration of gray mullets cannot be compared with the mercury concentra-
tion of other types of fish in other districts. By comparing the mercury
concentration of gray mullets from offshore of the estuary of the Midori
River, with that of gray mullets examined in 1971 in the Yatsushiro district
[2] (methyl mercury 0.003-0.005 ppm, total mercury 0.005-0.009 ppm) , Ushiku-
ka district [9] (methyl mercury 0.003 ppm, total mercury 0.007 ppm), Tomioka
district [9] (methyl mercury 0.002 ppm, total mercury 0.003 ppm), Nagasaki
Bay [7] (methyl mercury 0.001-0.002 ppm, total mercury 0.008-0.062 ppm), the
former exhibits a higher concentration than any others. Also, the mercury
concentration of short-necked clams in Osaki of the estuary of the Minamata
River [10] was previously established (methyl mercury 0.067 ppm, total mer-
cury 0.97 ppm; March, 1972). This concentration is based on dry weight.
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If it is converted to the figure based on the wet weight, it will be approx-
imately 0.016 ppm of methyl mercury and approximately 0.048 ppm of total
mercury. The mercury concentration of short-necked clams from offshore of
the estuary of the Midori River will not reach a poisonous level, as in the
case for the fish from offshore of Yushima, if a normal amount is consumed.
Observations of the relationship between the distance from the Minamata
Bay and the mercury concentration of fish reveal that for the Yatsushiro Sea,
the one in the Minamata Bay shows the highest [9] (methyl mercury 0.062-0.416
ppm, total mercury 0.112-1.015 ppm), followed by that outside of Minamata
Bay (around Awaji Island), offshore of the estuary of the Minamata River,
the fishing ground of scabbard fish off Minamata. It was also found that the
greater the distance from Minamata Bay, the lower the mercury concentration
becomes. The lowest mercury concentration of fish in the Yatsushiro Sea is
indicated in the fish from near Yatsushiro, measured in the previous investi-
gation [2, 9j. However, the mercury concentration of the fish in Yushima
which is further than Yatsushiro shows a higher value than that in Yatsushiro.
The tidal flow of the Yatsushiro Sea is such that during high tide the
current flows in from the outside sea into the Yatsushiro Sea to the north
through each channel, and during low tide it flows through the Yatsushiro
Sea in a completely opposite direction to the south. Approximately 98% of
the amount of flow to and from the Yatsushiro Sea is through three channels:
Motonojiri, Mebuki, and Kuro. The amount of flow to and from the Ariake
Sea through two northern channels of the Yatsushiro Sea, Mikaku and Yanagi,
is extremely small. Since the average water level of the northern part is
higher than that of the southern part, the normal flow is in the direction
of the south for the surface level (2m layer). Even for the 10 m level, the
flow of the northern part and close to the islands of Tengusa is in the direc-
tion of the south, similar to the surface level. It has been reported that
only the flow through the Kuro channel can go to the north offshore of Mina-
mata and reach the offshore of Hinaku [11] (see Figure 2 and Figure 3).
Since this south-bound normal current prevails, it is impossible that the
mercury flowing into the Minamata Bay flows into the Ariake Sea through
-------
Yatsushiro by the tidal flow. The following facts [12] prove that the mercury
flowing out to the Minamata Bay does not reach the Ariake Sea offshore of
Yatsushiro: the mercury concentration in scabbard fish in the estuary of
the Minamata river was 10.6 ppm, whereas the one in Yatsushiro was 0.4-0.08
ppm, as reported by Kitamura, et al. in 1959, and the mercury concentration
of fish in the Yatsushiro district indicates a lower value than that of the
Ariake Sea, as shown in 1971 [2, 9] and the present investigations.
During this investigation, the mercury concentration of the fish off-
shore of Yushima was higher than that in the Port of Nagasaki [7] and was
comparable or higher than that in the Goshoura and the Kuratake districts
of the 1971 investigation [2, 9]. Therefore, the reason for the mercury in
fish offshore of Yushima must be considered. In order for the mercury to
accumulate in fish, it is necessary that one of the following conditions
be met: tho area is mercury contaminated, fish swim from an area which is
contaminatou by mercury, or the fish are on the top of the feed chain and
easily accumulate mercury. As mentioned previously, Yushima offshore is
not contaminated by mercury flowing out from Minamata Bay. Also, except
sea breams, wellfish, bera, and garakabu, all three stay in fixed places.
According to the report by the Seikai district marine laboratory, [11] almost
all of the marked fish released in the southern part of the Yatsushiro Sea
moved to the south, and the only fish which moved northward were Konoshiro,
released in the middle part of the Yatsushiro Sea. Although the fact that
the fish run from the outside sea into Minamata Bay, stay there until the
mercury is accumulated, move into the Yatsushiro Sea northward, go out to the
Ariake Sea, and reach to offshore Yashima cannot be denied, the proportion
of such fish among fish offshore Yushima is extremely small and also the
mercury is not accumulated from the chain of eating fish offshore Yushima.
Therefore, it can be assumed that the Yushima area contains a relatively high
concentration of mercury and the mercury does not come from that discharged
from the Minamata Bay, but from some other sources. The information on whe-
ther the Yushima offshore was contaminated by mercury in the past is only
available through the results of measuring the mercury concentration in the
hair of people who lived in the three districts along the Ariake Sea in
10
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1961 [13]: Nagasu (average, 9.7 ppm), Kawauchi (average, 5.2 ppm), and Kawa-
guchi (average 10.1 ppm), and the 1959 report [12] that intestines of a cat
showed a relatively high concentration of mercury.
Some people in the Minamata district had more than 100 ppm of mercury
concentration in their hair in 1960 f!2, 13]. However, the mercury concentration
gradually declined to 2.6-73.8 ppm, average, 9.2 ppm (65 persons) in 1968,
1.2-18.3 ppm, average 5.5 ppm (44 persons) in 1969, and 1.2-9.5 ppm, aver-
age 3.7 ppm (26 persons) in 1970 [6], This decline matches well with the
decline of the mercury concentration in fish and shellfish in Minamata Bay [6].
In this investigation, the mercury concentration in hair in the Minamata
district was 2.14-14.82 ppm; the average was 6.16 ppm (34 persons). This
value is slightly higher than the mercury concentration in hair in general
at the present time, but is not exceptionally high. Sixteen out of 34 sub-
jects in the Minamata district have families who were diagnosed as having
Minamata disease, and are considered to have been exposed to high mercury
contamination in the past.
The mercury contamination in hairs of people in the Goshoura district
was 0.39-5.15 ppm and an average of 1.54 ppm (11 persons). This value is
lower than the value in general cases. Since the investigation of the health
conditions of people started there, they have begun not eating fish so often.
This is considered to be the reason for the low value of mercury in hair.
In general, the mercury in hair relates to the amount of mercury intake.
The more the mercury intake, the more the mercury in hair. According to
the report of the hygienic laboratory of Kagoshima prefecture [14], a per-
son whose hair contained 228 ppm of mercury in 1960 reduced the mercury
concentration to 33.1 ppm after 22 months; for a person with 144 ppm of mer-
cury it was reduced to 14 ppm after 20 months. For a person with 208 ppm it
was reduced to 18.8 ppm after 21 months, and for a person with 153 ppm it was
reduced to 15.8 ppm after 23 months by controlling the eating of fish and
shellfish under the prefecture's guidance. Therefore, the mercury contained
in hair is effective in determining the current contamination by mercury, but
11
-------
does not provide important information for observing the past contamination
of the mercury. In this investigation, people in the Goshoura district
showed a low value of mercury concentration in their hair. However, judging
from the fact that 13.4% of the subjects in 1960 (1160 persons) had 50-920
ppm [13] , it cannot be denied that the people in the Goshoura district were
contaminated in the past.
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14
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TABLE 5. COMPARISON OF MERCURY CONCENTRATION IN FISH
FROM VARIOUS DISTRICTS
Collection place
(1)
Inside the
Minamata
Bay
Outside the
Minamata
Bay
(2)
Offshore the
estuary of
the Minamata
River
(2)
Fishing ground
for scabbard
fish off
Name of fish
or shellfish
Kusabi
Sea bream
Kawahagi
Sillago
Sillago
Bera
Bera
Swellfish
Swellfish
Tiger goby
Short-necked clam
(Awaji Island)
Bera
Bera
Bera
Sillago
Swellfish
Sillago
Sillago
Flathead
Bera
Swellfish
Short-necked clam
(Osaki)
Scabbard fish
Scabbard fish
Scabbard fish
Scabbard fish
Minamata Scabbard fish
Methyl mercury
Hg ppm/wet wgt.
0.217
0.186
0.062
0.312
0.374
0.236
0.416
0.258
0.173
0.251
*
0.081
0.402
0.182
0.255
0.440
0.202
0.050
0.065
0.062
0.060
0.068
*
0.067
0.048
0.054
0.022
0.020
0.024
Total mercury
Hg ppm/wet weight
0.494
0.465
0.112
1.015
0.915
0.910
0.636
0.308
0.219
0.579
*
2.400
0.510
0.342
0.472
0.528
0.530
0.060
0.110
0.085
0.210
0.130
A
0.970
0.300
0.240
0.110
0.060
0.064
UT
Goshoura
Hantai
Yano
Itsusaki
Horse-mackerel
Sea bream
0.009
0.004
0.019
0.009
0.011
0.027
0.014
0.141
0.039
0.040
15
-------
TABLE 5 (CONTINUED
Collection place
(3)
Kuratake
(1)
Ushihuka
(3)
Near Yabushiro
(1)
Tomioka
Name of fish
or shellfish
Sea carp
Takaba
Itsusago
Anaki
Huehuki bream
Perch
Sea bream
Sole
Gray mullet
Itsusaki
Kosho bream
Urazurahagi
Kawahagi
Gray mullet
Gray mullet
Gray mullet
Perch
Konoshiro
Kuro
Perch
Chinu
Turbot
Konoshiro
Mebaru
Gray mullet
Aigo
Kaokaki bream
Shark
Methyl mercury
Hg ppm/wet wgt.
0.008
0.006
0.094
0.073
0.007
0.049
0.024
0.008
0.003
0.015
0.016
0.009
0.046
0.005
0.003
0.004
0.021
0.007
0.004
0.056
0.013
0.006
0.008
0.008
0.002
0.003
0.008
0.015
Total mercury
Hg ppm/wet weight
0.074
0.023
0.442
0.244
0.075
0.231
0.181
0.041
0.007
0.140
0.100
0.075
0.134
0.009
0.005
0.008
0.049
0.015
0.011
0.223
0.031
0.039
0.037
0.020
i 0.003
0.005
0.031
| 0.041
(2)
Offshore
Shimoda
I
{ Kawahagi
\ Kawahagi
i Horse mackerel
; Horse mackerel
Kitsukori
0.050
0.020
0.025
0.018
0.080
0.058
0.155
0.320
0.080
0.198
16
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TABLE 5 (CONTINUED)
Collection place
(2)
Offshore
Yushima
(2)
Offshore the
estuary of
the Midor River
(2)
Northern Sea
of
Hokkaido
(4)
Offshore
the Port
of Nagasaki
Name of fish
or shellfish
Sea bream
Sea bream
Swellfish
Bera
Garakabu
Gray mullet
Gray mullet
Clam
Short-necked clam
Prawn
Bream
Bream
Bream
Bream
Horse mackerel
Horse mackerel
Turbot
Turbo t
Turbot
Turbot
Scabbard fish
Gray mullet
Gray mullet
Horse mackerel
Black bream
Turbot
Short-necked clam
Methyl mercury
Hg ppm/wet wgt .
0.085
0.028
0.060
0.030
0.120
0.010
0.014
"X
0.075
A
0.080
0.014
0.014
0.011
0.008
0.007
Total mercury
Hg ppm/wet weight
0.098
0.115
0.072
0.045
0.205
0.022
0.040
*
0.220
*
0.240
0.085
0.145
0.080
0.053
0.044
0.010 ; 1.904
0.012 0.247
0.007 0.021
0.006 0.020
0.007 ! 0.022
0.007 : 0.020
0.004 0.046
0.002 0.062
0.001 0.008
0.007 0.067
0.022 0.100
0.005 0.035
* *
0.001 0.030
(1) Investigation of Environmental Contamination by Mercury, collected in
November, 1971 (Analyzed by Fujiki): compiled by Japan Public Health
Society.
(2) This investigation, collected in November, 1972.
(3) Fujiki, Tajima, Omori: Kumamoto Med. Journal, Vol. 46, 1972, p. 635
collected in November, 1971
(4) Fujiki, Tajima, Omori: Unpublished, collected in February, 1971.
*Hg ppm/dry weight
**Collected March 1971
17
-------
5. Conclusion
In this investigation, mercury contamination in fish of every district
did not exceed 1 ppm and was contained within the general concentration of
the natural environment stated in the "Measures for Environmental Contamina-
tion by Mercury" issued by the Ministry of Public Welfare. Presently, there
are no areas contaminated environmentally by mercury which may cause problems.
Relatively high concentrations of mercury in fish in some districts in
the Ariake Sea have been observed, compared with other areas. The reason
for the accumulated mercury in the fish is not related to the mercury flowing
out from Minamata Bay, but is considered to be due to the mercury from
other sources. Also, since there is no previous investigation ranging over the
entire Ariake Sea, we cannot say whether this district was contaminated
by mercury in the past or not . However, from the results of this investiga-
tion, a suspicion has arisen that there might have been many more mercury
contaminated areas in the past. This will be an important subject in the
further study of mercury contamination.
REFERENCES
1. Department of Medicine, Kumamoto University. Minamata Disease at the
End of 10 Years Research. Epidemiological, Clinical-Medical and
Pathological Study of Minamata Disease at the end of 10 Years,
1972, p. 41.
2. Fujiki, Motoshi, Shizuko Tajima and Akiko Omori. Surveys and Studies
on Mercury Contamination in the Surrounding Areas of Minamata District
and Its Transition. Kumamoto Medical Assn. Journal, Vol. 46, 1972,
p. 635.
3. Irukayama, Katsuo, Motoshi Fujiki, Shizuko Tajima and Akiko Omori.
Changes in Mercury Contamination Conditions in Fish, Shellfish and
Sea Floor Sediments in the Minimata Region. Japan Public Health
Journal, Vol. 19, 1972, p. 25.
18
-------
4. Yamaguchi, S and H. Matsumoto. Ultramicrodetermination of Mercury
in Biological Materials by Atomic Absorption Photometry. Industrial
Medicine, Vol. 10, 1968, p. 125.
5. Japan Public Health Society. Biological Contamination Survey of Water
Contaminated Areas; Guidelines on Metallic Analysis Method of
Examining Animals and Plants (Report No. 1), 1970, p. 14.
6. Fujiki, M. The Transitional Condition of Minimata Bay and the Neigh-
boring Sea Polluted by Factory Waste Water Containing Mercury.
Proceedings of the Sixth International Water Pollution Research
Conference, 1972, pp. C-6-12.
7. Fujiki, Motoshi, Shizuko Tajima and Akiko Omori. Unpublished.
8. Yamanaka, Sumie, Mie Suzuki, Takeshi Kondo and Kiichi Ueda. Mercury
Level in Tuna and in Hair of Tuna Fishermen (Report No. 2). Japan
Hygiene Journal, Vol. 27, 1972, p. 117.
9. Japan Public Health Society. Survey on Environmental Contamination
by Mercury; Detailed Survey on Minimata Bay. 1973, p. 1.
10. Pollution Bureau, Kumamoto Prefecture. Report on Surveys and Studies
Concerning Mercury Environmental Contamination of Minimata Coastal
Area. 1972.
11. Western Sea Region Marine Research Center. Surveys and Studies of
Marine Life Relative to Minamata Disease. 1964.
12. Kitamura, Seiji, Kyoji Ueda, Jitsuko Niino, Irei Ujioka, Hikoji Misumi
and Toshiyuki Kakita. Findings on Chemical Toxins Relative to Mina-
mata Disease (Report No. 5) . Kumamoto Medical Association Journal,
Vol. 34 (Supplement 3), 1960, p. 593.
13. Matsushima, Giichi. Survey of Mercury Level in Hair Relative to
Minamata Disease. Kumamoto Prefectural Hygiene Research Center
Report for 1970. 1972, p. 26.
14. Sakata, Akira, Takeo Orita, Muneyasu Koriyama, Kin Nakahara and Teiko
Hozumi. Survey of Mercury Level in Hair Relative to Minamata
Disease. Kanaito Prefectural Hygiene Research Center Report, No. 2.
1962.
15. Kitamura, Seiji. Extremely Small Amount of Heavy Metals in Food.
Food Hygiene Research, Vol. 21 (6), 1971, p. 19.
19
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2. STUDIES ON TRANSFORMATION OF INORGANIC MERCURY FOUND IN MINAMATA BAY
SEDIMENTS INTO METHYL MERCURY
Hygiene Seminar, Department of Medicine
Kumamoto University
Team member: Motoshi Fujiki
Research assistant: Shizuko Tajima
I. PREFACE
More than ten years have passed since the outbreak of Minamata disease
in Minamata Bay and the surrounding areas. When one observes the transition
of the mercury contamination situation [1, 2, 3, 4, 5] in the area of Mina-
mata Bay during this period, it can be seen that there were no changes in the
mercury level in sediments in Minamata Bay, but that there was a decrease of
mercury in fish and shellfish. At present, almost none of the fish and shell-
fish contain mercury in excess of 1 ppm. As for mercury in the hair of Mina-
mata residents, its level occasionally exceeded 100 ppm up until 1960 [1], but
gradually declined to an average 9.23 ppm around 1968, 5.36 ppm in 1970, and
is presently 3.75 ppm. Moreover, the acetaldehyde manufacturing facility of
the Minamata plant of the Chisso Corporation modified its mercury utilizing
process in June, 1966, to that of a complete circulation-type and suspended
its manufacture in May, 1968. Further, at the vinyl chloride facility, a
mercury removal device was installed in July, 1969, and the use of mercury was
dropped by revising manufacturing methods in March, 1971. No mew mercury con-
tamination has since been reported from that plant.
Jensen and his associates [6] claimed that anaerobes in sediments on
the floor of lakes transformed inorganic mercury into methyl mercury, while
Wood and his associates [7] held that methyl mercury was formed by the reaction
of methyl cobalamine found in anaerobes with inorganic mercury. Tajima [8]
20
-------
established the formation of methyl mercury through the reaction of acetalde-
hyde, acetic acid, and peracetic acid with inorganic mercury, as well as by
directing ultraviolet rays on acetic acid and inorganic mercury. Ukita and
his associates [9] formed methyl mercury through a reaction of inorganic mer-
cury in the liver of tuna. Sotomura and his associates [10] reported that
aerobes decomposed and transformed mercury compounds into metallic mercury,
whereas anaerobes decomposed methyl mercury and transformed it into inorganic
mercury, with a part of the anaerobes transforming inorganic mercury into
methyl mercury. Kitamura and his associates [11] contended that both aerobes
and anaerobes converted inorganic mercury into methyl mercury, followed by
reconversion of methyl mercury into inorganic mercury. Matsumura and his
associates [12] collected 35 kinds of microorganisms from sediments on the
bottom of a lake and cultured them in a culture containing phenyl mercury
acetate, but were unable to find any trace of methyl mercury. Tajima [8]
administered inorganic mercury in mice in an attempt to learn whether there
was transformation into methyl mercury in vivo, only to find that there was
no such transformation. There are various reports, as can be seen above.
Many researchers have confirmed, and it is widely accepted, that methyl mer-
cury can be formed by the reaction of methyl cobalamine, found in anaerobes,
with inorganic mercury and by the reaction of acetaldehyde and acetic acid
with inorganic mercury. However, there still is disagreement as to the
transformation of inorganic mercury into methyl mercury in microorganisms or
in vivo.
As explained earlier, the contamination of the biological environment
by mercury in the Minamata district has been alleviated to a great extent,
although it is still incomparable with that of the non-contaminated areas.
However, a large amount of inorganic mercury (thought to be primarily mercury
sulfide) exists even now in sediments in Minamata Bay. Based on numerous
reports on the formation of methyl mercury, it cannot be categorically stated
that inorganic mercury contained in sediments in Minamata Bay will not natur-
ally be transformed into methyl mercury. In our belief that further studies
were warranted, we conducted the following experiment.
21
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II. EXPERIMENTAL MATERIALS AND METHOD OF
ANALYSIS OF MERCURY
1. Experimental Results
1) Minamata Bay sediments
Minamata Bay sediments (containing 100 ppm of total mercury and 0.01
ppm of methyl mercury) were obtained from a point offshore the southern coast
of Myojin-misaki in the northern sector of Minamata Bay (see Sketch).
2) Waste water
The following five types were used as waste water for our experiment:
A: 1.5% acetic acid solution;
B: City sewage (from Kumamoto city limits);
C: Waste water from sorbic acid plant of Minamata plant of Chisso
Corporation;
D: Waste water from glyoxal plant of above plant;
E. Waste water from triacetate plant of same plant.
2. Method of Mercury Analysis
Analysis of the reactant and of methyl mercury in sediments was con-
ducted as follows:
The liquid layer was adjusted to pH 1 by adding hydrochloric acid;
following treatment with cuprous chloride, the methyl mercury was extracted
with benzene, treated with glutathione, re-extracted with benzene and
measured by the gas chromatograph method [13].
22
-------
The sediments were adjusted
to pH 1 by adding hydrochloric
acid, with the liquid level at
about 100 ml. Cuprous chloride
was added and allowed to stand
at room temperature for three
days, after which it was suction-
filtered, and methyl mercury
contained in the filtrate was
extracted by the usual method.
Measurement was by gas chromato-
graphy [13].
Myoj in-misaki
Umedo
>
Minamata plant
'
Koiji 'island Collection
Fukuroura
Figure 1. Site of collection of Mina-
mata bay sediments
The total mercury in the
sediments was measured by the
dithizone colorimetric method
by adding nitric acid to the
sediments and letting it stand for three days, after which it was suction-
filtered. An appropriate amount of filtrate was then taken, heated, and re-
duced with sulfuric acid and potassium permanganate.
III. EXPERIMENTAL METHOD AND FINDINGS
1. Reaction of Reagent with Inorganic Mercury, Acetic
Acid, City Sewage, and Industrial Waste Water
Three mg of mercury (II) nitrate and 2 mg of mercury (II) oxide were
added as reagent into each of the five 500 ml beakers containing waste water
A - E. Further, 300 ml of 1.5% acetic acid solution was added to A, 300 ml
of city sewage (from Kumamoto city limits) to B, 300 ml of wagte water from
the sorbic acid plant of Minamata plant to C, 300 ml of waste water from the
glyoxal plant of the same plant to D, and 300 ml of waste water from the tri-
acetate plant of the same plant to E. The beakers were then capped with a
23
-------
film of saran wrap and left outdoors from October 24 to December 18, 1972,
exposing them to sunlight for a total of 200 hours.
Table 1 reflects the results of measurements of methyl mercury formed in
the reactant upon reaction. All of the reactions produced methyl mercury.
TABLE 1. METHYL MERCURY FORMED FROM MINAMATA BAY SEDIMENTS, INOR-
GANIC MERCURY AND WASTE WATER (Hg pg)
Source of -_ __ .Type of waste water
inorganic mercury ____^
3 mg of mercury (II) nitrate and
2 mg of mercury (II) oxide
50 g of Minamata Bay sediments (wet sediments,
includes about 5 mg of total mercury and
about 0.5 yg of methyl mercury)
Liquid layer portion
Sediment portion
Minamata bay sediments to which 3 mg of mer-
cury (II) nitrate and 2 mg of mercury (II)
oxide have been added
Liquid layer portion
Sediment portion
A
0.90
0.00
0.52
-
—
B
0.36
0.00
0.42
-
—
C
4.14
0.00
0.50
0.00
0.52
D
2.34
0.00
0.45
0.00
0.51
E
0.27
0.00
0.48
0.00
0.49
2. Reaction of Minamata Bay Sediments with Acetic
Acid, City Sewage, and Industrial Waste Water
*
As in experiment 1, above, 50 g of Minamata bay sediments (including
about 5 mg of total mercury and 0.5 jag of methyl mercury) were put into each
of the five 500 ml beakers containing waste waters A - E. Then, 300 ml of
1.5% acetic acid solution was added to A, 300 ml of city sewage (from Kuma-
moto city limits) to B, 300 ml of waste water from the sorbic acid plant of
Minamata plant to C, 300 ml of waste water from the glyoxal plant of the
24
-------
above plant to D, and 300 ml of waste water from the triacetate plant of the
same plant to E. The beakers were then exposed to sunlight for 200 hours.
Following the reaction, they were suction-filtered, and methyl mercury
in the liquid layer and sediments was measured, with results as shown in Table
1. No methyl mercury was detected in any of the liquid layers. In the sedi-
ments, methyl mercury corresponding to a level of methyl mercury existing
prior to the reaction was noted, but no new methyl mercury was found.
3. Reaction of Minamata Bay Sediments, in Which the
Reagents Mercury (II) Nitrate and Mercury (II)
Oxide were Added, with Industrial Waste Water
Into each of the three 500 ml beakers containing waste waters C - E was
added 50 g of Minamata Bay sediments (including about 5 mg of total mercury
and 0.5 yg of metbyl mercury), 3 mg of mercury (II) nitrate and 2 mg of mer-
cury (II) oxide as reagents. Then 300 ml of waste water from the sorbic
acid plant of Minamata plant was added to C, 300 ml of waste water from the
glyoxal plant of the same plant was added to D, and 300 ml of waste water
from the triacetate plant of the same plant was added to E. And, as in the
experiment 1, above, they were exposed to sunlight for 200 hours.
Following the reaction, they were suction-filtered, and the methyl mer-
cury in the liquid layer and sediments was measured, with the results shown
in Table 1. No methyl mercury was found in any of the liquid layers, and no
newly formed methyl mercury was found in the sediments.
4. Effects of Aeration of Inorganic Mercury Source
on Methyl Mercury Formation
Fifty grams of Minamata Bay sediments from which water had been removed
by suction and 300 ml of deionized water were put into each of the three 500
ml triangular flasks and mixed well. One of these was immediately suction-
filtered, and methyl mercury in the liquid layer and sediments was measured.
25
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The remaining two were aerated for 40 hours at a permeability of 150 ml per
minute. Following aeration, one of the two was immediately suction-filtered
and methyl mercury in the liquid layer and sediments was measured. The last
flask was added with acetic acid to make a 1.5% solution, its contents trans-
ferred to a 500 ml beaker, and exposed to sunlight for 200 hours, as in ex-
periment 1, above. Following the reaction, it was suction-filtered, and
methyl mercury in the liquid layer and sediments was measured.
To the 500 ml triangular flask was added 5 mg of the reagent mercury
sulfide and 300 ml of artificial sewage [14] seeded with 2 ml of city sewage,
the contents being aerated for 40 hours at a permeability of 150 ml per
minute. Following aeration, acetic acid was added to make a 1.5% solution,
the contents were transferred to a 500 ml beaker, and exposed to sunlight for
200 hours, as in experiment 1, above. After the reaction, it was filtered
and measured for methyl mercury.
The above results are shown in Table 2. Methyl mercury in Minamata Bay
sediments increased slightly as a result of aeration. Also, when the reaction
was effected with 1.5% solution of acetic acid under exposure to sunlight
following aeration, methyl mercury was formed, being detected in the liquid
layer and in the sediments.
When reaction was effected with 1.5% solution of acetic acid under ex-
posure to sunlight following aeration with the reagent mercury sulfide, methyl
mercury was found in the reactant.
5. Adhesiveness of Methyl Mercury in Minamata
Bay Sediments
To each of the three separating funnels were added 50 g of Minamata Bay
sediments from which had been removed by suction 300 ml of deionized water,
and 0 yg, 1 yg, and 5 yg of methyl mercury, respectively. After they were
shaken and mixed for 3 hours, they were suction-filtered and methyl mercury
in their liquid layer and in sediments was measured.
26
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TABLE 2. EFFECTS OF AERATION OF SOURCE OF INORGANIC MERCURY UPON
METHYL MERCURY FORMATION (Hg yg)
Source of
inorganic mercury
I | Reactant after
Pre- | Post- aeration with
aeration iaeration* 1.5% solution
of acetic acid
50 g Minamata Bay
sediments (water
removed by
suction)
5 mg mercury
sulfide
Liquid layer
portion
Sediment
portion
Liquid layer
portion
0.00
0.80
"""
0.00 0.24
1.05
"
3.20
i AI
Conditions of aeration: 150 ml/min of air
over 40 hours.
TABLE 3. ADHESIVENESS OF METHYL MERCURY IN MINAMATA BAY SEDIMENTS
(Hg- Mg)
Amount of methyl mercury added (Hg- yg)
300 ml of deionized water to which methyl mercury was
added was shaken with 50 g Minamata Bay sediments
(wet sediments)
Liquid layer portion
Sediment portion
0
0.00
0.44
1.0
0.00
1.41
5.0
0.00
5.64
The results are shown in Table 3. Methyl mercury, in 1 yg and 5 yg
levels, was found only in the sediments, and not in the liquid layers.
6. Effects of Exposure Time to Sunlight on Methyl
Mercury Level
The standard aqueous solution of methyl mercury — 100 ml of 0.05 ppm,
0.5 ppm, and 2.5 ppm — was poured into 200 ml beakers and exposed to sunlight
for 200 hours, as in experiment 1, in order to study the effects of exposure
27
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time on the level of methyl mercury. As shown in Table 4, the level of
methyl mercury declined as time progressed.
TABLE 4. EFFECTS OF EXPOSURE TIME TO SUNLIGHT ON METHYL MERCURY
LEVEL (WITH 100 AS THE METHYL MERCURY LEVEL PRIOR TO SUNLIGHT
EXPOSURE)
unlight exposure time
O.CGppii, 100ml
0.5 pp-n, 100m!
2 5 ppm. 100:n 1
0 hrs
100
100
100
150 hrs
Oo
39
89
200 hrs
4
79
81
IV. COMMENTS
It is widely known [15] that various inorganic mercury compounds other
than mercury sulfide form methyl mercury [8] as a result of reaction with
compounds having active methyl groups, such as acetaldehyde, acetic acid,
and peracetic acid. However, no experiment has been conducted so far to
determine whether this type of reaction occurs in nature. As the first step
in our experiment to ascertain whether methyl mercury is formed in nature,
the authors initially studied whether methyl mercury can be formed as a
result of reaction between industrial waste water and inorganic mercury [16].
We learned as a result that a methyl mercury yield of from 0.6% to 2.4%
(yield relative to the level of mercury used) can be obtained as a result of
reaction of 300 mg mercury (II) nitrate and 200 mg mercury (II) oxide with
waste water from a sorbic acid plant, from a glyoxal plant, and from a tri-
acetate plant, and that methyl mercury is not formed when these waste waters
were treated with a cyclator or when the source of mercury was mercury sul-
fide. As the amount of mercury used in this experiment was relatively large,
we could not consider the situation to be identical in nature. For this
reason in our latest experiments, we utilized a level of reagents — inor-
ganic mercury and Minamata Bay sediments — equivalent to the density of
28
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inorganic mercury in Minamata Bay sediments, in order to ascertain whether
methyl mercury was formed in nature.
The reaction of the reagent inorganic mercury containing a level of mer-
cury identical to that in Minamata Bay sediments with industrial waste water
resulted in a low methyl mercury yield (relative to the amount of mercury used)
of from 0.005 to 0.08%, as compared to earlier experiments. The reason for
the low yield is believed to be due to the loss of newly formed methyl mercury
because of inclement weather during the experiment period, requiring about 40
days to acquire 200 hours of exposure to the Sun's rays. In the sunlight
exposure experiment with a standard aqueous solution of methyl mercury, a
distinct decrease of methyl mercury was noted after 200 hours. Thus, it is
possible that in our latest experiment the reactionconditions for formation
of methyl mercury were unsuitable.
Through the reaction of inorganic mercury with city sewage, a 0.07% yield
of methyl nercury was obtained. This was significant, in that it was an
indication of the dangers of methyl mercury formation, not only in industrial
waste water, but in nature as well.
In the Minamata Bay sediments, about 5 mg of mercury was found in the
form of total mercury. No methyl mercury was formed as a result of a reaction
between Minamata Bay sediments and acetic acid, city sewage, and industrial
waste water. Although methyl mercury was formed when the source of mercury
was the reagents mercury (II) nitrate and mercury (II) oxide, it was not
formed when the source of mercury was inorganic mercury in the sediments.
The reason probably is the abundance of sulfides in Minamata Bay sediments
[17], with inorganic mercury in the sediments assuming reactive inactivity in
the form of mercury sulfide. The fact that methyl mercury was not formed when
mercury (II) nitrate and mercury (II) oxide were newly added as reagents to
Minimata Bay sediments to effect a reaction with acetic acid, city sewage, and
industrial waste water probably indicates that sulfides in the sediments made
the newly added reagents of mercury (II) nitrate and mercury (II) oxide
inactive.
29
-------
As indicated by the results of the foregoing experiments, methyl mercury
will not form in Minamata Bay under existing conditions, despite the pre-
sence of inorganic mercury in the sediments and inflow of acetic acid, city
sewage, and industrial waste water. Even if there were an additional inflow
of inorganic mercury in an active form as mercury (II) nitrate and mercury
(II) oxide, it would change into an inactive form of inorganic mercury in the
sediments, provided the level of inorganic mercury was then equal to or less
than that in the sediments, without any possibility of methyl mercury being
formed in nature. However, methyl mercury could be formed under ideal con-
ditions, such as aeration of Minamata Bay sediments. As indicated in experi-
ment 4, should Minamata Bay sediments be aerated, inorganic mercury found in
the sediments will probably change into an active form with respect to the
formation of methyl mercury. As explained earlier, mercury sulfide is a
stable form and will not form methyl mercury in reaction with acetic acid
and industrial waste water [16]. However, Westoo [18] theorized, while lack-
ing any experimental evidence, that mercury sulfide was oxidized in nature by
aerobes and changed into mercury (II) sulfate, active in the formation of
methyl mercury. In order to verify this theory, the authors applied artificial
sewage seeded with aerobe-containing city sewage, aerated the reagent mercury
sulfide and, following aeration, effected a reaction with acetic acid in an
attempt to ascertain whether methyl mercury would form. It was found that a
greater amount of methyl mercury was formed than when mercury (II) nitrate and
mercury (II) oxide were used.
Following aeration of Minamata sediments and reaction with acetic acid
under sunlight exposure, methyl mercury thus formed was greater in the liquid
layer than in the sediments. This was an indication of the adhesive nature
of the sediments toward methyl mercury. In an experiment to determine the
adhesive property of the sediments on methyl mercury, 5 yg of methyl mercury
was completely adhered to 50 g of sediments from which water had been removed
by suction. Perhaps methyl mercury is not eluted, being bonded with a SH
group of humus in the sediments and surviving therein. The appearance of a
trace of methyl mercury in the liquid layer when methyl mercury was formed
30
-------
as a result of reaction following aeration of sediments was probably due to
a decrease of adhesivity of methyl mercury toward sediments, because of
partial decomposition of humus in the sediments under aerobic conditions.
The possibility of new dangers posed by the elution of methyl mercury in
sea water caused by the disturbance of Minamata Bay sediments containing very
small amounts of methyl mercury or by ingestion of methyl mercury containing
sedimentary particles by fish and shellfish has been pointed out. However,
it was found that, notwithstanding disturbance of Minamata Bay sediments and
elution of some methyl mercury, the latter tended to adhere to the sediments.
In 1959, when Minamata Bay was considered to be at peak contamination [19],
Kitamura and his associates [1] conducted a breeding experiment using Minamata
Bay sediments on lubworms, short-necked clams and small fishes, and measured
the mercury level in their bodies. Despite the fact that the sediments during
the breeding experiment were sufficiently disturbed, the deposit of mercury
in their bodies was very small. Such a deposit was negligible when compared
to the time when the Kumamoto Prefectural Marine Experimentation Station, in
an oyster breeding experiment in Minamata Bay, found that oysters from a
control district which were suspended in waters of Minamata Bay had as high a
mercury density (50 ppm) as local fish and shellfish. Based on such findings,
it is thought that the high level of methyl mercury deposit in fish and shell-
fish is largely due to methyl mercury existing in sea water, and that methyl
mercury adhering to sediments hardly affects them. Thus, even if sediments
in Minamata Bay were to be disturbed by dredging, safety can probably be
assured if aerobic conditions were avoided.
V. CONCLUSION
It has become clear that inorganic mercury, if present, will react with
city sewage and industrial water containing compounds with active methyl
groups, and form methyl mercury in nature. Methyl mercury will not be formed
in this instance if the mercury is in the form of mercury sulfide. However,
under aerobic conditions, mercury sulfide changes into inorganic mercury in
this reaction, and forms methyl mercury.
31
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Even now, sediments in Minamata Bay contain a large quantity of inorganic
mercury with the potential of forming methyl mercury. However, those inor-
ganic mercury compounds were of the inactive type, and did not form methyl
mercury during our experiment.
REFERENCES
1. Kitamura. Seiji, Kyoji Ueda, Jitsuko Niino, Irei Ujioka, Hikoji Misumi
and Toshiyuki Kakita. Findings on Chemical Toxins Relative to Mina-
mata Disease (Report No. 5). Kumamoto Medical Association Journal,
Vol. 34 (Supplement 3), 1960, p. 593.
2. Irukayama, Katsuo, Fumio Dai, Motoshi Fujiki, Takako Kondo, Shizuko
Tajima, Tsutomu Den, Hiroyuki Sasa, Masanori Hashiguchi and Sadao
Ushigusa. Mercury in Minamata Bay Sediments. Japan Public Health
Journal, Vol. 11 (9), 1964, p. 645.
3. Irukayama, Katsuo, Motoshi Fujiki, Shizuko Tajima, Akiko Omori, Hiroshi
Nakamura and Shunsuke Kuwahara. Mercury Contamination at the Time of
Suspension of Acetaldehyde Production at the Minimata Plant. Kuraamoto
Medical Association Journal, Vol. 43 (11), 1969, p. 946.
4. Irukayama, Katsuo, Motoshi Fujiki, Shizuko Tajima and Akiko Omori.
Transition of Mercury Contamination Conditions of Fish, Shellfish, and
Sea Floor Sediments of Minamata Region, Japan Public Health Journal,
Vol. 19 (1), 1972, p. 25.
5. Fujiki, M. The Transitional Conditions of Minamata Bay and the Neigh-
boring Sea Polluted by Factory Waste Water Containing Mercury. Pro-
ceedings of the Sixth International Water Pollution Research Confer-
ence, 1972, p. C-6-12.
6. Jensen, S. and A. Jernelbv. Biosynthesis of Mono- and Dimethyl Mercury.
Nordforsk Biocidinformation, No. 10. 1967, p. 4.
7. Wood, M. J., F. Scott Kenedy and C, F. Rosen. Synthesis of Methyl
Mercury Compounds by Extracts of a Methanogenic Bacterium. Nature,
Vol. 220, 1968, p. 178.
8. Tajima, Shizuko. Studies on the Formation of Methyl Mercury Compounds.
Kumamoto Medical Association Journal, Vol. 44 (10), 1970, p, 873.
31a
-------
9. Imura, Nobumasa, Hidemitsu Bo and Tadanoshin Ukita. Studies on Organic
Transformation of Inorganic Mercury; II, Reaction Transforming
Inorganic Mercury into Methyl During Tests in Animals. Collection of
Addresses before the 92nd Year Meeting of Japan Pharmacological
Society, Supplement No. 3., 1972, p. 196.
10. Tonomura, K., T. Nakagami, F. Futai and K. Maeda. Study on the Action
of Mercury-Resistant Microorganisms on Mercurials (1). The Isolation
of Mercury-Resistant Bacterium and the Binding of Mercurials to the
Cells. J. Ferment. Technol., Vol. 46, 1968, p. 506.
Yamada, M. and K. Tonomura. Formation of Methylmercury Compounds
from Inorganic Mercury by Clostridium cochlearium. J. Ferment.
Technol., Vol. 50, 1972, p. 159.
11, Kitamura, Masaji, Kimiaki Sano, and Masahiko Hirayoshi. Synthesis and
Decomposition of Organic Mercury Compounds by Micro-Organisms, Japan
Hygiene Journal, Vol. 24, 1969, p. 76.
12. Matsumura, F. ,Y. Gotoh, and G. M. Boush. Phenylmercuric Acetate: Meta-
bolic Conversion by Microorganisms. Science, Vol 173, 1971, p. 49.
13. Fujikl, Motoshi, Shizuko Tajima and Akiko Omori. Surveys and Studies
on Mercury Contamination in the Surrounding Area of Minamata District.
Kumamoto Medical Association Journal, Vol. 46 (11), 1972, p. 635.
14. McKinney, R. E. et al. Biocatalysts and Waste Disposal. II. Effect
on Activated Sludge. Sew. and Ind. Wastes, Vol. 25 (11), 1953, p.
1268.
15. Imura, Nobumasa. Changes in Mercury Compounds in Nature. Hygiene
Chemical, Vol. 18 (5), 1972, p. 291.
16. Pollution Bureau, Kumamoto Prefecture. Report on Surveys and Studies
Concerning Mercury Environmental Contamination of Minamata Coastal
Area. 1972.
17. Motosato, Yoshiaki. Report on Countermeasures Against Sludge off
Yatsushiro and in Mizunashi River.
18. Westloo, G. Personal communication, 1972.
19. Fujiki, Motoshi, Shizuko Tajima, and Akiko Omori. Transition of
Contamination by Mercury in the Minamata Region. Japan Hygiene
Journal, Vol. 27 (1), 1972, p. 115.
31b
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3. PROGRESS ON MINAMATA DISEASE AND ITS EPIDEMIOLOGICAL STUDY (Part 2)
Chair of Public Hygiene, Medical Department, Kumamoto University
Staff: Shigeru Nomura
Asst. Staff: Toshio Matsushita, Shin Nizuka, Noriki Arimatsu,
Atsushi Ueda, Junichi Misumi, Toshie Tomio,
Hiroyuki Teruya, Tadako Ueda
We already reported the results of a pilot study in the previous report
in regard to the environmental contamination due to organic mercury in
Minamata Bay, including its adjacent areas and along the Shiranui Sea, and
also in regard to the health damage to inhabitants in the seacoast area. In
the study, we conducted the health examination for the inhabitants of Tsukiura,
Idetsuki and Yudo of Minamata City, areas in which multi-breakouts of the disease
occurred and for the inhabitants of Goshoura-machi, Amakusagun, which are
areas susceptible to contamination.
In this report, first we investigated several health indicators that show
how the dynamic populations of these objective districts have been changing
for years due to the health damage to its inhabitants caused by the organic
mercury contamination along the coast area. Second, we investigated the way
that the inhabitants were examined in districts and the significance of the
examinations. Third, we investigated the actual conditions of the fisherman's
work and their dietary habits on the Shiranui Sea coast which area is extremely
susceptible to direct contamination by organic mercury from the sea. This is
why the Minamata Disease has broken out so frequently there. We also tried to
trace down the actual conditions of the Minamata disease in our investigations,
the results of which are described below.
32
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1. Influence of the Environmental Contamination as Viewed from the
Local Health Index
It is assumed that the environmental contamination due to organic mercury,
etc. has caused a number of Minamata disease cases, and has clearly affected
the health of the inhabitants who live in the contaminated districts; there-
fore, the health standard of the districts has declined. To clarify this
decline, last year we objectively interviewed families in the contaminated
districts. We checked the average age and causes of death of anyone in the
interviewed families who died between 1945 and 1971. The results showed that
the mercury contamination directly influenced the age and cause of death [1].
There are various health indicators to measure a health standard of a
district; however, an expert group of WHO particularly adopts the PMI (pro-
portional mortality indicator) [2], rough mortality rate and average remainder
of life based on the mortality statistics as the health indices. These are
considered to be reliable sources to use for the general health indices [3].
Furthermore, there is an index that gives average death rates [4, 5] which
displays the same characteristics as the indices described above, and its appli-
cability is being investigated [6].
Therefore, by using these indices, we investigated the influence of
organic mercury, etc. on the health standard of the contaminated districts,
and also tried to analyze its influence on the cause of death.
I. OBJECTIVE METHOD OF INVESTIGATION
We selected the districts of Tsukiura and Fukuro of Minamata City which
are heavily contaminated districts, and the district of Arashiguchi in
Goshouramachi which is on the opposite seashore of Minamata City as a sus-
ceptible district of contamination for our objective investigation. We com-
pared them with the results of the Akazaki, Suko and Ohura districts of
Ariakemachi that faces the Shimabara Bay, which were considered districts
33
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free of the contamination. The characteristics of these districts were des-
cribed in a previous report. The investigation dealt with the people who had
been living in these districts during the period from January 1, 1948 to
December 31, 1971. As an investigation reference, we used the death certifi-
cates of the inhabitants in the said districts obtained from each respective
town office for this 24-year period, and the official items were copied and
summarized for analysis.
The total number of deaths in the districts during this period were as
follows: male 468, female 374 in Minamata district, male 330, female 280 in
Goshoura district; and male 620, female 682 in Ariake district (these figures
excluded deaths due to war).
In addition, in order to obtain the mortality rate by age groups, the
corrected PMI and the corrected average death age for the Kumamoto prefecture in
1960, we standardized the age figures of the dynamic population statistics by
placing them in categories of 5-year differences. Furthermore, the classifi-
cation of the cause of death is based on a "50-Item Classification of Death
Causes (Table B)" of the "International Classification".
II. INVESTIGATION RESULTS
1. Index of Mortality Statistics
The actual condition of mortality in the districts investigated during
the 24 years from 1948 to 1971 was examined according to the indices of
mortality rate by age group and PMI.
(1) Mortality rate by age group
The mortality rate by age group in each district is obtained by
calculating the total deaths during the 24 years as indicated in Figure 1.
In every district, the mortality rate of school children, young and middle-
aged is comparatively low, and high in infants and the old, which is a
34
-------
tendency that is present throughout the country. However, when comparing 3
districts, there is some difference in the mortality rate by age group. Namely,
the mortality rate in the Minamata district is slightly higher for infants
and for those up to 59 years and less in the old as compared to the Ariake
district. This tendency is quite apparent in females. On the other hand,
the Goshoura district is very similar to the Ariake district except that the
mortality rate of baby girls and those in the age bracket of 45 to 49 is
slightly higher than in the Ariake district. When these are standardized
by the age grouping according to the dynamic population statistics of the
Kumamoto Prefecture in 1960, some different tendencies are observed. That is,
the mortality rate in the Minamata district is slightly lower than in the
Ariake district in infants and the young of both sexes and higher in
school children. It is slightly higher in the middle and old age brackets,
which indicates that both districts are similar. Furthermore, the Goshoura
district exhibits no particular differences in males but the rate is higher in
school children, and lower in the old, as far as females are concerned.
(2) Mortality of infants and stillbirths
The death rate in infants is often used as the index which sharply
reflects a local health standard. Using that index, we analyzed those dis-
tricts as indicated in Table 1. The death rate in infants for the 24 year
period is as follows: 26.3 in the Minamata district, 36.1 in the Goshoura
district and 32.8 in the Ariake district. When we check the yearly changes
for the 5-year periods, the death rate in the Ariake district markedly
declines year after year. In the Minamata district, it gradually declines
except it slightly increases from 1958 to 1962. On the other hand, in the
Goshoura District, the decline in the number of births does not parallel
the decline in the number of deaths, that is, the death rate in infants tends
to increase. The results of the existing statistics of the districts are
shown in Table 2. The death rate in infants in Minamata City and Ariakemachi
gradually declines, whereas the decline is slow in the Goshoura district,
which substantiates the results of the districts.
35
-------
Although a record of stillbirths is not dependable because each one
has not always been reported, we checked the stillbirth rate in the districts
from the existing references as shown in Table 2. The stillbirth rate in
Minamata City is slightly higher than in Goshouramachi and Ariakemachi. However,
we must take into consideration the discrepancy in notification of stillbirths
between the city and the remote village.
(3) PMI and death rate of the old
Good health can be maintained by eliminating the damaging factors and
a long life can thus be promised. Therefore, as the index to measure the
local health and the sanitation standards, the PMI and death rate of the old
are used frequently. With these standards, we investigated the mortalities
in the districts and indicated the results in Table 3. If we summed up the
total deaths in 24 years for each district, the PMI, as the index of popula-
tion structure, is 62.4% for males and 64.5% for females in the Minamata dis-
trict, which percentages are significantly lower than the statistics of
70.3% for males and 76.0% for females in the Ariake district. On the con-
trary, in the Goshoura district, the PMI is significantly lower than in the
Ariake district only for females.
The death rate for the over 65-year bracket, is the same as the PMI, i.e.,
41.9% for males and 46.1% for females in the Minamata district, whereas
the PMI is 51.9% and 62.3%,respectively, in the Ariake district. The death
rate for the old in the Minamata district is significantly (statistically)
lower than in the Ariake district for both sexes, which indicates a low
health standard. On the other hand, no noticeable difference is observed
in the Goshoura district.
In order to obtain the corrected PMI, we standardized the ages based on
the dynamic population statistics of the Kumamoto Prefecture in 1960. As
you can see in Table 4, all the districts show that the corrected PMI for
5-year-periods gradually increased for both sexes, which complies with a
yearly change. When we compared these between two districts, the value in
36
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(male)
Age group
(female)
.*_-*•
Minamat^ district
Goshoura district
- Ariake district
I I 1 1 1 1 1 1 1 L_
10
15
Figure 1. Mortality frequency classified by age group.
TABLE 1. LAPSE OF INFANT DEATH RATE
Years Minamata
No. No. inf. Inf.
i births deaths dth
rate
t
1948-1952 ' ;-,,, .„ -... s
1953-1957 "":' " -M '
1958-1962 i me, 1-. )., .->
1963-1967 i 4~|; ;' 'fj-j
1968-1221. ;
1948-1971 ; •.,,- ,- ,, ;
r
Goshoura i Ariake
No, No. inf. Inf.
bths. deaths dth.
rate
-'•is '.;; :>-> l
:r)ti n '0 :.
LOS y ,ii.;i
133 S 5'J '.',
l" ,;i •'
>l.-' :r> ;(
"Ml IS Si
."Ml ; .-,
Hi.'i 0 i1
C7H !'ii ,;3
^nfant
death
rate
1
;l
1
(1
.1
Note: 1) The number of births was obtained by the birth certificates
(Family register) of inhabitants in the districts.
2) Infant death rate per 1000 births.
37
-------
the Mlnamata district is generally lower than in the Ariake district, which
is quite apparent in females. Furthermore, the PMI value for females in the
Goshoura district is slightly higher than in the Minamata district. In
particular, we can say that local factors are recognized which make health
standards for females in the Minamata district inferior.
(4) Average age at death
We calculated the average death age by each 5 year period in regard to
the total deaths in 24 years for each district. As indicated in Table 5,
the average death age of the total deaths in 24 years is, 50.36 1 28.91 years
for males and 52.50 + 29.49 years for females in the Minamata district, which
is apparently lower than in the Ariake district, i.e., 56.56 + 27.74 years
for males and 61.22 + 28.06 years for females. This tendency is also observed
in the yearly change for each 5-year-period. On the other hand, the total
deaths in 24 years in the Goshoura district are significantly lower than in
the Ariake district for females and when the yearly changes are checked each
5-year period, the death average for both sexes between 1963 - 1967 are lower
in the Ariake district. From the above figures, we calculated the
corrected average death age by standardizing the ages according to the popu-
lation structure of Kumamoto Prefecture in 1960 as shown in Table 6. When
observing the yearly changes for each 5-year-period, the death ages in both
sexes for the respective districts are notably prolonged in proportion to
the passage of time. In addition, if the districts as a group are compared,
no noticeable differences are observed for males whereas the life expectancy
for females in both the Minamata and Goshoura districts are lower than in the
Ariake district.
2. Causes of Death
As regarding the cause of death written on a medical death certificate,
its preciseness has a certain limit; therefore, its dependability differs
according to every disease. Considering this factor, we investigated the
causes of death of the inhabitants in the Minamata district (which is a
contaminated district) and in the Goshoura district (which is a district
38
-------
susceptible to contamination) and checked if any epidemiological factors could
be observed. In this case, as the population is small, we analyzed the causes
of all the deaths for the 24 year period from 1948 to 1971.
(1) Death rate classified by causes of death
The total deaths for the 24 years in each district were divided into 5
groups, classified according to sex and causes of death, i.e., Group A (bacterial
infection), Group B (adult disease), Group C (diseases of pregnant women and
infants), Group D (non-disease) and Group E (others), and investigated their
characteristics in each district. The results are shown in Figure 2. When the
Minamata district is compared with the Ariake district, deaths occur less from
adult diseases and more from non-diseases (P < 0.05) in males, and deaths occur
more (P < 0.05) from bacterial infections and less (P < 0.01) from adult diseases
in females. In the Goshoura district, deaths occur less from adult diseases
and more (P < 0.01) from non-diseases in females. It is noted that the deaths
from adult diseases in the Minamata district are comparatively lower in both
sexes.
(2) Comparison of main causes of death between the districts
The total deaths in 24 years between the districts according to the
"50-Item Classification of Causes of Death (Table B)" are shown in Table 7.
When we compared males in the Minamata district with males in the Ariake district,
deaths by inflammation of the intestines and other laxative diseases, car
accidents and other unexpected accidents were apparently higher, and deaths
from senility (not accompanied by mental disease), non-inflammatory diseases
of the nerve center system were lower. Most of the deaths from other unexpected
accidents were caused by drowning in children and adults. When we consider females,
deaths from tuberculosis, meningitis and other unexpected accidents (mostly by
drowning) are higher, and deaths from cardiac diseases and senility (not accom-
panied by mental disease) are lower. In other words, for both sexes in the
Minamata district, it is very rare for anyone to complete the natural span of
life and many deaths were attributed to inflammatory diseases and accidents.
39
-------
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TABLE 3. PMI AND DEATH RATE OF THE OLD
PMIX) (%)
Male Female
Minamata Goshoura Ariake
62.4** 67.3 70.3
Male - Female
MLnanata Goshoura Ariake
64.5** 66.4** 76.0
Death rate (%) of those
over 65 years
41.9** 50.6 51.9! 46.1** 56.4
62.3
Total number of deaths
468
330
620 374
280
682
Note: 1) PMI: Proportional Mortality Indicator
(Death rate of those over 50 years in total deaths)
2) A P<0.1 *P < 0.05 **P < 0.01
Indicated the significant differences against the values of
the Ariake district according to the x -examination.
TABLE 4. COMPARISONS OF CORRECTED PMI BETWEEN THE DISTRICTS (Unit:%)
Years
1948-1952
1953-1957
1958-1962
1963-1967
1968-1971
Male
Minamata Goshoura Ariake
i>-, ; ;i ; -'• '•
;,; i, ii : -' '•
ID.I. ii :.
-li.^ i ' ii !'• •>
\* • " ., :#..;
Female
Minamata Goshoura Ariake
; i i ,-.._•
\>. '2 II -1 M 'i
i';.-i 11' 1 ,1i).>
!l ^ 1^ n I1.' V
Note: Age correction was made by using the dynamic population statistics
of the Kumamoto Prefecture in 1960.
41
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Years
TABLE 6. CORRECTED AVERAGE DEATH AGE (Unit: Years)
Male
Female
Male
Female
Minamata Goshoura Ariake; Minamata Goshoura Ariake
1943-1952
1953-1957
1958-1962
1963-1967
1968-1971
I-*. \
Note: Corrected ages by each 5 year group according to the dynamic
population statistics of the Kumamoto Prefecture in 1960.
Male
Female
0 10 20
40
30 60
(1948-1971)
o go ;oo r'
Minamata rX:X:X:::X:::X:xii^v ~
Goshoura
Ariake
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Goshoura
Ariake
f
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i i6«2i!
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Group A
(bacterial
infection)
Group D
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disease)
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C (diseases of
L_j pregnant women and infants)
2) *P <0.05 **P <0.01 (indicated the significant
differences against the values of the Ariake
according to x^ examination)
Figure 2. Death rate classified by causes of deaths.
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On the other hand, in the Goshoura district, deaths from cirrhosis of the
liver, nephritis, nephrosis and other unexpected accidents were higher, whereas
deaths from senility (not accompanied by mental disease), gastritis, duodenitis
and chronic gastroenteritis were lower in males. In females, deaths from
cerebral disease, nephritis, nephrosis, congenital abnormalities and other
unexpected accidents were higher, whereas the deaths from vesicular emphysema,
asthma and senility (not accompanied by mental disease) were lower, which
shows a reverse tendency as compared to the Minamata district.
III. GENERAL CONSIDERATIONS
This time we tried to investigate if the health standards of the
inhabitants of the contaminated districts have been affected by the waste
water from the factories which contains organic mercury, by using the health
indicators related to mortality. However, for the analysis of the references
obtained, we could not avoid a considerable extent of bias because each
district is so small and is divided into a limited district as a city or
town, and the population was also sparse; besides the collection of those
references was limited as the investigation required references from the past.
The PMI, rough mortality rate and average remainder of life, are
regarded to be very significant as health indicators to measure a local health
standard. However, their high applicabilities are better suited for large
population groups, such as a state. These are not appropriate indices to
measure the health standard of small local districts. It is thought, therefore,
that the indices can be used effectively by correcting the PMI or the average
age of mortality which are obtained by correcting and grouping the ages [6,7].
In order to correct the bias of the references due to the changes in
the population structure, we standardized the population and the age structure
of mortality in each district by using the 1960's dynamic population statistics
of the Kumamoto Prefecture. The year 1960 was just prior to the changes in the
population structures of the districts had started attributed to the influence
45
-------
of a high economic growth policy. According to the corrected PMI thus obtained,
the values for the Minamata district are lower than for the Ariake district for
both sexes and they are especially very low for females. The corrected average
age of mortality for females is slightly lower in the Minamata district than
in the Ariake district. Moreover, the stillbirth rate is slightly higher in
the Minamata district. In general we can assume that the health standard in
the Minamata district is inferior to that in the Ariake district.
In regard to the local differences in the causes of death, we must
take into consideration such differences as a concentration of medical care or
the social and economic conditions of the localities. As for the concentration
of medical care, the number of medical institutions in the districts are 2
internal disease clinics and 1 child and maternal center in the Goshoura
district, 2 internal disease clinics in the Ariake district, which indicates
the appropriation of medical care in the Goshoura district is slightly inferior
compared to the 2 other districts.
Comparing the causes of death in the districts classified according to
groups for causes of deaths, deaths from adult diseases are comparatively
lower in the Minamata district and deaths from non-disease or infectious
cases are higher than in the Ariake district. Acknowledging that adult diseases
have increased after the infectious cases have been put under control, by which
the national health trend in Japan has been transformed, we can assume there
is a mortality problem in the Minamata district.
2. Considerations of the Health Examination of Inhabitants who
Suffered from the Minamata Disease
Organic mercury affects human health in various ways which results not
only in a subclinical patient but also a non-subclinical or forme fruste patient
[8], In regard to examining inhabitants for the Minamata disease, the examina-
tion is conducted by questionnaires in order to screen the patient; it is
controversial how effectively this system is utilized. In recent years,
46
-------
a discussion has been centered on disease screening [9].
Then, in order to examine the health of inhabitants in the contaminated
districts from the organic mercury, and particularly to screen the people for
the disease, we examined adults (above 6 years), and investigated the
obtained information.
I. OBJECTIVE METHOD OF INVESTIGATION
For the districts, as in the previous report [1], we selected Tsukiura,
Idetsuki and Yudo of Minamata City, which are highly prone to the
disease, and Arashiguchi of Goshouramachi on the opposite seashore of
Minamata City, which are districts susceptible to contamination, and compared
them with the results of Akazaki, Suko and Ohura of Ariakemachi facing the
Shimabara Bay which have almost no seafood contamination.
We collected the investigation information similarly to the way it was
collected in the previous report, and used both along with the references
of previous investigations. Furthermore, we checked the results of clinical
diagnosis of the people with the Minamata disease; the diagnosis was conducted
by the Neuro-Psychiatry Department, Kumamoto University, and we investigated
the relationship between complaints and the inspection of clinical diagnosis.
II. INVESTIGATION RESULTS
(1) Relationship between clinical diagnosis and subjective symptoms
As reported previously, when we compared the Minamata district with
the other investigated districts, we observed a statistical significant
difference in the complaints of inhabitants in the over-30 age group who lived
in heavily contaminated areas. Then, we checked the relationship between
the main complaints and the clinical diagnosis for inhabitants over the age
of 30 in the Minamata district as shown in Table 8. We naturally counted many
complaints among the patients definitely having the Minamata disease, the
47
-------
patients afflicted by the Minamata disease and the patients susceptible to the
Minamata Disease, as compared to inhabitants of other areas. Particularly,
several complaints peculiar to the Minamata disease were observed. However, even
though some show typical symptoms of the Minamata disease, not all the
Minamata patients or the patients susceptible to the disease have reported com-
plaints when we check their symptoms individually. In other words, we en-
counter some similar complaints from patients who are not suffering from the
Minamata disease. It indicates that all the complaints are important just like
in the Hunter-Russel syndrome in the clinical diagnosis.
In this connection, we investigated how effectively we could use some
combinations of several complaints, which have been considered important for the
diagnosis of the Minamata disease, by the Minamata patients or the susceptible
patients who were screened for complaints. Therefore, we divided combinations
of complaints into 4 groups, i.e., disorder of perception, stricture of visual
field, disordar of movement and hearing disturbance; regarding the disorder of
perception as the main symptom, we then observed the frequency of the com-
plaints from the districts. As shown in Table 9, among those who exhibited
the disease symptoms, the frequency that their symptoms corresponded to the
4-item groups are 170 for males (49.4%) and 251 for females (52.1%) in the
Minamata district, which figures are significantly ( and statistically) higher
than the 81 for males (29.2%) and the 77 for females (23.5%) in the Ariake
district. Furthermore, when the frequency of these complaints are analyzed
by placing them in several of the 4-group combinations, the frequency of
correspondence to the combination of disorder of perception [hereafter
referred to as (P), stricture of visual field (V), disorder of movement (M)
and hearing disturbance (H)]showed to be 11.3% for males and 9.1% for females
in the Minamata district, which are figures significantly higher than the
2.2% for males and the 1.2% for females in the Ariake district, and the
frequency of the combination of (P) + (M) or (H) is also high. On the other
hand, no significant statistical differences were observed between the
Goshoura and Ariake districts for both sexes.
Comparisons of the relationship between the combinations of complaints
and the results of the diagnosis are indicated in Table 10. The symptoms of
48
-------
the patients in the Minamata district nearly corresponded to any of the
4-item groups of the Minamata disease for both sexes. More than 60% of the
symptoms of the patients, including the susceptible patients in the Goshoura
and Ariake districts, correspond to any of the 4-item groups. On the other
hand, approximately 20-30% of the symptoms of the patients in the Goshoura
and Ariake districts do not correspond to the Minamata disease, but neverthe-
less correspond to ar.y of the 4-item group of the disease. Moreover, such a case
is highly observed in the Minamata district, that is, the approximate value of
40% is statistically more significant than in the other districts, which is
noteworthy as it is quite possible the patients or the susceptible patients
are included among them.
We investigated the relationship between the combination of the subjective
symptoms and the clinical diagnosis in the Minamata district for both sexes.
As you can see in Table 11, when the frequencies of complaints correspond to
any of the combinations of (P), (V), (M) and (H), the percentages of the
patients diagnosed to have the Minamata disease or patients susceptible to
the disease were found to be 48.2% for males and 40.2% for females. On the
other hand, for those diagnosed as having the disease, or those susceptible
to the disease, the percentages of frequencies of their complaints corresponding
to any of the combinations of 4-item groups were found to be 76.7% for males and
82.1% for females, which figures are quite high.
The technique of screening the disease, which means the ability to dis-
tinguish between those having the disease from those not having the disease is
very important and is called "validity". The validity of a general screening
examination is indicated in Table 12. In this examination method, the ability
to classify those as infected patients who are the positive symptom bearers is
called "sensitivity" and the ability to classify the non-infected patients who
are the negative symptom bearers is called "specificity".
If the above combinations of complaints are adopted as the screening
method for the Minamata disease, the validity is as follows: sensitivity 77%
•nd specificity 63% for malas, and 82% and 58%, respectively, for females. The
49
-------
TABLE 8. RELATION BETWEEN CLINICAL DIAGNOSIS AND SUBJECTIVE SYMPTOMS
(Mtnafcata district, thos.e over
30 years.)
^xT" ^e*^
^^k^^
^^sT^oV. Group
^^^^Vjf^^s.
\^^>\^
^""^v. O^"*"""^
^^\!^" ^X^
^SsvftivN.
Subjective symptoms ^^^
Disorder of (Present
perception ' jpast
Disorder of perception
of the mouth or tongue
Stricture of visual field
Hearing disturbance
Smelling disturbance
Tasting disturbance
(morbid appetite)
Walking disturbance
Shaking
Muscular atrophy
Tremor
Muscular atrophy
Muscular~weakness
.. __
Articular pain
Amnesia
Decline in activity
Male
•o -
4J S
85
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M &
17
(100.0)
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(52.9)
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(G4.7)
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8**
(47.1)
8**
(47.1)
(29.4)
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(35;3)
(23.5)
9**
(52.9)
8**
(47.1)
8**
(17.1)
8**
(47.1)
11**
(64.7)
7a
(41.2)
10**
(58.8)
Qi
(52.9)
HeadacheTor heavy feeling rJTax
in the head $£
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s**
Vesical excretion disorder (47.1)
General, languor or 7
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(100.0) (
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(57.1)
15**
(35.7)
17**
(40.5)
16**
(33.1)
21**
(50.0)
27**
(64.3)
17**
(40.5)
17**
(40.5)
26**
(61.9)
92**
(52.4)
33**
(78.6)
7^**
(59.5)
24**
(57.1)
28**
(66.7)
17**
(40.5)
34**
(30.1)
1 1
cO
O.
46
100.0)
16**
(34.8)
23**
(50.0)
(65.2)
(10.9)
15**
(32.6)
(10.9)
(10.9)
. ]9**
(26.1)
12**
(26.1)
10*
'21.7)
(15.2)
10**
(21.7)
20**
M.3.5)
15
(32.6)
23**
(50.0)
26**
(56.5)
22^
(47.8)
22**
(47.8)
Q**
(19.6)
31*
(67.4)
co
n
&**
(39.6)
36**
(76.6)
20**
("42 6^1
11**
(23.4)
36**
(76.6)
0)
•H
*J; 4-1
cue
0)1 (U
n 4-1
3 co
co ex
52
(100.0)
20**
(38.5)
24
(46.21
7**
(13.5)
0*
(15.-!)
13*
'25.0)
8**
(15.41
L)
(.9.6)
00**
(•!2.3)
Q-**
(17.3)
(25.0)
(9.6)
(13.5)
20*"
(38.5)
22**
(42.31
26*
(50.0)
S 1'TJ|'
(59.6)
36**
(69.2)
16*
C30.8)
•3
(5.8)
42**
(80.8)
CO
-------
TABLE 9. COMPARISON OF THE COMBINATIONS OF COMPLAINTS BY
DISTRICT GROUPS
(Those above 6-years)
Male Female
Combinations of complaints -
MinamatajGoshoura Ariake MinamataGoshoura Ariake
\+fv?l r+/-M\M^ * r?U :;y ril-3>** -* (°-9) 6 (2-2) *» (9-D** * U.7) i vl-2)
•+- t.v; + KM; or (H) \ ].-, n *> jo r° 3) s (29; IT, (.",2)** t; ri.])j o (o o>
(P) + f(M) or (H)l r*'(14..V)** so (7.0) 17 i6.i> 7.i(!5.ij« 33 16.;.) J.; ;7.o)
(V) + [(M) or (H)J I ,1.2) 2 (0.5) 4 (1.4) 3 (1.0) 2 ;0.4) 3 (O.V>)
(P) + [any of (V) or (M) or (H) ] •'> Vl.7; 3 (0.7) 2 ro.7) •.' ;1.9^ 5 "\«> } 'o.H)
J Only (P) 68 (16.9) 67 (15.H) 44 (.15.9) 95 (19.7)* S3 (15.3) 40 (14.0)
Subtotals 1"" f-12-•!)**Tl'lJ (27.0) "" ~81 (2i).li)" 25f (52.1;** lTo~(25>.>) 7"7 (23.5)
Other subjective symptoms ;; i rr>o.fi) 313 (73.o) 196 (70.3) 231 (!7.9> 401 (74 r. 231 (76.5)
Totals 314(100.0) 429(100.0) 277(100.0) 4S2OOO.O) 3-1K 100.0} '32H(H3.0)
Note: 1) Classification of complaints
(P)... Disorder of perception
(V)... Stricture of visual field
(M)... Disorder of movement
(H)... Hearing disturbance
2) The numbers in the brackets indicate the percentages
3) AP< 0.1 * P < 0.05 ** P < 0.01
(Indicated the significant differences against the respective
values of the Ariake district according to x^-examination).
51
-------
TABLE 10. RELATION BETWEEN THE COMBINATIONS OF COMPLAINTS AND
THE RESULTS OF DIAGNOSIS - PART 1
(Those above 6 years)
Sex Combinations of complaints
patients Patients patients Others^
(M) + (fiy 9 16~ , ,., ;
(M) or (H)] 2 i 3
Male
Female
V '(PV+ f(M) or (H)r/J
(V) + f(M) or (H)l
,(P) + [any gl^p0^ (M) or (H) ],
I
Subtotals i
Other subjective symptoms |
! t
Totals i
1 i
(P) + M -»- (M) + (H) i
j (P) + (V) + [CM) or (H)]
1 (P) + I(M) orCH)]
C¥) + I (M)_ar IH1 3 ,
CP) + lany of OH of (M) or (H)]
Only (?) L
Subtotals
Other subjective symptoms i
! Totals
2
0
i
2
(S3. 9)
2
IS
(100.0)
10
4
2
0
tl
i
17
(100.0)
u
17
(100.0)
1
1
3
(S3. 3)
t
42
(100.0)
12
6
14
2
9
ii
47
;,83.7;
6
( loo.O;
14
0
l
12
3!
(CG.O)
1C
47
(100.0)
4
1
11
1
o
io
37
(69.3)
16
53
(100.0)
~ »
3
41
(37.1)
1111
237
(ir»i
-------
TABLE 10 (CONTINUED)
Goshoura
Ariake
Patients Susceptible0thers patientsSusceptIBle0 hers
patients patients
i}
o
0
0
0
1
1
C-o.o)
l
O
(iCH).n)
0
O
0
0
ii
u
0
(0.0)
1
1
(10(1. 0;
•{ |
4 <':
6 24
0 °
o 3
fi tit )
19 W
iCl.-'O IL'1.2)
12 HO.)
:;l -;%"
,100.0) i!*).0)
3 6
1 0
8 27
0 2
n f>
5 7f*>
17 123
C^.7) (21.1)
13 387
30 510 ;
(100.0) i 100.0) !
o
0
0
0
0
0
0
(0.0)
0
0
(0.0)
0
0
0
1)
'i
II
0
(0.0)
0
0
(0.0)
i
0
1
0
0
1
3
(00. 0;.
2
5
(100. U)
0
0
1
II
0
3
1
(.~>7.1'!
3
/
(100.0)
~)
s
ll>
»
2
-i.>
78
(28.7)
194
972
(100.0)
4
0
22
.i
i
13
73
(22.7)
1M.-5
321
(100.0)
53
-------
TABLE 11. RELATION BETWEEN THE COMBINATIONS OF COMPLAINTS AND THE
RESULTS OF DIAGNOSIS - PART 2
(Minamata district,
ahmro ft— voars}
\
Combinations of complaints
0)
r-t
si
CD
i-H
1
0)
Pn
(P) + (V) + (M) + (H)
(P) + (V) + [(M) or (H)]
(P) + [(M) or (H)]
(V) + [(M) or (H)]
(P) + [any of (V) or
(M) or (H)]
Only (P)
Subtotals
Other subjective symptoms
Totals
V
(P) + (V) + (M) + (H)
;(P) + (V) + [(M) or (H)];
(P) + [(M) or (H)]
(V) + t(M) or (H)] !
(P) + [any of (V) or
(M) or (H)]
; Only (P) '
Subtotals
Infected
patients
(M.l)
(ii-l)
ii
i
(3.6)
2
(11.1)
16
(88. 9)
O
(11.1)
IS
HXi 0)
10
(53.8)
4
(11-8)
0
0
1
(5.9)
17
(100.0)
Other subjective symptoms
: Totals ,
0
100.0)
Note: 1) Subtotals in brackets indicate the
2) The
by
Patients
16
i
16"''
(23. S)
1
(2.4)
1
(2.4)
(7.1)
33
(83.3)
(16.7)
42
(11,0.0)
12
(22.6)
fi
(11. J)
14
(26.4)
2
'3.8)
2
11
(20. ?j
47
(83.7)
6
(H-3)
53
(100.0)
in
I
<2 1
10.1 ,
11
C'9.^j
11
(2.:)
12
31
1 '*
CM.")
n'7,,:
i
i
1 1 ''"\
^ - ' ~ s
11
(""' 3)
1
(1.9)
C-1 '\\ 1)
n:,^!)
c,-,(5-,.i)
iKii '0
27(37.0)
3(C\0)
4(41 4)
.,,^,l.b)
101(40 2)
(82.1)
16 2_> (9 -,)
(30.2) (17.9)
(10J.C)
percentages
clinical diagnosis here is based on
the Neuro-Psychiatric Dept
j 123(23.3)
(100.0)
of the
that (for the
1
(50.0)
1
(50.0)
(!„;;.:»
0
i)
'-'
0
0
2
(6t;.n
9
(on. 7)
1
(33.3)
3
(100.0)
1
(100
(1
1
(1)1
0
0
1
f •""•
(l^S
r.)
:.-»
1
(12.3)
1
l~ 1'?
2
(25
5
(62
(3:
noo
horizontal
first year)
_
»j
'••')
5)
3)
0)
totals
done
. of Kumamoto University.
3) Classification of complaints:
(P)
(M)
4) The
. . . Disorder of perception,
... Disorder of movement,
validity of the screening
(V) ..
(H) ..
technique
. Stricture of
visual
field
. Hearing disturbance
designed to cope with
the
combinations of complaints:
/Sensitivity j8^. x 100=77 »ff
/Sensitivity -j!}5 "
Male /
\
'Specificity ^ x itx>=6j.°0
HO..
<'1°0
Female /
\ Specificity -3^ x
luo — js"a
54
-------
TABLE 11 (CONTINUED)
CO
Parkinson
disease
i
i
ii
"
it
2
(6,;. 7)
1
(3.'. 3)
(100 0)
0
1
(loo .0
0
o
0
0
I
(I'*? 0)
0
1
( 1 ( III 0 ;
T3
High bloo
pressure
f i
*
(1.2)
J |
(15.5)
9
(2.S)
If
17
(23.9)
(5l".9)
32
(15.1)
71
(Hr.")
13
(10.7)
s
(li «)
32
(26.4)
0
I
(S 3)
1^
(11.9)
72
(59 5)
19
(40.5)
121
(100 'M
Spinal
disorder
o
1
(50 n)
n
o
o
1
(50.0)
1
cioii...)
i
(25.0)
0
0
o
0
1
(25.0)
•>
(50 0)
2
(50.0)
4
(loo n)
to
•H
C
0)
Schizophr
0
0
o
0
1
(33.0)
1
(33.3)
o
(6ti.7)
3
(10.1 0)
n
ii
0
0
0
0
0
1
(10) 0)
1
(100 0)
C
Depressic
i
o
i
(50.0)
0
0
0
(100.0)
0
2
(liiO.O)
0
0
0
0
0
0
,)
0
0
01
CO
o
Nerve
idisturban
0
it
o
(50.0)
0
(1
1
(25.0)
3
(75.0)
1
(25.0)
4
(100.0)
0
0
0
0
0
1
(50.0)
1
(50,0)
1
(50.0)
2
(100.0)
•f i
•H
iJ
O
-------
TABLE 12. VALIDITY OF THE SCREENING EXAMINATION
(Remein & Wilkerson) [9]
Screening
results
Positive
Negative
Totals
Classification of diseases according to groups of people
who look healthy in appearance
Patients
Has the disease and the exami-
nation result is positive
(True-positive)
Has disease but the exami-
nation result is negative
(pseudo-negative)
Total patients included
people in whom the disease
is still undetected.
Non-patients
Has no disease but the ex-
amination result is positive
(Pseudo-positive)
Has no disease and the ex-
amination result is nega-
tive (true negative)
Total of non-disease
Sensitivity -
Specificity =
The number of those having the disease and positive results
of the examination
Total number of sufferers in the group
The number of those not having the disease and negative
results of the examination
Total number of non-sufferers in the group
56
-------
TABLE 13. RELATIONSHIP BETWEEN THE EXAMINATION OF OBJECTIVE SYMPTOMS
AND THE CLINICAL DIAGNOSIS
(Minamata district, those
above 10 years)
Have both the subjective symptoms and the
abnormal recognition by the objective symptoms
examination
Sex
No. of people
(%)
Total male and
female (%)
Disorder of
perception
M F
15 23
(5.5) (5.9)
38
(5.7)
Stricture
of visual
field
M F
21 19
(6.6) (4.4)
40
(5.3)
Hearing
disturbance
M F
78 76
(13.2) (9.3)
154
(10.9)
Disorder of syner-
gic movement
M F
15 44
(3.6) (8.1)
59
(6.1)
Have the subjective symptoms but no abnormal
recognition by the objective symptoms
examination
Disorder of
perception
Stricture
of visual
field
Hearing
disturbance
Sex
No. of people
(%)
Total male and
female (%)
M F
32 58
(11.8) (14,8)
90
(13,6)
j
M F M F
1
14 21
(4.4) (4,8)
35
(4,7)
44 56
(7,4) (6.8)
100
(7.1)
M F
18 54
(4.3) (9.9)
72
(7.5)
Disorder of syner-
gic movement
Note: 1) Criteria for the abnormal value in the objective symptoms examination.
Disorder of perception ... Pain sensation in the fingers at the finger
periphery part when over 3 g were applied in the examination.
Stricture of visual field ... Less than 80° by the Forster peri-
meter (stricture of visual field)
Hearing disturbance ,.. Loss of over 30 db measured by the audiometer
for the 6-division method,
Disturbance of synergic movement ... Over (—a) deviation from the
mean value of the respective age group in the Ariake district
according to the matchboard test.
2) "Not tested as no measurement is required according to the perimeter"
is included in "No objective symptoms" in the "Stricture of visual
field".
57
-------
TABLE 13 (CONTINUED)
Have no subjective symptoms but abnormal
recognition by the objective symptoms
examination
Disorder of
Stricture of
perception visual field
Sex ' M F
No. of people 17 13
(%)
Tot. M and F
(%)
No. of people
(%)
Total male
and female
(%)
(6.3) (3.3)
30
(4.5)
M F
16 38
(4.1) (8.7)
54
Hearing Disorder of synergic
disturbance movement
M F M
48 108 59
(8.1) (13.2) (14.1)
156 131
(7.2) (11.0) (13.6)
F
72
(13.3)
Have neither the subjective symptoms nor
the abnormal recognition by the
symptoms examination
Disorder of
perception
M F
208 298
Stricture of
visual field
M F
266 357
(76.5) (76.0) (83.9) (82.1)
506 623
Hearing
disturbance
M F
422 581
(71.3) (70.8)
1003
(76.2) (82.8) (71.0)
Disorder
movement
M
328
(78.1)
objective
of synergic
F
373
(68.7)
701
(72.8)
Note (Continued):
3) For the "Hearing disturbance", the total number of both ears is
indicated.
4) Frequencies (%) indicate the rate of the total number of the
respective items.
58
-------
TABLE 14. RELATIONSHIP BETWEEN THE EXAMINATION OF OBJECTIVE SYMPTOMS
AND THE CLINICAL DIAGNOSIS
(Minamata district,
those over 10 years)
Investigation item
Finger pain
sensation
Stricture of
visual field
Hearing
disturbance
Disorder of
Division
Abnormal
Borderline
Normal
Abnormal
Normal
Abnormal
Normal
Abnormal
1
'" w°
•— i
£>
t3 CO -H
CU 4-J 4J
*-> C P.
o cu cu
CU -H 0
•H 4J CO
C n) 3
l-l P. CO
' 26 (
31 (In. I.;
i> (14.7-)
r«( is.fi)
si (it. :>)
21 (7.1)
Male .
'
CO CQ
cu n]
.C 4J
U 0
o |_ H j
5 (i.7)
SI (10.6) 202 1,100.0)
i66 (.„>.;,)
! (1.4)
2% (iftl.ir,
2SO (100.0)
171 (60.2)
7 (2.1)
Female
rH " '
cd :
u
T3 CO -H
4J C P. 2 CO
U CO CO Ql rH
CU -H O £ (fl
m w co tj *J
d n) 3 0 o
|_M P. CO H
22 (M) .;j (s^'.^cw-O
4. i. 12.") J .-1 ;••: ..•)
v; (U ..) -, (_] ;;
!i (1! ".) 2~.-. (7...0)
5. (11.7) i.- (I.'. 3)
45 (11.6) 23? (61.4)
IS (.V) 22 (0.1)
in^ornpi or *»i-«»»v...«.«.-~ _iv..*/ (^_,iy
c=vnPrpfr movement Borderline 22 (7.5) 2* (S 8) 291 (L>..9) 12 (3.3) 36 (i-).o)
synergic movement Normal 47 (io.o) I7i (5H.2) 39 (!o.o) 233 (6i.;
(Matchboard)
Note: 1) Criteria of the abnormal value in the objective symptoms examina-
tion.
Disorder of perception ... Pain sensation in the fingers at the
finger periphery part when over 3 g were applied in the examination.
(Included the abnormality of a finger in one hand). "Borderline" is
above 1 gless than 3 g.
Stricture of visual field ... Less than 80° by the FHrster perimeter
(those not required to take the test are judged as "normal" accord-
ing to the confrontation check).
Hearing disturbance ... Loss of over 30 db by the audiometer of
6-division method (Includes the abnormality in one year)
Disorder of synergic movement ... Over (-2 o) deviation from the
mean value of the respective age group in the Ariake district
according to the matchboard test. "Borderline" is
less than (M-a) ^M - 2 a ).
2) Division of clinical diagnosis
Infected ... Infected patients of the Minamata disease
Patients ... Diagnosed as Minamata disease
Susceptible... Susceptible patients of the Minamata disease
59
-------
Note for Table 14 (Continued):
3) The numbers in the brackets indicate the frequencies (%).
4) The validity as a screening technique in the respective examinations
(in case "borderline" is included in "normal").
Investigation
item
Finger pain sensation (a)
Stricture of visual
field
Hearing disturbance
Disorder of synergic
movement (b)
M
Sensitivity
29%
47
54
23
F
Specificity
98%
98
87
97
M
Sensitivity
22%
55
56
26
F
Specificity
98%
98
83
92
a) When screening level is over 1 g,
(66%, 82% respectively, in males
(53%, 87% respectively, in females.
b) When screening level is over 2 a,
(48%, 84% respectively, in males
(43%, 80% respectively, in females.
60
-------
so
1 ' I ! ' M
' I i " ' - - -
• •----; ----- - '— \ •;—+, p- 1
: " ~'i r"~r7f ;"
: J i / i ; -
, .._ _ _ .... J-!v.-r ,
. ... . _ . . ...y._ i , ^
— • '~"~t~' ',~j""\~~ " 1 i ~ 6°
~~: ' I /^T~ ' 1 ~ 4°
'• '• f '• • 3 :
L . ""''/' ''~ "!"•"" ; ^l" -
: j'^/.iii;:;:"!:].:!".;..,..
T - 7 | tr , ^ J > , 1 s« 1 | 51 S j S. .
i -j j 8 i ": :•- -1!"'!574 1618
1 : J 1 j ! i ! 1' 1 01
! ' 1 ! ! ' ! ! 1 j_1 OI
.. ^ i ! i ! 1 i li---
•' ::. j.i :<= 4j - r-1) ;; no o: 7u 754.. ° 0-
.'J':j L ! !/i : ; ; !.-• ! :/
; . • •'..-. t _
[]-lT'": :'"' ': !>:?v
" ''" ~ .
' - '" ' ' i
^ : sV' ;_ t_ ', _ ( : i
L- -f-:.- ' : : '' 3 T
I ' 1 ' • a • ' J
f ' ' 1 '
t • - :•'--•?
, --4^ 5 _,._ - 6^^;__
i/' • 7 - i :•' ? , ;j 5 74 4
.',' ' 8 ' • .- • •- 9 ' r. < r :
•' t
--• i '- • ; i i ! ; ' :- i j i ! j
• 1 , ; , : i :- i 1 . i ' j
! ; ' , " ' r -
J'> 10 .'J rj tlj -, ^,- , , ,_u ij/ ;,_, j , _rl, , . ],
I I 1 i •
10 j ; - --1 •- - " i j . . , •, . , . , . .
)
,1
Note: Males over 30 years
Note: Males over 30 years
Figure 3. Regular probability curve Figure 4. Regular probability curve of
of matchboard test values. blocking test values.
1- Cumulative relative frequency; 1- Cumulative relative frequency;
2- Minamata district; 3- Ariake dis- 2- Minamata district; 3-Ariake district;
trict; 4- district; 5- 25%-ile value; 4- district; 5- 25%-ile value;
6- 75%-ile value; 7- Minamata; 6- 75%-ile value; 7- Minamata;
8- Ariake. 8- Ariake.
61
-------
J"igure 5. Patients' examination system of the Minamata disease.
1- Inhabitants susceptible to environmental contamination; 2- First
examination; 3- Investigation of examination items and criteria;
4- (Questionnaire, several examinations); 5- Those without abnormal diagnosis;
6- (Re-examination at a certain interval); 7- Those with abnormal diagnosis;
8- Second examination; 9-(Close examination, discrimination of diagnosis);
10- Investigation of examination items and criteria; 11- Surveillance;
12- Those as either normal or abnormal; 13- (Borderline group);
14- Minamata disease patients; 15- Patients of other diseases; 16- (Diagnosis
distinguished); 17- Treatment of diseases, living patterns advised;
18- or; 19- Observation required (pre-disease condition); 20- Prevention
of diseases; 21- Development of a cure; 22- Rehabilitation; 23- Observation
and study required; 24- Close examination at a certain interval; 25- Those
who require observation; 26- Criteria problem; 27- Establishment of a
disease picture and a diagnosis method.
62
-------
degree of false-negative is rather small, while the degree of false-positive is
relatively large. That is, approximately 20% of the patients having the
Minamata disease are dropped while approximately 40% of the patients not having
the Minamata disease are picked. Therefore, we must consider the above point
if we use this method for screening the Minamata disease.
(2) Relationship between the examination of objective symptoms
and the clinical diagnosis
We observed the relationship between the patients' complaints and
the examinations of objective symptoms in regard to some symptoms which are
considered the important characteristics of Minamata disease. As shown in
Table 13, 5-10% have both the subjective symptoms and the abnormal recognition
in the objective symptoms examination, and 70-80% have neither the subjective
symptoms nor the abnormal recognition in the objective symptoms examination,
although there is some difference depending on the examination items. Further-
more, approximately 10% have the subjective symptoms but no abnormal recognition
in the objective symptom examination, whereas approximately 10% have no sub-
jective symptoms but the abnormal recognition in objective symptom examination.
Such results should be considered for the analysis.
Next, we observed the relationship between these examination results and
the clinical diagnosis as shown in Table 14. In examining the finger pain
sensation, 8.9% of the males and 5.6% of the females were found to show
abnormal signs of those recognized as having the disease or those susceptible
to the disease, whereas 21.9% and 20.2%,respectively,were found to exhibit
normal signs to the examination of those who either recognized patients
as having the disease or those susceptible to the disease, w^BTP^fii 21.9% and
20.2%,respectively,were found to exhibit normal signs to the examination of
those who either recognized patients, as having the disease, or those susceptible
to the disease. When we consider these results for "validity" as the screen-
ing examination of the Minamata disease, the sensitivity is a low 29% for males
and 22% for females; on the other hand, the specificity is a high 98% for both
sexes. A similar investigation was done for stricture in the visual field,
63
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hearing decline and disorder of synergic movement (matchboard test), and the
results are as follows: the sensitivity was approximately 50% and specificity
was over 80% in all cases. That is to say, false-negative was large while false-
positive was relatively small, from these results we noticed the problem of
this existing method for the screening of the Minamata disease.
(3) Problem of examination items and screening level
The screening level which we used in Table 14 showed that the specificity
is high while the sensitivity is low in general. From a public hygiene stand-
point, however, the examination items and the screening level application should
be chosen so as to produce less false-negative than false-positive.
In this regard, we described the results of the matchboard test in a
regular probability paper as shown in Figure 3, in order to see the disorder
of the synergic movement. The Ariake district shows a relatively straight normal
curve while the Minamata district shows a slight inclination to the left as a
whole, (besides a skewness to the left in the middle is recognized). This
indicates not only a group of slightly low values but it also includes an
apparent abnormal group as compared with the values of the Ariake district.
(This is also assumed by 25%-ile value, 75%-ile value, M ± a, median value and
mode value.
When we plotted the measured values of the blocking test on a regular
probability paper in Figure 4, the skewness has increased and no straight lines we
observed. Namely, the Ariake district shows neither a normal distribution nor
straight line, and the Minamata district shows extreme skewness. Therefore,
in screening the Minamata disease by using examination items of such results,
it is very important which value is to be adopted as a screening level,
and the degrees of false-negative and false-positive are variable depending on the
the values used.
Regarding the matchboard test, we calculated the mean values and the
standard errors of the respective age groups in the Ariake district, by
64
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judging the deviation of (-2o) or more from the mean value as an abnormal
value. According to this measure, the specificity is as high as 95%, and the
sensitivity is as low as 25%. This indicates that the false-negative is so
large that this measure is not suitable for the screening for that condition.
Then, judging the abnormal value when the deviation is ( -o) or more from the
mean value, we obtained a specificity of approximately 45% and a sensitivity of
approximately 80%. Although they decrease or increase respectively, the
false-negative is high, so that the patients would not pass the screening test
which makes it difficult to apply them to the screening of the Minamata disease.
Now, we established this criterion of abnormal values for examining
finger pain sensations, that is, if pain is felt in any finger (of hand or
both hands) other than the thumb at or above the second knuckle when more than
3g of metal weight is applied, the pain is regarded as abnormal. According
to this criterion, the sensitivity is approximately 25% and the specificity is
98%. Furthermore, when we relaxed this criterion of abnormal values by apply-
ing just over the Ig of metal weight, the results are approximately 60% for
sensitivity and approximately 85% for specificity. The specificity slightly
decreases and the sensitivity increases; that means, from a public hygiene
standpoint, the percentages of patients dropped by the screening method is
small. Therefore, it seems to be preferable to use. However, the percentages
of patients not having the disease would increase as the objectives of the
second examination becomes large.
In the examination method for screening the disease, a dependability
(reappearance, accuracy) and a practicality (expense, hours needed, etc.)
are just as important as the validity. The examination items and their
screening level should be decided upon the above matters. In this case, as in
the combinations of complaints, several combinations of examination methods,
or the combinations of complaints and examination methods for some functions
are considered effective to raise the validity of the screening examination
of the Minamata disease in the infected patients; this, however, depends highly
Upon further investigations.
65
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(4) Inhabitants examination system of the Minamata disease
We charted the procedures of the examination of patients in the district
susceptible to contamination as described in Figure 5. To start, we conducted
the first examination of all the patients in the district susceptible to
contamination, and separated them according to abnormal views and normal
views. For this we selected examination items according to the screening
principle of the disease, in which a validity or dependability should be high
and economical, as well as practicable. Furthermore, a screening level of the
applied examinations should be positive with at least a false-negative, and
the items and the criteria are to be adopted with as high a specificity as
possible. Here, although the questionnaire investigation is highly significant,
it has its limits; therefore, we must recognize a risk in which the abnormal
cases without subjective symptoms should be dropped from the screening procedure
[22].
If the abnormal views or traces of the Minamata disease are recognized
in the first examination, we conduct the second examination. Mainly clinical
doctors participate in this stage, and the close examination is given to
those who have been selected by the screening process and each symptom is dis-
tinguished by referring the items for epidemiological examinations. Again, the
same considerations as in the first examination are given to each examination
item and its criterion. If the abnormal views are recognized in the second
examination, we can distinguish the Minamata disease (including complications)
from non-Minamata disease. However, we still cannot disclose the normal views,
nor judge them as normal or abnormal. The latter case is called "The
borderline group" about which we must disclose the disease pictures and the
diagnostic methods from future observations and investigations, and the
criteria for the diagnoses of diseases should be investigated. If their
clinical diagnoses are disclosed, the medical treatment of the disease and
the life pattern should be given, and as a matter of course, we must expedite
the rehabilitation process as quickly as possible. Furthermore, some exhibit
symptoms of the pre-disease condition, the diagnoses of which are
already known; therefore, preventive measures for this disease are necessary.
66
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Moreover, if patients need to be further observed, thorough examinations should
be given regularly in order to discover the disease in the early stage, as well
as to give medical treatment as early as possible. The significance of
surveillance is especially important in the Minamata disease due to the fact
that the crisis may happen after several years, or as a possible influence from
the antenatal conditions.
III. CONSIDERATIONS
In considering an approach to the disease, the ordinary medical treatment
involves the going of patients with various complaints to the hospital. On
the contrary, the screening of diseases in the public hygiene sense deals
with people who seem to be healthy in appearance when going to the hospital,
or at least who have complaints but not related to the diseases or disease groups,
that is, the objects of screening. On that account, there is a difference
between the two as mentioned above. Therefore, when dealing with the
Manamata disease, basically we must keep in mind that such a difference in the
treatment method has existed. A so-called "inhabitant" examination belongs to
the latter approach.
For the clinical diagnosis of the Minamata disease, the efforts of
systematization were made by Tokuomi [10] in the early stage, and further by
Tsubaki, et al. [11], and Tatetsu, et al [12]. In the Minamata disease, the
Hunter-Russel syndrome is unanimously regarded as the main constituent in
the advanced stages. However, recently in the disease picture of the Minamata
disease, another noted symptom appears [12], so that the difficult problem
arises in its screening, for which a disease picture has not yet been
established. If a new disease picture is established as a significant one,
a screening method should be adopted, based upon that disease picture.
Therefore, even if a certain screening method for the Minamata disease has
been presented, it must not be accepted unquestioningly, but should be im-
proved by continuous efforts that parallel the establishment of disease pic-
tures and the development of new methods.
67
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In this study, we first investigated the significance of the complaints
examination in the screening of the Minamata disease. We focused on the 4-item
complaints, such as disorder of perception, stricture of visual field, disorder
of movement and hearing disturbance which have been considered as typically
important symptoms of the Minamata disease. Recognizing the disorder of per-
ception as a main symptom, we investigated the validity of the screening of the
Minamata disease by the extraction method depending on the combinations of
those complaints. As a result, approximately 80% sensitivity and
approximately 60% specificity, which is such a high false-negative pattern
that the patients would be dropped from the screen. On one hand, to screen
the Minamata disease based on complaints from the questionnaire examination
is advantageous, as it can be done promptly and economically, but by the same
token, it has certain limits in its applications. Secondly, as regards some
function examinations in the health examination of the patients in the
Minamata district, we investigated its validity for screening the disease.
As a result, the specificity is relatively high; however, the degree of false-
negative is large if the screening is done by using these examinations,
according to the criteria we adopted. Therefore, if only the first item of
the respective examination is used for screening, there is a considerable
risk that the patients would be dropped in the screening process. Further-
more, for the problem of a screening level applied to this case, we analyzed
the results of a few examinations given to inhabitants of the Minamata
district. There were many cases which did not indicate a normal distribution
as a group, besides they deviate from the results in the Ariake district as a
whole. Therefore, a thorough investigation is required for the adoption
of the criteria.
To control the health level of the inhabitants who have been contaminated
by waste water (with organic mercury) from the factories, serious consideration
must be given not only to the disease control of the organic mercury poisoning
in patients, but also to the health standard of the whole local area. Thus,
even though it has not been determined that the diseases or the symptoms have
been caused by water contamination due to its organic mercury content,
68
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it must not be neglected and the proper measures should be taken. A so-called
"multiphasic" or "multiple mass screening examination" should be intro-
duced which is used to distinguish not only the patients of the specific
disease, but also the susceptible patients of various kinds of diseases.
Furthermore, a so-called surveillance of the health conditions of inhabitants
shall be undertaken for an extended time by using a proper screening procedure
which should be definitely conducted in the contaminated district due to the
contaminated waste water from the factories.
3. Actual Conditions Relating to the Fisheries and Fishermen's Diets
(Fishing Seasons of Katakuchi-sardine and Young Ayu) along the
Shiranui Seacoast.
One of the aspects underlying the outbreak of the Minamata disease
is considered to be connected to the living area of the fishermen along the
Shiranui Seacoast. However, few results concerning the actual conditions
of the fishermen's life have been accumulated. We now explain the purpose
of introducing the above new investigation subject. First, it is to investi-
gate the background of the outbreak of the Minamata disease relating to the
fishermen's life from a public hygiene standpoint. The basic references
(based on medical labor matters) in regard to the fishing industry along the
Shiranui Seacoast are collected, and the factors contributing to the health
impediment are sought through references such as aspects of the fishermen's
labor, labor conditions or labor environment. To collect references about
the characteristics of the fishermen's diets; especially, concrete references
about the intake of fish products is a principal subject for investigating
dosages of methyl mercury in the living body. Secondly, the outbreak of
the Minamata disease is considered to relate to the fishermen's life itself,
if so, then the basic references in regard to the fishermen's life should be
collected for the investigations on the contamination caused by methyl mercury,
the subsequent outbreak of Minamata disease and its progress afterwards.
However, there are two phases in general when observing the local
conditions at the present. Namely, one still remains nearly the same
69
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(such as, construction of life hours) as in the years from 1955 - 1965 during
which the Minamata disease frequently broke out, and the other has seen changes
(such as technical renovations in fishery labor, different diet, etc.) as com-
pared to those times.
Therefore, in regard to the objectives and assuming that their whole lives
completely depend on the fish industry, we investigated the actual conditions
of their lives from a public hygiene standpoint.
I. OBJECTIVE METHOD OF INVESTIGATION
We selected a fisherman's family from the Tsunaki-machi, Ashikita-gun
and Kumamoto Prefecture as the sources of this investigation. Thirty-three
families in this district consist of fishermen and farmers (citrus-culture,
etc.) except one merchant. The main focus is put on one of three fishermen's
bosses in this district. The family structure is as shown in Figure 6. Among
seven members of the family (including the lodgers), two are patients who have
the Minamata disease (one of which is a patient who has the congenital Minamata
disease). The fish labor is usually operated by the family members, as
husband, wife, eldest son, eldest daughter and second daughter, and three
netters are added during the busy fishing season.
As shown in Figure 7, the busy fishing season which is mainly net fish-
ing, along the Shiranui inshore, is from June to September whereas January and
February are relatively slack. We conducted the investigation in the first
part of August of 1972 for Katakuchi-sardine fishing and in the last part of
February of 1973 for young Ayu fishing. Our investigation was as follows.
We checked the working hours of the fisherman's wife, eldest son, and eldest
daughter for three consecutive days, in which the investigation sheets were
marked by the investigators. The hours were divided in seconds. During the
fishing operation, we also used a stop-watch in order to obtain more
accurate results. In the three consecutive days, the nutritional value of
five members of this family, i.e., husband, wife, eldest son, eldest daughter
70
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"51
2
V
70 3
4
rt
•15 3
5
•»? 3
5
6
-£ 20 5
- £ 185
-£ 165
- $ 12 6
Figure 6. Family construction for the investigation objectives.
1- (Lived separately); 2- dealer of fish products; 3- (Lodger);
4- (Susceptible); 5- fisherman; 6- (Recognized)
P
• CO ^ •
•H *•*
I 2
M
Fishing fo
w
m
» -i
scabbard-
fish-
5 6
^ !-i
Fishing fo
7
1
Katakuchi-
B 9
rn -.
sardines
10 11
M
Fishing fo
12
(-1
M-l
CO
j Month
Figure 7. Fishing season along the Shiranui inshore (net fishing).
and second daughter was investigated, of which the net quantity of their diets
including snacks was measured respectively. In the meantime, in regard to
the fish labor and its incidental work, their energy metabolism was measured
using both the Douglas bag method and the gas analyzer (Institute for
Science of Labor), distinguishing their respective works. Furthermore, the
weather conditions , such as temperature, humidity, velocity, cata-cooling
power and radiant heat, were measured continually every hour from 4:00 A.M.
to 10:00 P.M. by the sanitation examination method (Japan Pharmaceutical
Association), at prescribed points on the beach close to the fisherman's
house. Especially the noise of the diesel engine of the fishing boat, etc.
was measured by a noise indicator, simple noise scale and octave analyzer
(Lion, SA-55).
71
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II. RESULTS OF OUR INVESTIGATION
(1) Distribution of their life hours
The distribution of their life hours per day are indicated in
Figures 8 and 9. Namely, in the fishing season of the Katakuchi-sardines, they
go out fishing twice a day — at 4:00 A.M. and 4:00 P.M. and afterwards
work on the processing of making dried sardines. In this case, the distri-
bution is generally 7 hours for fishing, 5 hours for processing, 5 hours for
sleep and 7 hours for leisure. During the fishing season for young Ayu, they
fish 3 times a day — at 6:00 A.M., 8:00 A.M. and 2:00 P.M. and here the
distribution is 8 hours for fishing, 8 hours for sleep and 7 hours for leisure.
However, according to the weather condition or current condition, the evening
fishing for Katakuchi-sardines and afternoon fishing for young Ayu continues
for 10 to 15 days a month, and Ayu fishing during the winter season is often
prevented by bad weather.
Fishing for Katakuchi-sardines is done from a main boat of approximately
2 tons equipped with a diesel engine of 15 h.p. and a fishing radar, two
3.77 ton netting boats with a diesel engine of 20 h.p. and a manual jolly boat.
For young Ayu fishing, the above main boat and jolly boat are used. In addi-
tion, a tow net for Katakuchi-sardine fishing and a small roll net for young
Ayu fishing are used.
Fishing for either Katakuchi-sardines or young Ayu consists of a
series of continual work such as, searching a shoal, moving the boat toward a
shoal, preparing the net setting, net withdrawal (by both machine operated and
manual) and taking up a haul. The hours required for the operation are 60-80
minutes from the net setting to the haul in for Katakuchi-sardines, and the
net setting is done 1-2 times per fishing. On the other hand, only 5-10
minutes from the net setting to the haul is required for Ayu fishing. This
operation is repeated often and the net setting reaches 13-15 times a day.
The distribution of hours of respective work during this period is indicated
in Tables 15, 16 and 17. From these tables, you can see that the main part of
72
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Assorting
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Figure 8. Distribution of daily life style hours (Katakuchi-sardine fishing),
) 1 2 3 4 5 6 7
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Preparation for departure
I 1 |
Searching for a $hoal
'Netting
Net withdrawn'.
> » i
Fish scooping
jReturnj
Transport
Figure 9. Distribution of daily life style hours (Young Ayu fishing)
73
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fish labor at sea is the withdrawal of the net. In fishing for Katakuchi-
sardines, a considerable amount of energy is consumed in processing the dried
sardines. This work consists of assortment, boiling, drying (drying storage),
selection, encasing and shipping. The relative metabolic rate (hereafter
referred to as R.M.R.) of the respective work is shown in Tables 15, 16 and 17.
In the fish labor at sea, from 0.4, searching for a shoal and waiting while
moving (sitting position) to 2.7 for a net withdrawl, is considered as light
labor according to the distribution of hours. For this the calories consumed
due to the fishing operation are 669 for males and 323 for females per operation
(one-time net setting) for the Katakuchi-sardines and 822 calories for males and
665 calories for females for three operations (17 time net setting) for Ayu
fishing. On the other hand, for processing Katakuchi-sardines, from 3.8 for a
fish case transportation (weight: 30 kg) to 7.7 for taking them in/out of
drying storage, is considered as heavy labor. The calories consumed in the
processing work is 1020 for males and 1,268 for females when handling the raw
weight of 1500 kg.
In addition, for the manual work of withdrawing the net, the R.M.R.
is calculated as the sum total value for a series of work, and since the work
on a one-to-one basis is operated under very tense conditions, it is
difficult to set up a model labor, therefore, the values have somewhat inclined
to be lower than the actual ones.
The total calorie consumed per day by the Katakuchi-sardine fishing is
3069 Cal. for males and 2718 Cal. for females per operation, and for two oper-
ations (two net settings), it takes 3254 Cal. for males and 2857 Cal. for females
which is regarded as slightly heavy work. Furthermore, for three operations of
young Aku fishing, it takes 2544 Cal. for males and 2287 for females, which
is regarded as normal work. In addition, an example of the use of the female's
time is shown in Table 18 in which the fishing operation has been interrupted by
bad weather. That is, the total consumed calories per day are 2176 which is
about 100 Cals. less than for a usual fishing day.
(2) Nutritional conditions
The caloric intake classified according to 5 individual categories as
obtained from investigation and according to the food groups is indicated in
74
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TABLE 15. DISTRIBUTION OF WORKING HOURS AND ENERGY CONSUMPTION (KATAKUCHI-
SARDINE FISHING, FOR ONE OPERATION)
Wife, 42-years old
Description.
Preparation for departure
Waiting on the boat (searching for a
shoal)
Preparation for netting
Netting
Net withdrawal (machine-operated)
Net withdrawal (manual)
Transport of fish cases (30 kg)
Assorting
Taking in/out of drying storage
Meal
Working
Bathing
Personal things, etc.
Rest
Hrs.
20 mins.
R.M.R.
0.4
120 ; 0.5
Q
15
1.8
1.0
30 : 2.1 4 Cumulative
31
21
89
114
55
42
20
189
299
Sleep 1387
2.7 1593 Cal.
3.8 (448 min)
4.4
7.7
0.4
1.8
2.0
0.4
0.2
-10%B
Total per day 2,730 Cal.
Eldest son, 18 years old
Description
Preparation for departure (engine
adjusting)
Hrs.
24 win.
Steering the boat | 202
Preparation for netting
Netting
Net withdrawal (manual)
Taking up the haul (fish scooping)
Transport of fish cases
Fish drying work
Taking in/out of drying storage
Inspection inside the boat.
Freezing work to freeze the fish
Meal
Working
Bathing
Personal things, etc.
Rest
33
47
R.M.R.
0,5
0.6
1.8
1.0
16 ,2.7
37
22
64
76
31
37
77
7
15
45
363
Sleep t 344
2.2
3.8 * Cumulative
6.8 1689 Cal.
7,7 (589 min.)
2,1
2,1
0,4
1.8
2.0
0.4
0.2
-10%B
Total per day 3,150 Cal,
75
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TABLE 16. DISTRIBUTION OF WORKING HOURS AND ENERGY CONSUMPTION (KATAKUCHI-
SARDINE FISHING, FOR 2 OPERATIONS)
Wife, 42 years old
Description
i
Preparation for departure
Waiting on the boat (searching for
a shoal)
Preparation for netting
Netting
Net rolling (machine operated)
Net rolling (manual)
Transport of fish cases (30 kg)
Assorting
Taking in/out of drying storage
Meal
Working
Bathing
Personal things, etc.
Rest
Hrs. R.M.R.
27 min. 0.4
128 0.5
13 1.8
13 ; i.o . _ , _.
,„ 21 Cumulatxve
43 2.7 1602 Cal
12 ! 3.8 ,.__ . .
• (aoT mm i
107 j 4.4 *• ;
100
74
64
26
205
271
7.7
0.4
1.8
2.0
0.4
0.2
Sleep 315 -10% B
Total per day 2857 Cal.
Eldest son, 18-years old
Description Hrs.
Preparation for departure (engine
adjusting)
Steering the boat
Preparation for netting
Netting
R.M.R.
43 min. 0.5
160 0.6
26 1.8
30 1.0
Net rolling (manual) '36 2.7
Taking up the haul (fish scooping) 40 2.2
Transport of fish cases 22 3.8 * Cumulative
Fish drying work
Taking in/out of drying storage
Inspection inside the boat
Freezing work to freeze the fish
Meal
Working
Bathing
Personal things, etc.
Rest
58
67
60
51
81
16
26
51
6.8 1607 Cal.
7.7 (593 min.)
2.1
2.1
0.4
1.8
2.0
0.4
35 0.2
Sleep
Total per day
328 -10%B
3,254 Cal.
76
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TABLE 17. DISTRIBUTION OF WORKING HOURS AND CONSUMED ENERGY (YOUNG ASYU
FISHING, FOR 3 OPERATIONS)
Eldest daughter, 21-years old
Description
Preparation for departure
Waiting on the boat
Preparation for netting
Netting
Net pulling (manual)
Taking-up the haul (fish scoop assis.)
Taking up the haul (fish scooping)
Stick work
Net withdrawal
Rowing
Landing work (and putting in order)
Transport of fish (bucket)
On the truck
Light work on the land
(cleaning the uruck,etc.)
Meal
Working
Bathing
Personal things, etc.
Rest
Hrs. R.M.R.
13 min. 0.4
236 0.5
23 1.8
22 1.0
81 2.7
20 2.2 , _ n _
* Cumulative
10 2 1 665 Cal
2Q 2 1 (479 mins.)
19 ' 2.7
16 1.8
19 3.8
5 1.2
73 2.0
66 0.4
145 ' 1.8
15 2.0
25 0.4
300 ! 0.2
Sleep 357 -10%B
Total per day 2,287 Cal
Eldest son, 19-years old
Description Hrs . R.M.R.
Preparation for departure
Steering the boat
Preparation for netting
Netting
Net pulling (manual)
Taking up the haul (fish scpoop
assistance)
Net withdrawal
Landing work (and putting in order)
Work in the boat (inspecting
inside of boat, etc.)
Driving the truck
Light work on the land
(cleaning the truck, etc.)
Meal
Working
40 min. 0.5
263 0.6
4 1.8
46 1.0
84 2.7
47 2,2 *Cumulative
20 2,1 822 Cal.
21 1,8 (568 min.)
43 2.1
26 1.2
68 2.0
64 0.4
18 1.8
77
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TABLE 17 (CONTINUED);
(Eldest son, 19-years old)
Description T Hrs.
Bathing
Personal things, etc.
Rest
15 min.
26
245
R.M.R.
2.0
0.4
0.2
Sleep
Total per day
410 -10%B
2,544 Cal.
TABLE 18. DISTRIBUTION OF LIFE HOURS AND CONSUMED ENERGY (IN CASE THE FISHING
IS INTERRUPTED BY BAD WEATHER OR WINTER CONDITIONS)
Eldest daughter, 21 years old
Description
Meal
Working
Personal things, etc.
Rest
Driving the truck
Shopping
Light work
On the truck
Attending the meeting
Sleep
Hrs.
51 min.
387
35
180
90
95
40
45
145
372
R.M.R.
0.4
1.8
0.4
0.2
1.2
1.0
2.0
0.4
0.4
; -10%B
Total per day
2,176 Cal.
Tables 19 and 20. The most important observation is that fish consumption
for males is very high. The mean value of fish consumption for three days
in summer is 410 g for the head of the household, and 333 g for the eldest
son. Even in February, which is considered the lowest diet consumption month
of the year, the mean value for three days is 286 g for the head of the house-
hold and 361 g for the eldest son, and on the 25th of February, 513 g for the
head of the household and 489 g for the eldest son were recorded as they had a
good haul of fish. These values are well over the 80 g of the target value
for 1975 which is set up by the National Institute of Nutrition. In this
connection, the fish they consume is derived from their fish haul, such
as scabbard-fish, garakabu, mebaru and snipefish that reside in the inland
sea or inland bay. In addition, the vegetable consumption and especially milk
and dairy products is very small, and males eat double the amount of rice and
78
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females eat double the amount of fruits, such as watermelon and citrus fruit
as the respective target values. Furthermore, a lack of caloric consumption
in general is seen in a 42-year-old who has the Minamata disease and a 12-
year-old. A comparison of their caloric consumption with the respective
required consumption values as classified by the nutritive elements are shown
in Figures 10, 11, 12 and 13. Namely, a similar pattern of caloric consumption
exists between the head of the household and the eldest son, and the wife and
the eldest daughter, and an inclination of high caloric or high protein due
to the large fish and rice consumption notable in males. Females, on the
other hand, have a notable lack of Ca, Fe, V-A, V-B.. and V-B2. Particularly, the
second son who has the congenital disease, shows a caloric consumption of
1,389 Cals, 25.0 g of protein and 36.8 I.V. of V-A in August, and 1,487 Cals,
43.2 g of protein and 19.lg of fat which indicates an extreme lack, of a proper diet.
The caloric ratio is as shown in Tables 21 and 22. Especially, the
protein calorie ratio and the animal protein ratio are high for the head of
the household and the eldest son, which reflects the large fish consumption,
while the second son shows extremely low values as a whole, as mentioned above.
The calories consumed daily were 2800 calories for the eldest son
and 1782 calories for the wife in August, and 3041 calories for the eldest
son and 1574 calories for the wife and 1487 calories for the eldest daughter
in February. When these are compared with the total consumed daily
calories aforementioned, there are 200 calories less for the eldest son and
900 calories less for the wife in August, and 500 calories more for the eldest
son, 600 calories less for the wife and 800 calories leas for the eldest
daughter in February.
(3) Environmental conditions
1) Weather conditions
Daily changes in velocity (current), degrees of excess wetness,
degrees of excess dryness, blackbulb temperature, temperature and hum^d^ty in
August and February are shown in Figure 14. These were measured di4T"1-ng the
day for three consecutive days for the labor investigation period. The
weather of the measured days were fair in August and cloudy in February;
especially the weather in February was so bad as' to interrupt the fishing.
In summer, little labor is performed in the sun as the fishing operations occu,r
79
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TABLE 19. CALORIC CONSUMPTION AS CLASSIFIED BY THE INDIVIDUALS AND BY THE
FOOD GROUPS (AUGUST) (Unit: g)
Objectives -13 yrs. 12 yrs. 20 yrs. i.s yrs. 12 yrs.
UgUf 3 . 4 Avg 2 3 I ,Avg2 3 ' 4 Avg2 ,3.1 Avg2 3 4 Avg
!'l .Rice 413 175 502 -JG3 213 227 333 258 181 274 335 203 291 3i(. 431 316 11^ ',•". !21 !>l
& Bread 120 40 90 3o 4" 14 ion _'» io
GO Noodles 9 3 19 ; 6 37 12 14 5 13 5
0' Potatoes 64 > 32 32 124 23 49 95 30 125 92 57 49 W i 33
•^ Sugar . ! 13 5 6' 31 5 12 7 4442 2 24 3 9
(§; Confectionary 70 21 80 27. ieo 54 GO 20 isu 60
(yAlch.beverages+soft drink 100 11 138 1% 261 150 100 i?e, 123 2002211 518 ps- 100 116 272
(?) Oils, and fatS IS 20 30 23 35 20 24 26 27 10 30 22 10 59 95 32 28 5 3 12
^Soybeans •*• soybean prods. 27 9 5! is 54 is is , 6
(P> Soybean paste. 10 35 21 22 18 35 15 23^ 36 6S 31 15 36 2! 2J 27 12 9 17, 13
O? Other beans ' ; i • , 20 T 23 j 8
& 'Fruits j 735 : 245 270 565 210 358 21" 720 400 443 360 120 440 545 420 463
Oj? Green vegetables 40 14 12 14: 132 ) :<:-° -l" *'-'-' 3a"
© Green vegetaoies 8 S5 38 7 29 3 12 4 10 3
©Light-colored vegetables 161 45 14 73 87 78 28 64 187 82 45 105 138 8 49 113 33 19 55
rtf
-------
(August)
122 0
70.1
|0)~ - ,
^ ^
\
\M \
45-year,case (head of
household)
42-year, case (infected patient
of the Minamata disease)
Figure 10. Caloric consumption as classified by the individuals (average for
3 days).
(August)
131.7
12 year, case (congenital patient of the Minamata disease)
Figure 11. Caloric consumption as classified by the individuals (average for
3 days).
81
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(February)
104.3
n.s 46-year, case 43-year, case (infected
(head of household) patient^of ITie Minamata disease)
Figure 12. Caloric consumption as classified by the individuals (average for
3 days).
(February)
'"<> 125.3
21-year, case
,1.29
30
19-year, case
Calorie
Figure 13.
3 days) .
13-year, case (congenital
patient of the Minamata disease)
Caloric consumption as classified by the individuals (average for
82
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TABLE 21. CALORIC RATIO
(August)
Objectives
45 year-male
42 year- female
20 year-female
18 year-male
12 year-male
Target value for 1975
Cereals
cal.
ratio
63
37
58
45
36
50 *• i
60%
Protein,
cal.
ratio
18.3
15.7
14.4
18.1
7.2
&out 15%
Animal
protein
ratio
74
65
31
65
15
40 -x-50%
Animal
fat
ratio
60
28
39
50
6
i
Fats ,
cal.
ratio
14.4
21.1
14.3
20.9
3.9
20 * 25%
TABLE 22. CALORIC RATIO
(February)
Objectives
46-year-male
4 3-year- female
21-year- female
19-year-male
13-year-male
Target value for 1975
Cereals
cal.
ratio
62
60
61
52
63
50 * 1
60 %
Protein
cal.
ratio
16.7
12.7
14.0
16.5
11.6
Uxmt 15%
Animal
protein
ratio
67
45
51
73
43
Animal
fat
ratio
42
41
55
29
49
40 ^50%
i
Fats
cal.
ratio
19.6
10.7
11.4
26.5
11.6
.20 ^25%
early in the morning or in the evening. In winter, on the contrary, the net
withdrawal work takes place in the sea at temperatures from 0 - 1QB C and
a humidity of 50-60%, which should be considered and evaluated as abnormally low
temperature conditions.
2) Noise due to the dlesel engine.
As aforementioned, fishing for Katakuchi-sardines is operated by a main
boat, two netting boats and a jolly boat, and among which, a diesel engine is
83
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equipped in the main boat and the netting boat. The operation of the engine
is done in the following 4-steps according to the fishing conditions. Namely,
the idling condition (net withdrawal while the boat is stopped, taking up a
haul), low speed condition (net setting, net pulling), medium speed condition
(moving by searching a shoal, within a relatively short distance) and
high speed condition (moving toward a shoal, transporting a haul, for a rela-
tively long distance). Under these 4-steps for operating the engine, the
noise is continuous and very stable for it remains at a certain level without
intervals while the work takes place. Table 23 shows the extent of the noise
in relation to the worker's ears on the main boat and netting boat, the hours
exposed to the noise per fishing operation and their distributions. It is
distributed between 79 - 83 phons while idling and 114-116 phons while in high
speed, and as a whole, the extend of the noise is high. The result of a fre-
quency analysis while idling and in high speed is as indicated in Figure 15,
according to the octave analysis. You can see the peak at about 100 Hz, and it
retains a high level up to a considerably high frequency range. These noises
as an absolute value exceed the permissible sound value (480 min. value, 240
min. value) recommended by the Japan Industrial Hygiene Society. Also, the
noise on the fishing boat when the engine is not operated is still as high as
68 - 72 phons which is more than expected, due to the wave sounds or the
noise from the other fishing boats. In addition, the noise distribution on the
fishing boat is as follows: the muffler part of the engine is naturally the
highest which is 116 - 118 phons, 101 - 107 phons in the stem part, 101 -
109 phons in the stern part and 107 - 113 phons in the steering room.
Furthermore, while fishing for young Ayu which is done by one main boat
and one jolly boat, there are 78 - 82 phons while idling, 82 - 84 phons at
low speed, 85 - 86 phons at medium speed and 88 - 93 phons at high speed.
III. CONSIDERATIONS
The difference between the Minamata disease and methyl mercury poisoning,
which is poisoning present in certain occupations in factories, is that the
Minamata disease is transmitted to humans through certain foods at the inception
84
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Current
Temperature
3
2
1
" 0-
50
40
30
20
10
First part of August (fair)
Current
Excess dryness
Black-bulb
''temperature^
Humidity
3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 ;„ 19 20 21 22
Last part of February (cloudy)
25
20
15 Degree of
10 excessiveness
5
80 Humidity
70 _
60 if
14
12
10
Current s
•L 6
4
2
0
10
Temperature
Excessive
wetness
Black-bulb'
temperature
'Humidity
Temperaturl
3 4 S 0 7 8 9 10 Jl ]2 )3 14 IS 18 17 18 J9 JO 21 23
Degress of
1 excessiveness
0
•100
90
80
„ Humidity
50
Figure 14. Daily changes in the weather conditions.
85
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TABLE 23. NOISE LEVEL ON THE BOAT DUE TO THE DIESEL ENGINE AND THE
HOURS EXPOSED TO THE NOISE
(for each fishing operation)
Operation of
engine
Idling
Low speed
Medium speed
High speed
Netting boat
Noise
level
T9~83phon
93~95
104~107
1U~116
Exposed
hours
79'5i" (36.5fo)
46'28"(21.5/0-7')
• 90'12"(42 0"o)
I 1
Main boat
Noise
level
79~65
92~94
lU4~iu5
13'53"(15
37'20" (42
36'50"(4i
0
1
Exposed
hours
SfJ)
5,*<0
oO
Remarks
When fishing for 216 mins.
31 sees.
When fishing for 88 mins.
5 sees.
13
B
0)
c'
•H
Q)'
Ol
iH
0)
ressur
a
-a
120
110
100
90'
80
70
60
50
40
High speed
\ Idling
9fl U-,
31.5 03 125 250 500 1000 2000 4000 SOOO
m Center of frequency in the band (Hz)
to
to
ex
Figure 15. Frequency analysis of noise due to the diesel engine on the
fishing boat.
86
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of the disease [13]. In regards to industrial poisoning in the factory, the
content of the poisonous substance in the working environment, the physical or
chemical characteristics, the retaining hours and the time lapse are the
important problems. In regards to the Minamata disease, the problem is not
only the content of mercury in the fish, but also the circumstances surrounding
the fish consumption as a condition of exposure [14]. At the same time, an
understanding of the actual condition and diets of the fishermen's lives and
the Minamata diseased patients is the essential matter for investigating the
outbreak of the Minamata disease and its progress afterwards. Furthermore, in
order to control the health conditions in the future of the local inhabitants
and the Minamata diseased patients, a basic understanding of the fishermen's lives
and diets is needed.
The investigation dealing with the fisheries conducted by Kitamura,
et al., at the early stage (the interview investigation of a fisherman's
family and the analysis of fishery statistics)[15] is considered a worthy
study from the above viewpoint. Regarding the above study, we tried to
positively grasp by a case study the 'actual conditions of the fishermen
and their families' lives and eating habits. .
Despite the dependence of Japan on seafood for the greater part of
protein resources, references concerning inshore fishery studies are very short
except for a study by Kitoshi, et al., [16].
The medical labor characteristics for Katakuchi sardine fishing and
young Ayu at the Shiranui inshore are described below. That is, R.M.R. does
not exceed 3 in any kind of fishing work at the sea. In other words, the work
is relatively light as a labor strength. On the contrary, the processing work
to make dry fish of the Katakuchi sardine fish is very trying which can be
considered heavy work as a labor strength. The distribution of daily hours
completely depends on the weather conditions or the ocean conditions such as
sea currents, and the individual fishing work requires complete attention. The
fishing condition, that is, the estimated haul of fish on any day is unpre-
dictable. Therefore, it is difficult to balance the hours of work with the
87
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hours of rest, which has caused a lot of unevenness in the density of labor,
and thus, it is not necessarily easy to construct a definite proportion. How-
ever, it seems that a working pattern, which is completely united with the
natural phenomena and is not restrained by artificial power, cannot be
evaluated by the past labor medical concept.
In this regard, the calorie consumption for the Takakuchi sardine
fishing for two operations is equal to bricklaying or moulding work and for
young Ayu fishing, it is equal to keypunch work [17].
In addition, there is a report [17] in regard to the labor strength
inshore fishing, in which the total calorie consumption per day is reported to
be 2,580 cal. for a fisherman who operates the net fishing in the Yamaguchi
Prefecture. However, this value is less than Katakuchi sardine fishing and
approximately equals the total calorie consumption per day in young Ayu fish-
ing which is investigated by us.
From the results of our investigations this time, we can cite signifi-
cant problems below due to environmental conditions such as the noise of the
diesel engine and the work at sea under low temperature conditions in
winter. The noise of a diesel engine for a fishing boat shows a slightly
higher level than the noise of a diesel engine for a bus or truck, which
was investigated by Itoh, et al., [18]. However, they are similar when view-
ing the contribution of spectrum. As indicated in the report of 1971 by this
study group, noise and the exposure are enough to cause deafness or cause a
hearing disturbance which is suspected of the noise deafness. In regard to
working at sea under low temperature conditions in winter, there is a report
[19] which mentioned that the circulating of the finger periphery of fishermen,
who operate the net fishing on the icy water of the northern sea, is superior
to that of the controlled people, and the partial cold-resistance is high
therefore. We intend to further investigate by observing the function as well
as the relation of the peripheral nerve function.
Next, we describe the fishermen's diets, especially as regards fish
consumption. Of late, in the controversy on the interim restrictive value
88
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relative to the safety standard of the P.C.B., it has been discussed how
to estimate the amount of exposure of fishermen considered as consuming lots
of fish. Then, in order to set the interim restrictive value, we used the
national mean value classified by the classes based on the People's Nutrition
Investigation of 1968 as a basic reference. According to that mean value, the
seafood intake is 75.9 g min/day, 139 g max/day and 86.3 g av./day and the
intake ratio of inshore and pelagic fish is respectively 57.0 g min/day and
189 g min/day, 98.2 g max/day and 32.7 g max/day, 64.7 g/av/day and 21.6 g av/day
[20], about which the comment is added that the intake value may not exceed
200 g, however, all of them are fishermen. The problem here is at what level
the maximum consumption is judged. In the examples of fishermen of the Shiranui
inshore who consume the inshore fish, that is, the seafood of their own produce,
the average net consumption for three days is from 286g day in winter to 410 g
day in summer, which is far above the estimated value by the Investigation
Committee of Food Sanitation. According to the preinvestigation conducted in
February of 1972 prior to the investigation this time, in which 4 fishermen and
non-fishermen families of the Minamata district seacoast were examined by the
self entry method, it was observed that the fish consumption is about 200 g even
in the non-fishermen's families. From these results, a reinvestigation regard-
ing the fish consumption condition is required in accordance with the distri-
bution channel of seafood by focusing on the fishermen's families. Upon which,
the reestimation of the present safety standard and the present contamination
condition due to the fish products in the Minamata Bay area is required,
besides it is considered that the dose-response relating to the effect of
methyl mercury on the living body should be reinvestigated.
On the other hand, the wife, especially, and the second son who have
suffered from the Minamata disease, generally show an imbalance in the caloric
consumption plus a shortage of absolute caloric amount is observed. In this
regard, the second son who is affected by the congenital Minamata disease has
a caloric intake of 1389 in summer and 1487 in winter which slightly exceeds
the base metabolic amount of 1287 cal. per day for that age. Therefore, strict
health control measures of their whole daily life should be investigated promptly,
not only for those stricken by the congenital Minamata disease who are in the
89
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physical and mental growth period, but also for all those stricken by the
Minamata disease.
Based on our present investigation, we shall continue to collect the
basic references relating to the fishermen's families along the Shiranui
seacoast by investigating the actual conditions of the fishermen's labor for
net fishing and their life environment.
CONCLUSION
First, we tried to find out the effect of the environmental contamination
due to the factories' waste waters containing organic mercury on the health
standard and the causes of death in the said districts. Namely, we investigated
the health indicators as well as the classification of the causes of death
based on the information in the death certificates and the medical death
certificates of those who had lived in the said districts during the 24 years
from 1948 to 1971. The results are as follows.
1. In the Minamata district, the stillbirth rate is slightly higher and
the frequency of mortality by age group is less in the older age group as com-
pared with the Ariake district, which is considered nearly free of contamina-
tion.
2. The PMI and the death rate of the old age group over 65-years are
respectively 62.4% and 41.9% for males, 64.5% and 46.1% for females, and
those for females are significantly (statistically) less than in the
Ariake district which are respectively 70.3% and 51.9% for males, 76.0% and
62.3% for females, and even the corrected PMI changed by correcting the ages,
the females show younger values than in the Ariake district.
3. The average death age is 50.36 ± 28.91 years for males and
52.50 ± 29.49 years for females in the Minamata district which are younger
than 56.56 ± 27.74 years for males and 61.22 ± 28.06 years for females in
the Ariake district, and even of the corrected average death ages, the females
show slightly younger values than in the Ariake district.
90
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4. When compared, the construction of cause of deaths classified by
the group of cause of deaths, Minamata district has less groups of deaths by
adult disease both in male and female than Ariake district, and contrary,
more groups of deaths by non-disease in male and by bacterial infection in
female.
5. A significant difference was observed between the districts when the
main causes of deaths were compared. That is, in the Minamata district,
the deaths are mostly caused by inflammation of the intestines, other laxative
diseases, car accidents and other unexpected accidents (mostly by drowning) for
males, and tuberculosis, meningitis and other unexpected accidents (mostly by
drowning) for females, while less deaths by senility (not accompanied by
mental disease), non-inflammative diseases of the nerve center system for
males, and cardiac diseases and senility (not accompanied by mental disease)
for females were reported.
Secondly, we investigated the results of the inhabitants' examinations
in the Minamata, Goshoura and Ariake districts in order to study the way of
inhabitants examination of Minamata disease, and the results are as follows:
1. We pointed out the validity and limitation in the screening
examination method of the Minamata disease based upon complaints of patients.
The validity of screening is approximately 80% in sensitivity and approximately
60% in specificity when using combinations of the 4-item complaints, which are
disorder of perception, stricture of visual field, disorder of movement and
hearing disturbance which are considered important for diagnosing the
Minamata disease.
2. As a result of investigating the validity of the screening process
of the Minamata disease in regards to the examination of some organs, several
problems are pointed out for selecting examination items and the application
of the screening level, and a reinvestigation of the above points and their
combinations are required.
91
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Thirdly, for the purpose of grasping the actual conditions of the fisher-
men's labor and their diet along the Shiranui seacoast, we conducted investiga-
tions of the actual conditions of a fisherman's family (Minamata disease
patients) in the Tsunaki-machi, Ashikita-gun, Kumamoto Prefectures during the
fishing seasons of the Katakuchi-sardine and the young Ayu.
The results are:
1. The labor strength for the labor at sea is relatively light;
however, the daily caloric consumption including the processing work is
slightly heavy or corresponds to normal work, and the distribution of life
hours is irregular.
2. The working environment, particularly the noise due to the
operation of the diesel engine, and the sea labor under low temperature con-
ditions in winter need to be noted.
3. Fish consumption of fishermen's families is far above the estimated
values by the Investigation Committee of Food Sanitation, etc.
4. The daily caloric consumption of those stricken by the Minamata
disease is apparently low as a whole, and from such a viewpoint too, it is
pointed out that the daily health control measures of the patients should be
promptly investigated.
REFERENCES
1. Shigeru Nomura, et al. Progress of Minamata Disease and its Epidemic
Study. The Results of Health Examinations of Inhabitants in
Minamata and Goshoura districts (Part 1). The report written by the
investigation group on the "Minamata Disease Ten Years Hence", Medical
Department, Kumamoto University, 1972, pp. 6 - 36.
2. Swaroop, S. and K. Uemura. Proportional Mortality of 50 Years and Above.
Bull. Wld Hlth. Org., Vol. 17, 1957, pp. 439-481.
92
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3. WHO Study Group. Report on the Measurement of Levels of Health.
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4. Toshiaki Miyoshi, Manzaburo Okamoto: The Significance of the
Average Death Age as a Death Index Classified by Causes of Deaths,
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5. Ministry of Health and Welfare, Statistics and Survey Division:
The Comparison of.Causes of Deaths between Pre-War and Post-War
Ages According to the Life Table, Index of Welfare. Vol. 15, 1968,
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6. Kazuo Shirosaki, et al.: The Corrected Average Death Age as a
tlealth Index. People's Hygiene, Vol. 36, 1970, pp. 123-129.
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8. Tadao Takeuchi, et al.: a) Minamata Disease Ten Years Hence and its
Change. Japan Medical News Report, No. 2402, 1970, pp. 22-27:
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by Dr. Hisashi Matsumoto — Short Commentary Report of Dissection,
Saikai Medical Report, Vol. 252, 1969, pp. 9-12.
9. Wilson, J. M. G. and G. Jungner. Principles and Practice of Screening
for Disease. Public Health Papers (WHO) No. 34, (Japanese transla-
tion), 1968.
10. Haruhiko Tokuomi. Clinics of Minamata Disease — Minamata Disease in
Adults. Minamata Disease (Compiled by the Investigation Group of
Medical Department, Kumamoto University, 1966, pp. 48-81.
11. Tadao Tsubaki, et al. A Clinical Diagnosis of Organic Mercury
Poisoning along the Agano River Coast, Progress of Neurology,
Vol. 13, 1969, pp. 85-88.
12. Masayori Tatetsu, et al. A Neuro-Psychiatric Study of the
Minamata Disease — A Clinically Epidemiological and Symptomatological
Study of Minamata Disease. The Report written by the Investigation
Group of the "Minamata Disease Ten Years Hence" of the Medical
Department, Kumamoto University, 1972, pp. 41-65.
13. Shoji Kitamura. Epidemiology of the Minamata Disease — Epidemiological
Approach of Organic Mercury Poisoning, The Latest Medical Science,
Vol. 26, No. 10, 1971, pp. 1966-1972.
14. Shigeru Nomura. Occupation Disease and Pollution Disease as an
Occupational Illness, Science, Vol. 41, No. 3, 1971, pp. 138-145.
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15. Shoji Kitamura, et al. The Results of an Epidemiological Investi-
gation Relating to the Ill-defined Disease of the Nerve Center
System which Occurred in the Minamata District. Journal of
Kumamoto Medical Society. Vol. 31, (Supplement 1), 1957, pp. 1-9.
16. Yoshihito Kitoshi. The Investigation Report of Fishery Labor of
Net Fishing for Sardines at Nobomura, Nishikanokine-gun, Nagasaki
Prefecture, Fisheries Agency, 1952.
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for Science of Labor, 1972, pp. 23-24.
18. Takeshi Ito. Noise and Its Control, Corona Co., 1959, pp. 44-51.
19. Nelms, J.D., et al. Cold Vasodilatation and Cold Acclimatization in
the Hands of British Fish Filleters. J. Appl. Physiol., Vol. 17, 1962,
pp. 444-448.
20. Investigation Committee of Food Sanitation: The PCB Regulation for the
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21. Shoji Kitamura. Accumulation of Agricultural Medicines and Heavy Metals
in the Human Body and its Significance. Mercury, Journal of Japan
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22. Ferrer, H.P. Screening for Health. Theory and Practice. Butterworths,
London, 1968.
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III. A Clinical Study of the Minamata Disease (Part 2)
4. A STUDY CONCERNING EFFECTS OF CONSUMING FISH CONTAMINATED BY
ORGANIC MERCURY ON RESIDENTS ALONG THE SHIRANUI SEA
Neuro Psychiatry Department, Kumamoto University Medical School
Group member: Masatoshi Tachitsu
Research Assistants: Kazuo Seida, Masasumi Harada, Taichei
Miyakawa, Hisao Tomonari, Satoshi Inoue, Toru Teraoka,
Shiro Sumiyoshi, Eiichi Murakami, Fumie Yasuoka, Kiyoshi
Nakamura, Motonori Deshimaru, Takeshi Tsukiyama, Noriuki
Hotta, Shozo Egami, Teruo Hirahara, Ryuichi Minami, Noritake
Tanaka, Hideo Hattori, Shotaro Hanawa, Kosuke Kono, Hideaki Goto,
Tadashi Fujino, Hitomi Goto, Toshio Fujimoto, Koichi Fujiwara,
Norihito Koga, Shunsuke Kuwabara, Toshio Fujioka, Noriko Hotta,
Kanji Matsumoto, Keikichi Kashima, Tomosuke Sakai, Kou Shikai,
Masahiro Nishi, Tadashi Kuramoto, Yoriko Fujimoto, Minhei Miyakawa
The aim of this study is to clarify the number of patients and their
health conditions resulting from organic mercury poisoning among people along
the Shiranui Sea, and to provide information on planning living situations and
medical relief for the patients and on preventing the outbreak of the disease.
At the same time, this study aims to clarify problems concerning the stages of
organic mercury attacking the human body from the clinical standpoint.
In order to achieve the above objectives, the following were done —
simultaneous examination of residents and attempts at treating organic mercury
poisoning patients detected from the examination; investigation of the
poisoning conditions of people who were moved out to some other prefectures
from the areas contaminated by organic mercury; analysis of the relation-
ship between the occurrences of poisoning and the amount of mercury in
residents' hair and fish in the contaminated areas.
95
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PART 1
SIMULTANEOUS EXAMINATION
Chapter 1. Subjects and Methods of Investigation
Residents in Tsukinoura, Detsuki and Yudo of Minamata City and Arashiguchi,
Koshiji, and Sotohira of Goshoura town, Tengusa County were selected as sub-
jects for the investigation. The Minamata area mentioned above is considered
to be the area which was most contaminated by organic mercury in the past.
Actually, prior to the investigation, i.e., between December, 1956 and
July, 1971, 67 persons out of 85 (78.3%) who were determined by Kumamoto pre-
fecture to be suffering from organic mercury poisoning, i.e., Minamata
disease, were from the Minamata area. Twenty-six persons out of these 67
(38.8%) were already dead. Health conditions of residents in Goshoura, which
is only 16.5 km away across the sea from Minamata City, were also considered
to be affected by organic mercury. In fact, in January, 1972, two persons
among residents of Oura, Goshoura town, were determined to have the Minamata
disease. For the purpose of comparing with these two areas, residents in
Akasaki, Sugo, and Oura of Ariake town, Tengusa county, of the southern shore
of the Ariake Sea, were selected. People in these areas were considered at
first not to be contaminated by organic mercury.
Table 1 illustrates the number of people registered in these
areas and their ages. According to Table 1, the ratio of people over 65
in these areas is high. For the Goshoura and Ariake areas, the ratio of
children under 14 is high and that of working age people between 15 - 64
years old is low, and the ratio of people between 20-29 is remarkably low,
compared with that of the entire nation. For the Minamata area, the ratio
of the labor force is almost the same as that for the entire country.
The investigation of residents was done in about a year and a half. First,
it began by asking people to list their health conditions on questionnaires
sent from the Public Hygiene Department of the Medical School of the Kumamoto
96
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TABLE 1. AGE STRUCTURE OF PEOPLE IN INVESTIGATED AREAS
Age
0 -- 1
5 — c>
in- li
15- 19
•'(I- ''-I
3' 1 - 3J
55- -39
40—41
43- 49
50- -51
55- -59
60- -61
65-69
70- 74
^- M
85-89
90- 34
95 -99
Unknown
0—11
15—61
Over 65
0- 15
16-40
Over 41
21—50
Over 51
0 10
Over 11
5 —30
Over 31
Total
Mina-
mata
I o
4J
< co,
81
79
103
100
-•<
65
67
73
6?
i 7
70
46
41
11
3
0
o
1
263
751
120
283
356
481
432
316
171
049
418
621
""
7.2
7.1
0 T
8 *-1
1 7
5 8
6.0
6 . 5
8.8
6.1
6.9
6.4
5.1
1.1
3 7
2 0
i .11
0
0.2
0.1
23.5
65.3
11 3
25 3
3 ! . 8
48.0
38.6
28 2
15 3
81 7
37.3
55 4
resident
Gosh-
oura
1 o
? K
jj
O rHi
< cfl
140
149
263
MS
1 ,>
M
100
1(>8
112
120
120
125
100
76
-•>
49
11
1
1
—
55°
1045
' 248
584
458
S05
61 iO
..,-
1518
686
1019
°o
7.6
8.1
14.3
5.9
5 7
1.6
5. 1
5.9
6.1
6.5
6.5
6.8
5.4
4 1
3.9
2.7
2.0
0.6
0.1
0.2
—
29.9
56 . 6
13.4
\ 31.7
i 24.8
43.5
32.5
30 1
17.7
82.3
37.2
55.2
S
Aviake
1 o
3 55
4J
7
4.9
5 9
7.2
o.O
5 6
7.1
7.1
6.2
5.4
.', o
i . (
'.'.3
0.2
ij.l
32 . 1
oti.O
i U . V
32.3
1.-..G
48. 1
32.7
35 . 3
20.1
79.6
3-!. 6
o9./
Entire
country
£. '
8.5
7.9
7.6
8 7
10.1
••>.?
."-.1
7.8
7.1
O . 1
4.6
4.3
8.8
2.9
2 . 1
1 2
D.O
O..S
0.1
II. Ill
23.3
59.1
. . L
2.j i
-*-•'-'
16.6
18.5
17.9
82 1
4!. 9
55 0
Note:
1970.
1120
1845
1165
924
Age structure of entire population in the country is from a census in
The total number is 104,665,171.
97
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University (initial examination). Then as the first simultaneous
examination, the direct examinations of all the residents were carried out
by members of this Neuro-Psychiatric Department and the Pediatrics Department,
by referring to the items entered in the above questionnaire (Table 2). Neuro-
psychiatric examinations were done from August 21-28 in the Goshoura area, from
September 7-12 in the Minamata area, and from October 22-26 in the Ariake area.
However, the examinations continued until January, 1972 in order to supplement
them. The results of this first examination were reported in "Epidemical,
Clinical and Pathological Studies of the Minamata Disease after 10 Years",
issued in March, 1972.
Since April, 1972, the examination has continued in the Minamata area,
especially focused on people who were not examined during the first medical
examination. However, in the examination mentioned above, many cases were
observed to be difficult to diagnose. Therefore, in order to accurately
diagnose, as well as to establish the conditions of the disease in detail,
with more precise examinations, the second simultaneous medical examination
(the third examination) was held. Subjects for the examination were pri-
marily people who were diagnosed or suspected of organic mercury poisoning, or
people in whom the effects of organic mercury were detected during the first
examination (Table 2). The examination at each area was carried out as
follows: Ariake area: subjects were examined during July 27, 1972
and March 23, 1973 by either asking them to come to the area elementary
school or visiting them in their homes; Goshoura area: subjects were
examined during September 2, 1972 and February 28, 1973 by either asking them
to come to the area elementary school or day care center or by visiting them
in their homes in case they could not come; Minamata area: subjects were
examined during October 25, 1972 and March 14, 1973 by either asking them to
come to the Minamata City Hospital, or visiting them in their homes when they
could not come to the hospital. Table 2 illustrates the number of people
who were examined. Also, x-ray pictures of their spines were taken at
the Radiology Department of the hospital attached to the Kumamoto University
Medical School for people who were suspected of spinal diseases. The date
and the number of subjects for this case are as follows: Ariake area patients:
98
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TABLE 2. NUMBER OF RESIDENTS AND NUMBER OF EXAMINED PERSONS
Area
Minamata
Goshoura
Ariake
Total No.
of resi-
dents
Male
524
895
564
Fern.
596
950
601
Total
1120
1845
1165
Persons
examined
1st time
Male
425
819
410
Fern.
540
904
494
Total
965
1723
904
Persons
examined
2nd time
Male
144
62
12
Fern.
169
71
15
Total
313
133
27
10 persons between July 27, 1972 and August 2, 1972; Minamata area patients:
39 persons between February 16, 1973 and February 28, 1973; Goshoura area
patients: 39 persons between March 2, 1973 and March 7, ,1973. Also, since
it was felt that in the Minamata area many people suffered from recurrent liver
diseases, several persons among those who were examined during the second
simultaneous medical examination were examined for alkaline phosphatase in
their blood, GOT, GPT, and cholesterol counts. Also, some of the patients
examined by the Neuro-Psychiatric Department were examined by specialists from
the Ophthalmology and the Otorhinolaryngology Departments of Kumamoto Univer-
sity. The contents of this report are the result of the investigation men-
tioned above.
The Minamata area is further divided into three: Tsukinoura and Yudo are
directly facing the sea, whereas Detsuki does not have a shore line. Village A
of Tsukinoura surrounds the inlet and is located approximately 1,700 m at a
direct distance from the outlet of the drainage of the nitrogen plant. This
inlet is considered to be one of the worst areas contaminated by organic
mercury. Among people in Village A, 4-5 persons are fishermen and the rest
are engaged in work, such as ship carpentry, stone masonry, and temporary labor.
They are poor, and few are farmers. The "Minamata disease" was first noticed
here and patients were isolated in the contagion hospital. Their parents and
99
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siblings were also isolated from their neighbors. Other parts of Tsukinoura
contain farm land and from the center of the land to the shore of Village A is
about 200 m in a direct line. Many people in Detsuki engage in farming or are
employed by the nitrogen plant. The distance from the center of Detsuki to
Village A is 500 m in a direct line. Yudo also faces the inlet surrounding
the Fakuro Bay and the distance between this inlet and the plant drainage is
approximately 2,250 m. One-half of the people in this area are engaged in
farming, and the rest in fishing. The distance between the center of this
area and the shore is about 100 m. It is believed that currently the people
engaged in fishing are about 1/3 of the total population.
Chapter 2. Results of Investigation
Section 1. Rate of Persons Having the Disease
The examinations of residents were continued from the beginning of the
first simultaneous examination until the end of the second simultaneous
examination, i £. , from August 21, 1971 until March 14, 1973. Table 3
illustrates the frequency of the actual number of persons having diseases
against the total number of people who were examined; i.e., disease rate, in
the areas examined during the-period, grouped by types of neuro-psychiatric
diseases.
The frequencies of total neuro-psychiatric patients are 59.48 ± 1.58% in
the Minamata area, 27.63 ± 1.08% in the Goshoura area, 31.30 ± 1.54% in the
Ariake area, and 10.30 ±0.62% in Heianza Island, Okinawa [3]. The difference
between the number at each area of this investigation and that at Heianza
Island is significant fz!>jj!8.2':!, P<0 001) . Similarly, the differences
between the number for the Minamata area and that for the Goshoura area, and
between the Minamata area and the Ariake area are significant r/^'2^3.71, P<0 001).
Residents of Heianza Island ar-e either farmers or fishermen. 2,379 of the
residents centered around Herian were all examined together in 1965 neurologi-
cally and psychiatrically by a team of the Neuro-Psychiatry Department of
100
-------
Kumamoto University.
These three areas including the Ariake area contains patients who
exhibit the symptoms of the Minamata disease. The frequencies of subjects
who were diagnosed as having the Minamata disease in these three areas are
28.50 ± 1.45%, 1.97 ± 0.33% and 0.89 ± 0.31%, respectively. The differences
between these numbers are significant for the Minamata and the Goshoura areas
(-/:•> i2i.6i, P". P')] ) . Also,
the differences between the numbers for Detsuki and Tsukinoura (excluding
Village A), and between Detsuki and Yudo are significant C/."V-2j.39. P<0 (Wl) .
However, any significant difference between the numbers for Tsukinoura
(excluding Village A) and Yudo cannot be proven (x:?:'--v '.
The frequency of people with the Minamata disease as well as with a
suspicion of the Minamata disease, is 83.05 ± 4.88% at Village A, 32.24 ±
3.23% at Tsukinoura excluding Village A, 35.07 ± 2.38% at Yudo and 18.62 ±
2.29% at Detsuki (Table 4). The difference between the number for Tsukinoura
(excluding Village A), Yudo, and Detsuki is significant (x2^'1-1"- ^ -•'' ' •''! ' .
The difference between the numbers for Tsukinoura (excluding Village A) and
Yudo and that of Detsuki is also significant i'x->:23.28, P<^ 0.001).
101
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TABLE 3. DISEASE RATE
1
Minamata
area
Actual
No.
Total residents 1120
Examined persons
Persons with
nervous and
mental disorder
Total disorder
965
573
Minamata disease 275
Suspected Mina-
mata disease 38
Deferred
diagnosis
Other diseases
15
221
%
-
86.1
59.4
Goshoura area
Actual
No.
1845
1723
476
%
-
93.4
27.6
28.5 34 1 2.0
3.9
31 1.8
1.6 ! 29 1.7
23.9
382
22.2
Ariake
Actual
No.
1165
901
282
8
2
6
266
area
%
-
77.3
31.3
0.9
0.2
0.7
29.5
TABLE 4. EXISTENCE RATE OF ORGANIC MERCURY POISONING (MINAMATA
DISEASE) AND ITS SUSPECTED PATIENTS AMONG PEOPLE IN INVESTIGATED AREA
! j
Examined
Investigated area residents
Minamata
Village A 59
Minamata
disease
Actual %
No.
Minamata disease
+ its suspect
Actual %
No.
44 74.6 ! 49
Tsukinoura excluding '
Village A 214 j 56 26.2 ; 69
Yudo 402
Detsuki 290
130 32.3
45 15.5
Total examined areas 965 275 28.5
Goshoura 1723
Ariake 901
34 2.0
8 0.9
141
54
313
65
10
83.1
32.2
35.1
18.6
32.4
3.8
1.1
102
-------
The frequencies of patients of other diseases, i.e., people who do
not show the symptoms of organic mercury poisoning, are 22.90 ± 1.37%,
22.17 ± 1.00%, and 29.52 + 1.52%, respectively, for these three areas
(Table 3). The differences between these numbers are significant for the
Minamata and the Ariake areas \/.-~~10.,7), P< 0.01) and for the Goshoura and the
Ariake areas (x:>l/-l^, P<0.001) . However, no significant difference between
numbers for the Minamata and the Goshoura areas is proven.
Section 2. Classification of Acquired and Hereditary
(Congenital) Minamata Disease and Combination
with other Mental Diseases
Minamata disease patients or suspected Minamata disease patients
mentioned above are further divided as follows:
In the Minamata area:
Acquired Minamata disease: 268 persons
Hereditary or congenital Minamata disease: 6 persons
Hereditary + acquired Minamata disease?, or
weak mind + acquired Minamata disease? : 1 person
Among hereditary Minamata disease patients, one weak mind + acquired
Minamata disease patient (female born in November, 1941), one mental
breakdown -f acquired Minamata disease (30 years old) are included. The
former was born in Goshoura, moved to Yudo at the age of 8; mental retarda-
tion was observed right after her birth; at the examinations in September and
December, 1972, the following were proven: mental retardation, noticeable loss
and dullness of the senses around the mouth and the extremities of four limbs,
loss of hearing, loss of balance, speech problem, etc.; her mother (55 years
old) is also a Minamata disease patient. The latter is a female born in
March, 1942 in Yudo; when she was a sophomore at a senior high, she fell ill
with the suspicion of the disease, later entered mental hospitals several times,
such as the Psychiatry Department of Kumamoto University, diagnosed as nervous
103
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breakdown; on the examination in February, 1972, the following were proven:
cold and superficial feeling, decline in mental alertness, jerky motion and
motionless style, phony laugh, stiffening of feeling, problem in personal
relations, dullness in the extremities of four limbs, minor loss of balance;
both father (57 years old) and mother (49 years old) were diagnosed as having
the Minamata disease. One last example of difficulties in determining
whether the mental retardation which was estimated to start at the beginning
of the infancy was due to organic mercury poisoning or not, is as follows:
born in April, 1957, in Yudo; slow in starting walking and the grades at the
elementary school were low; had epileptic fits since the sixth grade; the
conditions in December, 1972 were: mental retardation, narrow centripetal
vision, high degree of dullness in senses at the extremeties of four limbs,
loss of balance, outbreak of the 8 wave in brain waves, jerky motion, body
stiffening, cold feeling, inability to be friendly, etc.
In the Goshoura area:
Acquired Minamata disease: 34 persons
Hereditary + acquired Minamata disease? or
weak mind + acquired Minamata disease? 1 person
Suspicion of hereditary Minamata disease: 1 person
An example of difficulties in determining whether the disorder in
mental development which was noticed at the early infancy is due to organic
mercury poisoning or not is a female born in November, 1957; started walking
at the age of 3, did not speak at all; at the examination in September,
1972, the following were proven: mental retardation, deaf-mute, excessive
centripetal vision narrowness, high degree of dullness in the senses of
aching and touching around mouth and the terminals of four limbs, loss of
balance in moving. This patient's mother (38 years old) has a high degree of
dullness in the senses of aching and touching at the extremities of upper and
lower limbs and minor loss of balance, but does not have subjective symptoms;
thus unclear when the disease occurred. The 14-year-old patient mentioned above
was included among the patients with acquired Minamata disease. An example
of suspicious hereditary Minamata disease is a boy born in August, 1960. The
104
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following were observed: started walking and talking at the age of a year and
a half and 3 years, respectively; at the March, 1972 and March, 1973 examinations,
the following symptoms were observed: mental retardation, sensory disorder of
warmth and vibration at both hands and feet, loss of balance, excessive centri-
petal vision narrowness, minor fits, epileptic abnormal brain waves (irregular
exceptional wave, frequent occurrences of 6 waves, etc.); his mother (born in
September, 1937)also has mild mental disorder and epileptic abnormal brain
waves (sudden occurrences of irregular exceptional waves, sudden outbreak of
sharp waves by flashing light stimula).
In the Ariake area, no patients with hereditary Minamata disease were
found.
Section 3. Examples of Patients Diagnosed as having
the Minamata Disease
I. PROGRESS OF EXAMINATION
As shown in Table 5, the number of cases diagnosed as having the
Minamata disease increased in the Minamata and Ariake areas and decreased in the
Goshoura area from a comparison of the results from the first and second
examinations. The number of cases suspected as having the Minamata disease was
remarkably decreased in the second examination in every area.
II. EPIDEMICAL AND SOCIOMEDICAL ITEMS
Occupation
Profession or business of Minamata disease patients who were identified at
the simultaneous examination in the Minamata area is as follows: fishermen: 69,
half-fishermen - half farmers: 6, farmers: 32, nitrogen plant workers: 22,
other companies employees: 20, carpenters: 14, temporary laborers: 9, self-
employed: 8, public officers: 7, sailors: 4, drivers: 3, lumber workers, doctors,
nurses, self-defense force soldiers, etc: 2 -1. As depicted above, persons who
105
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TABLE 5. HISTORY OF DIAGNOSES
. — .,_
Area
Minamata
Goshoura
•
Course of
diagnosis
First examination
Second examination
First examination
Second examination
Ariake First examination
; Second examination
.,
Minamata
disease
Suspected
case
185 105
275 38
39 39
34 31
5 24
2
engaged in fishing were only 69 out of 215 persons, i.e., 32%, or 35% even if
the persons whose work is half farming and half fishing were included.
The occupations of Minamata disease patients in the Goshoura area are as
follows: 15, half fishermen- half farmers: 2 farmers: 5, public officers and
self-employed: 2 each, carpenter, pearl cultivater, inn owner, monk, etc.: 1
each, unknown: 3, welfare supported: 1, etc.
In the case of the Ariake area, they are: fishermen: 6, half farmers -
half fishermen: 2.
Economic conditions
We, the staff at the Neuro-Psychiatry Department, examined Minamata
disease patients by visiting their homes from 1961. At that time, we noticed
that these patients' families, or in general, villages to whom they belonged,
were extremely poor. The eaves and walls of many of their houses did not stand
straight. Many houses were dark and small. For some patients' houses, roofs
were broken so that the sky could be seen from the inside and walls were
fallen so that the wind blew through the room. Some of the patients could
not afford to provide their daughters with mandatory education, and some of them
had to force two or three of their daughters to become housemaids. Presently,
106
-------
the conditions are considerably improved. Under the economic conditions
mentioned above, they did not have a choice except eating fish caught at the
nearby sea for their meals. Many of the families whose entire or majority of
members suffered from the Minamata disease seriously or fatally were exceptionally
poor.
Some Minamata disease patients who exhibited clear symptoms and suffered
seriously did not take any treatments for a long time, since they could not
afford the transportation cost to the medical facility or they could not afford
the cost of medical care.
Consumption of fish, and amount of mercury contained in shellfish.
All of the patients consumed a great deal of fish. The methods of obtain-
ing fish are as follows: when they were fishermen and caught fish by themselves;
when they were not fishermen but caught fish by themselves; when they obtained
fish from relatives or neighbors who were frequently fishermen; when they were
given as a remuneration for their ship carpentry work or accupuncture work;
when they bought fish.
Especially in the Minamata area, poor families, families without farm land,
families who lived near the shore where fish could be easily caught and
fishermen's families naturally ate a great deal of fish every day. In some
cases, no other way besides eating fish existed in order to survive.
In the Ariake town, seven cases were fishermen: five cases used the
Ariake Sea as their fishing ground, and two other cases (couple) used mainly
the Ariake Sea and went fishing to the Shiranui Sea for about five months
(actual fishing period was two months) in 1963. The remaining case was a
farmer who purchased fish and ate fish occasionally.
The results of measuring the amount of total mercury in bina, caught
from the shore of the Ariake area in April, 1972 are as follows: bina caught
at Ariake: 0.000 PPM (caught on April 8), 0.054 PPM (April 17); bina caught at
Suko: 0.061 PPM (April 19); bina caught at OShimako: 0.030 PPM (April 20).
107
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Date of illness
Years when the Minamata disease patients in the Minamata area started
suffering from the disease range from 1942 to 1972 (Table 6).
An 18-year-old boy who fell ill in 1972 (household number: 551) said that
he started having speech problems this year. The examination held in
February 13, 1973 proved that he had speech problems, sensory disorder in
touching, aching, warmth, coldness and motion (worse at the extremities of four
limbs, and some around his mouth), mental retardation, high blood pressure
(158/82). His grandfather (69 years old) living with him also had the
Minamata disease. The second example is a case of a 58-year-old housewife
(household number 558). She had felt burning sensation in her head since
April, 1972. Her body started shaking in September, and started having a
buzzing in her ears in October. The examination in March 7, 1973 showed
that she had remarkable subjective symptoms (aches in her waist, easy to fall
and get injured, dizziness, etc.), and minor loss of balance
at the knee bend test, medium degree of muscle tension, shaking, dullness of
the senses higher at the terminals of four limbs and also around her mouth,
hearing difficulty, minor mental retardation, depression, high blood pressure,
etc. Her daughter (35 years old) was also diagnosed as having the Minamata disease.
For the first case in the Goshoura area, a subject fell ill in 1972
(male; household number: 593). The initial symptoms were aches in lower limbs
and the bottom of his feet. Although symptoms in September 3, 1972 (74 years
old) were minor, he showed speech problems, loss of balance, loss of strength,
vision narrowness, dullness of the senses worse at the extremities of four
limbs, dullness of the senses around his mouth, hearing difficulty, medium
degree of mental retardation, high blood pressure, etc. The subject for the
second case (male; household number: 599) showed blurred eyes, and languid
legs in 1972. His conditions on September 3, 1972 (66 years old) were minor,
but showed loss of balance, muscle tension, narrow vision, dullness in the
sense of warmth at the extremities of four limbs, medium degree of muscle
contraction (calf, biceps, etc.), hearing difficulty, noticeable mental
108
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retardation, etc.
The case in which the disease was suspected to start in 1941 was a girl born
in Yudo in November, 1941 (household number: 757). Her birth was normal and
she weighed 700 kg. She was nursed with her mother's milk until her first birthday.
However, from the beginning, her mental development was slow. She started
walking alone and speaking at the age of 7. Until then, she suffered from
spontaneous paralysis. She entered into Ryonan dormitory in Motowatari in 1969.
She has been frequently in bed due to paralysis in her right foot since the
fall of 1972. Her conditions at December 6, 1972 were as follows: small built,
walking with her left foot dragging, muscle contraction of her left hand and
foot, loss of the senses of aching and warmth (40° C) at 1/5 of both of her arms
from the edge and 1/3 of her left lower limb, dullness of the senses of touching
and coldness at the terminals of her four limbs, medium degree of hearing
difficulty, minor loss of balance, high degree of speech problem, high degree
of mental retardation, etc. Her mother (55 years old) was also a Minamata
disease patient.
The case in which it was considered that the illness started in
1942 was, as reported in the previous report, a subject both of whose parents were
Minamata disease patients (household number: 592). The patient's sister, who
lived with them until July, 1971, was also a Minamata disease patient.
This patient was born in Tsukinoura in October, 1938, grown up normally.
He suffered from paralyzing fits four times in February, 1942. He did not
have fevers but had stopped growing mentally since then. The examination in
November, 1972 showed symptoms, such as a high degree of mental retardation,
noticeable loss of balance in getting up, walking, finger movement,
and nose-pointing test, high degree of speech problem compared with his attitude
and clothes which were in good order, abnormality in eye movement which brought
the suspicion of the Minamata disease:although vision measurement was not
possible, athetosis of left hand and leg, remarkable.
109
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TABLE 6. YEARS WHEN PATIENTS WERE DIAGNOSED AS HAVING THE MINAMATA DISEASE.
THE NUMBER IN PARENTHESES IS FOR THE HEREDITARY MINAMATA DISEASE
rH CM
ON ON
Minamata i i
area
Goshoura -
area
Ariake
CM rn
vO \o
ON ON
rH rH
Miramata ;n p
area O)
Goshoura 4 -
„ area
Ariake - 2
area
ro m vo-
ON ON ON
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vO vO vo
ON ON ON
rH i-l rH
7 9 16
52-
— — —
oo ON «-i CM en ^3-" m
<»• vf m m m m m
ON ON °^ Oi ON ON ON
113443 21,-,^
- - - 2 -- 1 1
r~ co ON o iH CM
vO vo vo r-* r~ t~~
ON ON ON ON ON ON
i-l rH i-l i-l i-t rH
12 4 13 9 3 2
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1 3 - - -
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m m m in vo vo
ON ON ON o-\ ON ON
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1 - 3 l 1
Unknown
6
4
9
From Table 6, years when many patients started having the disease
were 1955 - 1962 and 1966 - 1969 in the Minamata area and 1959 - 1967 in
the Goshoura area.
Illness within a single dwelling family
From Table 7, for the Minamata area, for instance, 81.8% of patients
have other Minamata disease patients, and 86.2% of patients have other
Minamata diseases or suspected Minamata disease patients within their families
living together. In the Minamata area, there were many cases with suspected
Minamata disease and for many cases, they had Minamata disease or suspected
Minamata disease patients within their families living together. However, the
frequency of this phenomenon decreased among patients in the Goshoura area.
There were 2 in the Ariake area.
Among these families, there were many cases where an entire family
had suffered from the Minamata disease. For example, there were cases where
a couple and all of their six children, a couple and 7 out of 10 children who
came for the examination, a couple and all of their three daughters, a couple
and 6 out of 9 children, and a couple and 5 out of 6 children who came for the
examination were suffering from the Minamata disease.
110
-------
Abnormality seen in domesticated animals
For the Minamata area, among 216 persons diagnosed as having the
Minamata disease, 144 persons (66.7%) claimed that their domesticated animals
died mad, 16 persons claimed that neighbors' domesticated animals died mad,
26 persons showed unknown, and 30 persons (13.9%) indicated no such incidents.
Also for persons who claimed their domesticated animals die mad, nine were
among 19 persons who were suspected of the Minamata disease from the examina-
tion, 3 were among 16 persons who were held for further diagnoses, 3 were
among 6 patients of other diseases. For domesticated animals which died mad,
131 persons who were diagnosed as having the Minamata disease indicated cats,
15 persons - pigs, 13 persons - dogs, 9 persons - chickens and 1 person
each claimed a goat and a rabbit, respectively. One hundred thirty-four
persons were investigated in the Goshoura area. Five persons who were diagnosed
as having the Minamata disease, 5 persons who were suspected of the Minamata
disease and 3 persons who were held for further examination observed that
their cats (11) and chickens(2) either died (5 cats) or showed abnormality
such as dizziness, spinning, and loss of strength.
For the Ariake area, cats owned by 2 persons who were diagnosed as
having the Minamata disease and a cat owned by a person who was held for further
examination died.
TABLE 7. OCCURRENCES OF THE DISEASE AMONG MEMBERS OF A FAMILY.
THE NUMBER IN PARENTHESES IS WHEN THE SUSPECTED PATIENTS ARE ADDED
Minamata disease
Suspected Minamata
disease
Deferred diagnosis
Minamata area
Actual
no.
225(237)
9 (10)
3 (8)
%
Goshoura area
Actual
no.
81.8(86.2) 5 (13)
23.7(26.3)
20.0(53.3)
1 (8)
0 (2)
cr/
14.7 (38.2)
3.2 (25.8)
0 (6.9)
Ariake area
Actual
no.
2(0)
0(0)
0(0)
%
25(0)
0(0)
0(0)
111
-------
III. AGE AND SEX
Table 8 shows patients' ages and sex.
For patients in the Minamata area, the rate of those over 40 years old,
especially over 60 years old, is high compared with that of the total
patients examined. Thirty-two out of 34 patients in Goshoura and all of
nine patients in the Ariake area were over 50 years old. A similar tendency
is seen among patients, surviving or dead, who were known to have the
acquired Minamata disease in Kumamoto prefecture (Table 8). On the other
hand, the number of Minamata disease patients under 39 years old in the
Minamata area is small. Similarly, a small number of people under 39
years old are known acquired Minamata disease patients in the Goshoura and
Ariake area (Table 8).
For 275 cases found at the simultaneous examination, the
ratio between male and female Minamata disease patients is 897:100. The ratio
for the entire persons examined in the Minanata area is 83.0 : 100 (Table 8).
IV. AGES WHEN THEY FELL ILL
From Table 21 shown later, 42.5% of patients fell ill when they
were younger than 39 and 54.2% of them fell ill when they were older than
40.
V. INITIAL SYMPTOMS
Initial symptoms for 215 patients in the Minamata area were as follows:
numbness in their hands and feet (75 cases), headaches (21 cases), waist
aches (20 cases), shivering (18 cases), dullness (16 cases), muscle spasms
(10 cases), weakening (10 cases), dizziness (8 cases), early fatigue (7 cases),
easiness in falling (7 cases), etc.
112
-------
00
w
persons
6
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cu
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at • ca
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C S w
C CO
H CU 4->
S CO C
CO CU
• (U -H
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CU CO
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examin
person
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0)
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rH rH rH rH rH
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m
cr>
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113
-------
TABLE 9. CHANGES AFTER DIAGNOSIS OF THE MINAMATA DISEASE.
THE NUMBER IN PARENTHESES IS FOR THE HEREDITARY MINAMATA DISEASE
Area
Mlnamata
Goshoura
Ariake
Worsen
152
14
4
Fluctuation
32
1
2
Steady
45(3)
10
2
Better
27(3)
2
-
Unknown
19
7
-
Examined
persons
275
34
8
VI. PASSAGE FROM THE BEGINNING OF ILLNESS TO MEDICAL EXAMINATION
Subjective symptoms observed yearly by 275 patients in the Minamata area
from the beginning of illness to the examination were as follows: worsen-
ing: 152; repetition of sudden worsening and sudden recovery: 32, steady:
45, improvement: 27, unknown: 19 (Table 9). Many patients observed that their
symptoms worsened year by year, according to the above figure. For the
Goshoura and Ariake areas, many patients got worse each year.
Many patients took examinations continuously at nearby hospitals after
they fell ill. Some of the patients received examinations by changing
their medical facilities frequently. However, for many cases, no noticeable
improvement in their subjective symptoms were observed. That is, even after
many visits to medical facilities or entering hospitals 1/2 - 2 years, their
diagnoses were not clear in most cases. It was frequently seen that many of
them showed symptoms for the Minamata disease and their noticeable pro-
gression. Many patients resorted to moxa.
114
-------
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115
-------
VII. CONDITIONS AT THE EXAMINATION
A. Acquired Mlnamata disease
1. Summary
Table 10 illustrates major symptoms of patients diagnosed as having
the Minamata disease. Major symptoms of 269 patients in the Minamata area
are as follows in the order of frequencies: sensory disorder 97.0%, subjective
symptoms 94.8%, loss of balance 93.7%, mental retardation 89.6%, memory
difficulty 85.5%, hearing difficulty 84.0%. They are followed by loss of
strength 67.3%, speech problem 62.5%, centripetal vision narrowness 59.5%,
etc. Also, 49.8% showed high blood pressure and 16% showed mental disorders be
sides retardation and memory loss.
2j. _ Subjective symptoms
The following show major subjective symptoms of 215 patients who were
examined rather in detail: numbness in hands and feet (82%), aches in hands
and feet (50%), other abnormal senses (9%), aches in head, back, waist,
four limbs, etc. (79%), dullness (65%), loss of sight (55%), narrow vision (31%),
loss of hearing (60%), a buzz in ears (51%), loss of smell (28%), loss of
taste (22%), easiness of falling (58%), difficulty in putting slippers on (36%),
sandals slip off (40%), difficulty in moving fingers (37%), difficulty
in moving hand (37%) , easiness in dropping things (43%) , difficulty
in buttoning (34%), difficulty in clear talking (36%), difficulty in talking
(41%), loss of strength in hands and feet (57%), body stiffness (this is
mostly stiffening paralysis partially on four limb muscles and comes with un-
comfortable feeling (71%), muscle spasms (56%), trembling hands and feet (43%),
insomnia (43%), early fatigue (68%), intense body (61%), laziness (40%), need
to stop work to sleep (16%), forgetfulness (75%), fits which cause dizziness
(42%), black out (16%), etc.
These subjective symptoms sometimes become controlling symptoms in clini-
cal cases: 22 cases in the Minamata area and 2 cases in the Goshoura area.
116
-------
3. Neurological symptoms
j>ensory_ ^isp_rdejs_
Table 11 shows that sensory disorders are so extensive that in 95% of the
patients even the tips of their extremities are affected. Many are affected
also around their mouths (54%) As for the degree of disorder, 67% manifested
TABLE 11. TYPE AND DESCRIPTION OF SENSORY DISORDERS AND SENSES AFFECTED
AFFECTED: CONGENITAL MINAMATA DISEASE PATIENTS ARE EXCLUDED
01
JS
(0
Ol
CO
•H
13
4-J
*4H O
O -H
Vi
O> 4->
p. CO
^> **^
H Q
0)
CO
to Minamata (actual
co number)
'a Minamata (%)
to Goshonoura (actual
<« number
g Ariake (actual
£ number)
« Minamata (actual
--H g en number)
rt 2 mGoshonoura (actual
o ;H;H number)
P-I
i
oj Minimata (actual
__. number
CO T3
•<-< v Goshonoura (actual
g ft number
CO
13 Q»
G •H
10 4-1
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M B
0) 0)
&. M tO 0)
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01 tO 4->
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CD 4J 0)
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|
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31 24 12
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17 9 7
29 14 6
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32 17
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2 2
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21
10
6
l
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a
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CO
c
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1-1
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rH tO
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rl CO C
rl O ,0
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Xi 4-) C O 4-J O
d o e xi E -H -ri
•H 3 C rH Q) CO 4J
CO O cd O t-i O O
PM H & a H fu S
21.; 20J 209 2.J7 137 12,- ;;,!
9B 9G 90 ?5 SO ."9 -IS
30 25 27 25 13 2 2
S 7 6 o 7 2 ;
10 17 IS l.-t l?i S ?
^f) 23 28 2ii 16 2 2
12 7 S 9 -I 2 4
19 12 19 19 3 1 1
•a
0)
c
•H
B
cd
cu
CO
a>
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CO
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M-l
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,
o
217
—
.1!
*
19
O
lo
2°
{* m Ariake (actual
^ number)
Note: Probable cases of Minamata disease in Ariake district are
not shown in this table.
117
-------
some loss of sensation, while 32% were affected throughout the whole body.
Tests of the sense of pain, touch, warmth, and coldness also indicated an
advanced degree of disorder. The disorders of the sense of tremor, especially
senses of position and motion, were difficult to establish in many cases.
Abnormal sensations were observed in 12%, primarily of the tip of extremities.
Other complaints consisted of feelings of a worm crawling on one's back, a
quivering of the lips, and a burning sensation of the tongue.
Ijoss_qf_ Coordination
The results of tests in which the phenomenon of loss of coordination
appeared under comparatively simple conditions and at a great frequency are
as shown in Table 12. The tests consisted specifically of kinetoses (in this
test, loss of coordination was confirmed in 90% of Minamata disease patients),
straight line walk test (69%) , finger-nose test (64%) , right turn test (63%) .
Romberg's symptoms were seen in only 37% of the patients.
Jnvoluntarv_ movements^
A description of involuntary movements is provided in Table 13. As is
shown, many cases of tremors were observed in both Minamata and Goshonoura
districts. During the examinations, fascicular contractions were frequently
directly observed.
j>ympj:oras_on iej£/r_igh_tjside. of__body_
Table 14 shows that of the 38 cases (of which 18 cases involve males)
in the left/right half of the body, 30 cases (of which 16 are males) are
severe, and the remaining 8 are of moderate degree. Thirty-nine cases (of
which 18 were males) showed marked sensory disorders in half of their body;
eight cases (of which 5 were males) manifested both paralysis of movement and
sensory disorders, all on the same side of their body. A peculiar character-
istic among the Minamata disease patients was that, despite a serious paraly-
sis of movement in the left/right sides of their bodies, no difference was
118
-------
1
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119
-------
TABLE 13. BREAKDOWN OF INVOLUNTARY MOVEMENTS; FIGURES IN PARENTHESES
INDICATE PERCENTAGE
Shaking
Athetosis
Hiolea
Involuntary movement,
but seemingly
voluntary
Tic
Fascicular contraction
No. of cases examined
Minamata district
Minamata
disease
120
(55.8)
8
4
5
1
8
20
217
Probable case
of Minamata
disease
6
(31.6)
-
-
-
-
1
17
Goshonoura district
Minamata
disease
14
(40.0)
1
1
-
-
1
34
Probable case
of Minamata
disease
12
(38.7)
1
-
2
-
-
-
31
TABLE 14. COMBINATION OF PARALYSIS OF MOVE-
MENT AND SENSORY DISORDERS IN LEFT/RIGHT
HALF OF BODY; BRAIN HEMORRHAGE. FIGURES IN
PARENTHESES SHOW NUMBER OF PERSONS STRICKEN
WITH BRAIN HEMMORRHAGE OUT OF THE PRECEDING NUMBER
Sensory
disorders
Movement
disorders
Total
-H-
8 (4)
(I
22 (2)
Total
30 (6)
8 _ _ 8
23 - ' - 23
39 (.4) - 22 (2)
Note: -H- — considerable difference in dis-
orders between left/right side; H moderate
difference between left/right side; 0 — dif-
ference between left/right side not established.
120
-------
found in sensory disorders between the left/right sides in 22 cases, and that
despite a severe sensory disorder in half of the body, no difference in more-
ment disorder between the left/right sides was noted in 23 cases. There was
a total of 6 cases of brain hemorrhage resulting in a paralysis of movement,
of which 4 cases involved also a sensory disorder of half the body, and 2
cases manifested no difference in sensory disorder between the left/right
sides. In the cases involving paralysis of movement, 35 were affliced with
symptoms of half of the body without accompaniment of brain hemorrhage, while
24 were afflicted with sensory disorders. All 6 cases with brain hemorrhage
suffered from a paralysis of half of the body.
Out of 214 Minamata disease patients, 6 or 2,80 + 1,13% were 40 or over,
and had a paralysis of half of the body as a result of brain hemorrhage.
This percentage was close to that of residents of Heianza Island [5] where —
out of 766 individuals — 20 persons or 2.61 + 0.57% had a similar condition.
In the case of general, movement-typr paralysis of half the body, the figures
for Minamata disease patients were 17.75 + 2.61%, and for Heianza Island
residents, 34 persons out of 766, or 4.44 + 0.74 — a significant difference
Cx'sHi-'"" CO. P< 0.001). For the inhabitants of Minamata, movement-type paralysis
designates those who drag one foot while walking and demonstrate a slight
difference between the left/right in innate reflexes or muscular tension. As
for the inhabitants of Heianza Island, the term embraces even those who simply
manifest a difference between left/right in their innate reflexes. The fre-
quency rate for symptoms of half of the body combined with both movement and
sensory type of paralysis was 61 persons or 28.50 + 3.09% out of 214 Minamata
disease patients, as oppored to 4.47% for Heianza inhabitants — a significant
difference (z^liO.GG, p<().001)
.Brain, disorders^, _dizzinessj_ gidd±ness_
Among Minamata disease patients in Minamata district, 81 (37.7%) out of
215 cases examined had fainting spells, and either grasped some object for
support or assumed a squatting position, while 33 cases (15.3%) felt dizzy or
121
-------
giddy. Such seizures were noted in 6 cases (17.1%) among Goshonoura in-
habitants.
EpJLlepay_(^ym^to^at^ijc epdlepsy)
Epilepsy among Minamata disease patients was 8.92 + 1,74% in the Mina-
mata district, and 2.86 + 2.82% in the Goshonoura district. In many cases,
the types of seizures were uncommon. For example, clonic spasms may occur
with or without disorders of the brain, or there may be sudden eruption of
electrical discharges without any mental disorders or seizures. The latter
case was seen in residents (2 cases) of A community in the Minamata district
in one of three sisters residing in Osaka, but they were not considered to
be epileptics.
4. Mental Symptoms
The mental conditions of Minamata disease patients may be classified
into reactions against the environment and an abnormal mental state.
(i) Reaction against environment
Existing in the mental state of Minamata disease patients is a reactive
element against one's illness or social influences, believed to fall within
the normal range, but considered unusual.
The patient possesses, relative to his illness, a sense of anxiety and
inferiority with respect to the following matters. For example, propriocep-
tive symptoms accompanied by pain, difficulty and lessened efficiency in
daily work due to decline of motor and mental functions, diagnosis as Minamata
disease, progress of disease and ineffectual therapeutic treatment; difficulty
and less chance for employment or marriage; transmission of disease to pos-
terity and other effects; diverse by spouse, and impact on fellow workers
and personal friends.
122
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With respect to the social aspect, the Minamata disease patient is con-
fronted with the following mental problems. For example, discrimination and
lower standing as a result of sickness; envious attitude of others over com-
pensatory payments; criticism that the intent behind application for designa-
tion as a Minamata disease patient was to receive compensation; oppressive
Minamata power of administrative, company, fishery officials and urban resi-
dents; a clash of interests between enterprises constituting the financial
pillar of the city and of oneself as a victim of such enterprises; distrust of
the close relationship between physicians and hospital institutions, on the
one hand, and the administration and enterprises, on the other; anger over the
attitude of the offender, the enterprises; the irony of fishermen-patients
facing livelihood and health problems because of decreased sale of fish as a
result of the emergence of Minamata disease patients, and anxiety over a sick
person being in the family.
For the foregoing reasons, some patients have moved from one job to
another or have been divorced. In addition, because of the complex environ-
mental factors, there were varied mental processes, standing, and interests
among the patients who split into numerous groups, advocating either delega-
tion of full authority to another party, litigation, personal negotiation,
wait-and-see, or evasive attitudes.
(ii) Abnormal mental conditions (mental
symptoms)
Among the Minamata disease patients, mental conditions were not confirmed
in 17 (6.2%) out of 275 persons from the Minamata district, A (11%) out of
35 from the Goshonoura district, and 1 (11%) out of 9 from the Ariake district.
Mental conditions associated with Minamata disease are the following
(Table 15).
123
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TABLE 15. MENTAL DISORDERS OBSERVED IN PATIENTS WITH, OR PROBABLY WITH,
MINAMATA DISEASE
Mental
disorders
Emotional dis-
orders
Delirium
Manic-depressive
condition
Menopause depres-
sive condition
Schizophrenic
type condition
Neurotic condition
Condition difficult
to classify
Schizophrenia
Mental retardation
Minamata
Minimata
disease
241
230
-
16
1
2
22
1
1
1
district
Probable
Minamata
disease
12
14
-
-
_
-
1
-
-
—
Goshonoura district
Minamata
disease
24
24
Probable
Minamata
disease
28
23
1
8
—
-
2
-
-
—
-
_
-
-
-
—
Ariake district
Minamata
disease
8
7
-
-
-
-
-
-
—
Note. Mental retardation is also included under mental disorders.
a. Those associated with organic mercury poisoning: mental dis-
orders, emotional disorders, hallucination-delusion condition, manic-depres-
sive condition, regressive-depressive condition, schizophrenic condition,
neurotic condition, and conditions difficult to classify.
b. Combination with symptoms of organic mercury poisoning: schizo-
phrenia (1 case), mental retardation (1 case).
124
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Among cases dealing with the foregoing mental conditions, 1 case each —
specifically, that involving neurotic conditions from Minamata district, and
depressive plus neurotic conditions from Goshonoura district (a total of 3
cases) — were determined as not being due to either mental or emotional dis-
orders. Also, mental disorders were not established in one case each
involving schizophrenic-type conditions, schizophrenia, and neurotic condi-
tions from Minamata district (a total of 3 cases) , and 1 case each involving
depressive conditions and neurotic conditions from Goshonoura district (a
total of 2).
Meiitjil_disc>rders
A serious degree of mental disorders was noted in 4% of Minamata district
patients, a moderate degree in 28%, and a mild degree in 65% (Table 16). In
cases of serious mental disorders, the patients required aid and supervision in
their daily livelihood because of impaired ability to think, judge, recall,
memorize, and understand. In cases of mild disorders, tests established the
degree of disturbed power of recollection, memory, and thinking, and such
disorders did not greatly affect the livelihood of the patients. The moderate
degree of mental disorder fell between the two areas above.
The case under this category involved a person born in May, 1918, and
stricken with Minamata disease around 1956 - 1957. As the disease progressed,
the individual attempted suicide in November, 1971, and was admitted to a
mental institution because of a serious depressive condition. Following ad-
mission, the patient was stricken with irregular clonic spasms, sometimes ac-
companied by poor memory, followed by the onset of hearing hallucination and
delusions. The condition of the patient as of August 17, 1972, included
hearing hallucinations, mental disorders, marked loss of coordination, poor
vision, hearing difficulty, articulation difficulty, shaking, and disorienta-
tion. Clinically, the existence of mental disorders could not be established.
The brain waves were of slow a-wave pattern, with occasional 8-waves. This
125
-------
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126
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case was also considered to be one of the epilepsy cases associated with
Minamata disease. The patient succumbed in February, 1973.
En»t_ipnal_ .disprderjs
Most emotional disorders consisted of dull emotions and diminution of
aggressive behavior (Table 16). The patient usually complained of various
proprioceptive symptoms, demonstrated tiredness and fatigue in expression and
behavior, and impolitely laid down in front of a physician while awaiting
his turn for examination.
As for manic-depressive disorders, there were 3 cases of manic-state
(mild), 14 of depressive state, and 1 of alternate, cyclic manic-depressive
state in the Minamata district. The depressive state was generally classifi-
able as a mild case, but four persons were observed to have a suicidal ten-
dency. In the Goshonoura district, there were 8 cases of depressive state,
of which 2 had suicidal tendencies.
These depressive states were generally in the mild category.
MenojJause_ jie
This case involved a farmer's wife born in October, 1929. When stricken
in July, 1972, she felt as if her head was burning, and her condition sub-
sequently became aggravated. Her condition as of March 7, 1973: complained
strenuously and exaggerated about aches running down her neck to her shoulder,
constipation, and heavy feeling in her head; repeatedly asked whether she has
any strange malady and whether she was going insane; restless; constantly
sighed; had her daughter massage her neck; spoke in a coquettish tone:
suddenly stood up to leave, only to return and repeat foregoing statements;
depressive; gloomy; sensory disorders; hearing difficulty; loss of
127
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coordination and tremors; eldest daughter (age 35), who used to live with
patient until marriage in 1963, also had Minamata disease.
Three cases involved psychoses characterized by tension. For example,
one case involved a youth, age 15, who displayed inhibition of motion, immo-
bility, muteness, stiffness, rigidity, coldness, and dark expressions, frown-
ing, stupor, negativity, no vitality, extremely slow reaction, hard to under-
stand, and inaccessible through communication; sensory disorders most serious
at tip of limbs and also emerging in islet-shape in the right upper arm and
on the back of the left hand, tremor, and mild mental disorder. The youth's
father (age 42) also suffered from marked Minamata disease symptoms, such as
sensory disorder, hearing difficulty, and loss of coordination, in addition to
similar schizophrenic symptoms. The third case also involved a 15-year-old
youth.
Included in this category were the following: among the Minamata district
patients, (a) 16 persons complained mostly of bodily and mental disorders,
i.e., the recurrence of previously described proprioceptive symptoms accom-
panied by an outburst of emotional feeling; (b) four were characterized by
depressive moods and anxiety; (c) one — by bodily and mental disorders plus
depression and anxiety; (d) one — by bodily and mental disorders plus pseudo-
imbecility, and (e) two — by exaggerated wavering at the time of Rom-
berg's test.
Among the Goshonoura district patients, there was one case each of
bodily and mental disorders, of bodily and mental disorders plus fear of
losing his/her mind, and bodily mental disorders plus depressive-agony
reactions.
128
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to.
This case involved a woman born in April, 1903, and with 6 children,
3 of whom had Minamata disease. She was stricken around 1954 - 1955, with
the onset of stiffness of hand, tremor, and excessive perspiration; she con-
cealed her condition in fear that she may also have contracted Minamata
disease after her eldest son was diagnosed as having Minamata disease; she was
examined in August, 1971, November, 1972, and in March, 1973, and found to
have proprioceptive symptoms, such as numbness of limbs and inability to walk
properly; in stupor and immobile, with hands on her lap and leaning against a
table when left unattended; appeared to be tired and fatigued; while lying
down on the treatment table, crossed her arms in front of her eyes and
pouted her mouth; lacked aggressiveness or "drive"; disinterested and slow
in speech, yet friendly and lacked inhibition, even asking a child eating
grapes nearby to give her some; short, fast steps noted in walking test; closed
eyes and mouth very tight during Romberg's test; in a finger-nose test,
sounded chants and thrust her head forward as if pounding rice and bent her
five fingers inward in the shape of a claw and attempted to poke her nose,
stopping 3 - 4 cm away from her nosetip; stroked her finger with the other hand
and poked her eye while chanting; when instructed to stand on one foot with
both eyes open, outstretched her fingers, extended both arms outward at her
side, arched her mouth and raised one leg as if dancing the Yasukibushi
(Japanese dance), asking the physician if her foot was elevated and then lower-
ing it with an exclamatory sound; when instructed to pick up an object on the
floor, would extend both her legs and gradually move the legs toward each other
as if trying to catch an escaping fish; when instructed to grasp an object,
would retain that position even though the object was removed from her hands;
when told to stick her tongue out, would hold that pose indefinitely. The
aforementioned abnormal behavior appeared unnatural, strange, and as if she
were putting on an act, even humorous. As for mental functions, there was a
loss of the sense of time, marked deterioration of thinking ability and
of knowledge.
129
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Mentjil_dL sorder as_aii _unan_t icij>ated
A case in which schizophrenia and mental retardation were respectively
determined to be an unanticipated accompanying symptom of Minamata disease
was previously described (Section 2, Chapter 2).
5. High Blood Pressure
The frequency of high blood pressure among the Minamata district
patients with Minamata disease was 48.91 + 3.01%. Patients aged 40 or over
totalled 214, or 102 males and 112 females. Among these, 129 had high blood
pressure, with 60.28 + 3.35%. Of 766 residents (of which 298 were males)
aged 40 or over from Heianza Island, those with high blood pressure numbered
238, with 31.07 + 1.67%. The difference in the frequency of high blood pres-
sure between Minamata district patients having Minamata disease and Heianza
Island residents was significant (>:2>60.93, P<0.001).
The frequency of high blood pressure was more pronounced with increasing
age. For Heianza Island, the frequency was: 40-year-old age group, 13.4%;
50-year-old age group, 20.8%; 60-year-old age group, 33.5%; 70-year-old age
group, 55.2%; 80-year-old or over, 55.2%. A comparison of the age make-up
between Minamata disease patients and Heianza Island residents reflected:
age 40 - 49, 24.8% and 27.0%; age 50 - 59, 25.7% and 21.9%, age 60 - 69, 24.8%
and 24.9%; age 70 - 79, 21.0% and 20.0%; age 80 and over, 3.7% and 6.1%. The
age composition for both groups was virtually identical; however, the per-
centage for the 40 - 49 and 80 or over age groups for Heianza Island residents
was higher. The frequency of high blood pressure for Heianza Island residents
age 40 or over was 25.8% for males, and 34.4% for females, a significant
difference (x;J?6.2.'i, P<0.02) . As for those over 40, the male/female ratio was
62 : 100 for Heianza Island residents, and 91 : 100 for Minamata disease
patients.
130
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6. Protein and Sugar in Urine
Of 112 Minamata disease patients examined at Minamata district, 5 (4.5%)
were found to have a slight amount of protein in the urine, but no sugar was
found in any. Of 8 cases of probable Minamata disease, 1 showed a slight
positive reaction for urine, and none for the presence of sugar.
As for Goshonoura district, 4 and 2 persons out of 32 Minamata disease
patients showed a positive reaction for protein and sugar, respectively. Out
of the 20 probable cases of Minamata disease, 3 were found to have protein
in the urine, and none were found with sugar in the urine.
In the foregoing diabetic cases, poor vision, sensory disorders, and
loss of coordination were noted.
7. X-ray Te&t of the Vertebrae
Of those found to require an x-ray test of the cervical vertebrae and
able to visit the Kumamoto University Hospital for such a test, Minamata
disease patients numbered 44 (of which 27 were males), 17 probable cases
(including 9 males), and 23 others with miscellaneous ailments (including 12
males). X-ray photographs were made of the patient's front, back, and side.
The findings based on the photographs are outline in Table 17. In the
cervical vertebrae, deformative spondylosis was primarily observed, along
with stricture of the disks, spinous formation in true vertebrae, and many
holes in the bony structure.
A calculation based on Table 17 revealed that the elderly, aged 60 or
over, constituted 81.8% of Minamata disease patients, 70.6% of probable
Minamata disease patients, and 56.5% of patients with other ailments.
Hitherto, it was considered that the changes of the vertebrae increased with
age and were more serious. However, our figures showed 86%, 82%, and 83%
for the foregoing ailments, respectively (-H-,+4-f) ; 30%, 24%, and 22% (no significant
131
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TABLE 17. OBSERVATIONS FROM X-RAY PHOTOGRAPHS OF THE CERVICAL
VERTEBRAE; FIGURES WITHIN PARENTHESES INDICATE FEMALES, OTHER-
WISE MALES
Age
Minamata disease
patients
J - Jt + 0
Probable case of
Minamata disease
ff -H- + o
1
; Patients with other
! aliments
i -f * . + o
12—71'
• ,1
-in
—50
—70
—71'
- -
_ —
1 2
- 2
2 3 (3) .
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3(2)
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1 • 1 (2) 5 (5) . 2 (1) - 3 (2) 7 (7) 2 (2)
Note: +++ — serious changes in cervical vertebrae; -H change of
moderate degree; + — change of mild degree; 0 — no change
difference; /:~>O.I5)) for moderate and serious changes, respectively: 92%,
92%, and 92% for total cervical vertebrae changes in those aged 60 or over
(+, ++, +++) , and 63%, 60%, and 70% for total changes in those under age 60.
Next, we tested for the existence and degree of 8 symptoms, such as loss
of coordination and decrease of roughness potential, which may have some re-
lationship with changes in the cervical vertebrae, in order to determine their
effects (Table 18). We found that in cases without neurological symptoms,
there were no or little changes in the cervical vertebrae. However, the
opposite relationship was true in the case of muscular atrophy. The frequency
of occurrence of cases involving a moderate and serious degree of the same 8
symptoms appeared to have an increasing trend in moderate-serious changes of
the cervical vertebrae as far as loss of coordination, decrease of roughness
potential, and sensory disorders were concerned. However, according to the
X2 determination, no significant differences were found between 81.1% and
84.6% in the column on the absence of pathogenic reflexes, between 9.7% and
15.4% in the column on the frequency of occurrence of marked loss of coor-
dination, and between 6.5% and 23.1% in the column on decrease of roughness
potential.
132
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TABLE 18. EXTENT OF CERVICAL VERTEBRAE CHANGES AND RELATIONSHIP
BETWEEN THE EXISTENCE AND EXTENT OF SYMPTOMS. FIGURES DENOTE THE
NUMBER OF MINAMATA DISEASE CASES; FIGURES IN PARENTHESES UNDER
ACTUAL NUMBER COLUMN DENOTE THE NUMBER OF PROBABLE MINAMATA DISEASE
CASES, AND THOSE UNDER THE PERCENTAGE COLUMN — THE NUMERICAL VALUE
FOR BOTH
2
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Loss of coordination
Cervical vertebrae
changes: 0-4
31 cases (13 cases)
Actual
%
number ;
i (i)
Decrease of potential ' 12 f9'
roughness
Increase of muscular
tension
Decrease of muscular
tension
Abnormal innate reflex
12 (10)
19 (13)
3 (4)
3.2 (4.5)
38.7 (47.7)
33.7 (50.0)
61.3 (72.7)
9.7 (15.9)
Pathogenic reflex r 27(12) • 8", .l(st.C)
Cervical vertebrae
changes: 4+ - 444
13 cases (4 cases)
Actual
number
.
u (u;
IV,. 1 Or>.l) t 3 (2)
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Sensory disorder
Loss of coordination
0 (2)
3
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potential
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tension ^
Decrease of muscular
tension
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Pathogenic reflex
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0
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0
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0 (2) , 0 (6.5) ; M > v:i.2,
•-
9
3
1
ii
0
"
u
Examination of cases diagnosed as Minamata disease, irrespective of
changes in the cervical vertebrae, indicated sensory disorders around the
mouth, articulation difficulty, and poor vision to be prevalent in the family.
133
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Among the Minamata disease patients, serious changes in the lumbar ver-
tebrae were noted in a total of 10 persons, or 9 males and 1 female (6 ,
Minamata district; 3, Goshonoura; 1, Ariake district). Those changes con-
sisted of serious deformity and spinous condition in L~ ,.; narrowing and
J ,4, j
unsymmetrical cavity between L. <.; ossification of the posterior, longitudinal
ligament of LOC? serious deformity throughout; vertebral detachment of L •
fibrous fusion and spinous condition of LC_£>-, ; serious side curvature on the
right convex, fusion and wedge-like deformity of L9 » and narrowing of the
cavity; serious frontal curvature, narrowing of cavity in L o» spinous condi-
tion and migratory vertebrae; gliding backward of L,., narrowing of cavity in
L, and spinous condition; bone fracture caused by pressure on D.. „ and L, and
spinous condition; temporal gliding of L.. , spinous condition, and fusion of
spinous projections. In these cases, changes were also noted, though to a
mild degree, in the cervical vertebrae. Sensory disorders, abnormal muscular
tension, abnormal innate reflexes, decrease of roughness potential, and other
symptoms were more serious in the lower extremities than in the upper ex-
tremities in 6 cases. There were no differences, however, in the remaining
4 cases.
8. Biochemical Test of Blood Serum
Tests were conducted on a total of 224 Minamata district residents
covering 5 items listed in Table 19. Of the 224 residents, 193 were Minamata
disease patients, 13 had probable Minamata disease, 14 were patients on whom
diagnosis was reserved, and 4 had other ailments. A similar test was also
conducted on a total of 115 residents of Goshonoura, a breakdown of which was
34, 29, 21, and 31, respectively. As for syphilitic reaction, it was noted
as positive if either or both of the Ogata method or glass disk method indi-
cated positive results. A level in excess of 13 units (K.A. Unit) for alkali-
phosphatase, 40 units for GOT (Karmen Unit), 35 units for GPT (Karmen Unit)
and 250 mg/dl for total cholesterol was termed as positive.
134
-------
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135
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The results of the tests are outline in Table 19. Figures are cited
according to district and type of disease. The Minamata disease group is
defined as the total of Minamata disease and probable Minamata disease cases,
and the control group — as the total of diagnoses reserved and other ailment
cases. Finally, the various disease types were totalled, and two major
classifications for the Minamata and Goshonoura districts were established
for comparison.
Items determined to reflect a significant difference in the positive
ratio based on x2 determination are below. Specifically, the positive ratio
of GOT between Minamata and Goshonoura district residents was 20.7% and 5.4%
/->i2 79. P.-;<) f.\ , and of GPT — 17.6% and 4.3% ''r?-l-.).r,2. P^« 01-t respectively.
The items in which the difference was determined to be somewhat significant
are below. In other words, they were the positive ratio of GPT between the
Minamata disease group and the control group — 17.6% and 7.1% '•'• - ' () ''' ~() °''
— and of GTP, 15.0% and 5.7% "'-v'•<.'>. P<.,U.'J7 . On the other hand, no signi-
ficant difference was noted between the numerical values of the positive ratio
of items below. In other words, there was no significant difference between
the numerical values of 12.6% and 7.1% -r= 1.06) for a syphilitic reaction
between the Minamata disease group and the control group; between 10.1% and
15 . 7% Cy/:~l .c'.;: for alkaliphosphatase ; and between 3.7% and 1.4% (y-~-:-Q'.W for
total cholesterol. Further, no significant difference was found between the
positive ratio of 12.1% and 10.4% for syphilitic reactions, 11.3% and 11.3%
for alkaliphosphatase, 4.5% and 1.7% for total cholesterol between the
Minamata and Goshonoura district residents, respectively.
The syphilitic reaction of blood serum was positive, in the case of
males, in 13 (11.9%) of 109 persons in the Minamata district, 6 (9.5%) out
of 63 in the Goshonoura district, and 0 out of 2 in the Ariake district; in
the females, the count in respective districts was 16 (13.6%) out of 118,
6 (9.8%) out of 61, and 0 out of 3. The positive ratios for all three dis-
tricts were: male, 10.9%; female, 12.1% and 11.5%, combined. The difference
between male and female in the Minamata district was insignificant '^/.' ()•^•'\
136
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Cases with a high GOT, GPT value all involved Minamata disease patients.
A woman, aged 73, with a reading of 142 and 126 units, respectively, had under-
gone surgery for removal of a tumor from between the pancreas and the liver
when she was 61 years of age; a 62-year-old male with a count of 125, 5, and
60 units claimed to have had an ulcer at age 45; a 31-year-old housewife with
a count of 105 and 120 units complained of proprioceptive symptoms, such as
tiredness and marked fatigue, loss of strength, and pain; a 51-year-old woman
with a count of 90 and 110 units showed nothing in particular.
9. Moxa Cautery Scars
Among the Miramata disease patients, numerous moxa burns were observed
on the shoulder, nape of the neck, hip, elbow joints, forearm, knee joints
and on the lower thighs. They represented a record of therapy over many years
against bodily pain, aches, fatigue, loss of strength, numbness, and muscular
twitching.
10. Clinical Picture
Among the symptoms of patients diagnosed as having Minamata disease,
some occurred frequently due to rather limited nervous system disorders.
These are, for example, sensory disorders, loss of coordination, hearing dif-
ficulty, articulation disorders, and centric field of vision constriction.
Table 20 is the result of study of the symptoms making up the clinical picture
of cases diagnosed as Minamata disease.
Based on this table, the following points are notable: (1) there is a
variety of combination (16 types) of symptoms; (2) there was a combination
of 6 symptoms, and, in one case, there was only one symptom (sensory disorder);
(3) among the different combinations, the greater the variety of symptoms, the
greater was the frequency of appearance, and vice versa; (4) the greatest
frequency was when there was a combination of 6 symptoms (A), followed by
those lacking a field of vision constriction (a), those combining sensory
137
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TABLE 20. COMBINATION OF MAJOR SYMPTOMS MAKING UP THE CLINICAL
PICTURE; CONGENITAL MINAMATA DISEASE IS EXCLUDED
A
a
A
a
B
b
C
c
]j
d
E
e
f
G
g
h
I
J
Minamata | Goshonoura
district
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district
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Total no. examined
269 37
15
34 31
16
Note (i) S — sensory disorder; L — loss of coordination; I —
mental disorder; H — hearing disorder; A — articulation disorder;
C — centric visual field constriction.
(ii) Where diagnosis was reserved, the figures are for patients
who received their second examination.
disorder, loss of coordination, and hearing difficulty (b), a combination of
the latter plus a field of vision constriction (B), a combination of sensory
disorder and loss of coordination (c), and the latter plus field of vision
constriction (C); (5) centric field of vision constriction occasionally ap-
peared with only sensory disorders (G), hearing disorder (I), loss of coor-
dination or sensory disorder (J).
138
-------
11. Degree of Affliction; Degree of Affliction and
Date of Onset
From the general standpont of physical and mental disorders, the follow-
ing three levels of affliction were adopted.
Serious degree: comprising the following two items:
1. Almost 100% assistance required to move, eat, eliminate
and change clothes.
2. About 50% assistance required to perform the above; requires
constant observation; dangerous if left alone.
Moderate degree: Includes the following two items:
3. Able to care for oneself, but cannot or find it difficult
to engage in work; requires supervision in daily work.
4. Able to do simple work, but inefficient.
Mild degree:
5. Normal efficiency in the case of light work,
6. Almost no trouble in ordinary job.
Table 21 is the result of classification based on the foregoing criteria
of 275 Minamata disease patients of the Minamata district, following a general
examination. According to this table, 13.5% are rated as serious, 64.7% —
as moderate, and 19.61% — as mild cases. The percentage includes 6 cases
of congenital Minamata disease, i.e., 5 serious and 1 mild cases. Of the
43 Minamata disease patients of A community in Minamata district, 4 (9%) were
serious. 26 (61%) were moderate, and 13 (30%) were mild cases. As for
Goshonoura district, there were 2 serious, 26 moderate, and 7 mild cases;
in Ariake district, 0, 2, and 6, respectively.
139
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TABLE 21. AGE AT ONSET AND DEGREE OF AFFLICTION AMONG MINA-
MATA DISTRICT RESIDENTS. FIGURES DENOTE ACTUAL NUMBER: FIGURES
IN PARENTHESES GIVE THE PERCENTAGE
Age
0
1-5
6-3^
40—59
60—
40—
0 — 5
Unknown
Over 0
Serious
I 5 (83)
2 (40)
7 (6.5)
11 (11.1)
12 (24.0)
23 (15.4)
i 7 (64)
37
-------
of Minamata district, 3 (7%) required hospitalization, 13 (30%) had to make
regular hospital visits, 17 (40%) — periodically, and 10 (23%) required
no therapy.
TABLE 22. CASES OF MINAMATA DISEASE DIAGNOSED AS REQUIRING OR NOT
REQUIRING THERAPY; NUMBER OF CONGENITAL MINAMATA DISEASES CASES
EXCLUDED: FIGURES IN PARENTHESES INDICATE PERCENTAGE
Minimata
district
Goshonoura
district
Ariake district
Hospitalization required
Regular hospital visits required
Periodic hospital supervision required
Therapy virtually unneeded
Therapy unneeded
Total number examined
13. Designation
The number of individuals designated by Kumamoto Prefecture as having
Minamata disease was 18 (also, 3 other congenital Minamata disease patients)
during the period of December, 1956, through November, 1962; 1 in May, 1969;
16 (also, two other congenital Minamata disease patients) from January, 1970,
through July, 1971. An additional 44 were designated during the period of
this survey, from August, 1971, through March, 1973.
B. Congenital/Fetal Minamata Disease
Congenital Minamata disease patient from Minamata district numbered
2 males (born November 1958/April 1962) and 4 females (born August 1955, July
1956, October 1956, June tl»57). The male child horn April, 1962 was first
uncovered during the general examination. He was stricken 45 days after birth
with an onset of convulsions. As of February, 1973, he showed mild imbecility,
disorders in the upper extremities and face, loss of coordination, breakthrough
141
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of the 0-wave in the brain, and multiple higher/slower waves in the right side
of the brain. He belongs to the mild category, probably congenital 4- posteriori
Minamata disease. Both parents were designated as having Minamata disease, and
application by the brother (age 19) for such a designation is pending.
Symptoms for the 6 cases were: mental disorder, 6 cases; primitive
reflex, 4; inhibition of motion or involuntary movement, 5; cerebellum dis-
order, 4; seizures, 5. Degree of infliction: 5, serious; 0, moderate; 1,
mild. Two required hospitalization, and 4 required hospital visits.
Of the six individuals, five have been designated by the prefecture as
having Minamata disease.
Section 4. Probable Minamata Disease Cases
A probable Minamata disease case, with reference to Minamata district,
means an individual who manifests only basic symptoms, such as sensory dis-
orders or sensory disorder + field of vision constriction, and there are no
other genuine Minamata disease patients in the family. In the case of Goshon-
oura district, those having a mild constriction of vision, or one good eye,
even though the other eye had been lost, a cataract, or even old age, were
counted as probable Minamata disease cases. The actual cases are enumerated
in Part 3.
a. Epidemiological Matters
Year of onset: With respect to the 19 cases (of which 8 are males)
scrutinized in Minamata district, onset of disease occurred between 1955 and
1972, with 11 being stricken between 1963 and 1969.
Outbreak in family: In the families of those with probable Minamata
disease, 23.7% were afflicted in the Minamata district; the ratio in the
Goshonoura district was lower, and none in the Ariake district.
142
-------
Age afflicted: age 40 or over in the case of 10 persons, under 39
in the case of 9 persons, and unknown in one case.
b. Condition at Time of Examination
Vajriouj? jsymjrtoms
All of the symptoms seen on the case diagnosed as Minamata disease were
observed on probable cases (Table 10)
Proprioceptive symptoms were identical to those of Minamata disease.
For example, they consisted of pain (16 cases), numbness (11 cases), weakness
of extremities (10 cases), aches (9 cases), tiredness (9 cases), forgetfulness
(9 cases), loss of strength (9 cases), fatigue (8 cases), falling down easily
(8 cases), cloudy vision (6 cases), and ringing in the ears (6 cases).
Sensory disorders also resembled those of Minamata disease, such as
serious disorders on the tip of the upper and lower extremities, disorders
around the mouth, islet-type disorders, disorders of the whole body, serious
disorders (loss of senses), and abnormal senses (Table 11). Loss of coordina-
tion as noted in various tests was also similar to that of Minamata disease
(Table 12). Several tremors were also noted in movement (Table 13).
A review of cases marked by unconsciousness and dizziness showed that
6 out of 19 persons from Minamata district, and 4 out of 31 persons from
Goshonoura district suffered from the same.
As for mental disorders, excluding those of the intellect and emotions,
there was 1 case involving neurological conditions (complaints of bodily and
mental disorders plus depression and anxiety) from Minamata district, and
another case involving a 59-year-old woman from Goshonoura who suffered from
occupational delirium and excessive sleep for about 8 years. As of February,
1973, the latter was unable to change body positions on her own power; had
delusions of a cat climbing on her buttocks and of working in the field;
143
-------
constantly spoke to herself; lacked inhibition; excitable, serious disorder of
mental functions, primitive reflex; loss of coordination and tremors as deter-
mined by finger-nose tests; sensory disorders of the mouth; serious vision
impairment; excessive sleep, loquacity, and readily changing symptoms. Degree
of affliction: l; required hospitalization.
An x-ray test of the cervical vertebrae was conducted on 17 cases
(Table 17). The results have been reviewed in the course of comparison with
those of Minamata disease patients (Chapter 2, Section 3, VII, A, 7). In 3 of
those cases, serious changes were also noted in the lumbar vertebrae. For
example, the first case involved a 67-year-old woman characterized by a marked
curvature of L_ to the left; sensory disorders in the right half of the body;
increase of muscular tension and of innate reflexes, and increase of roughness
potential. Although such symptoms were serious, there was no great difference
between the upper and lower extremities (Goshonoura), The second case involved
a 64-year-old male with L~ crushed in the frontal portion, moderate spondylosis;
inability to tell left from right in movement or tremors; no difference was
noted in the degree of disorder in upper and lower limbs with respect to
muscular tension, innate reflex, and roughness potential (Minamata district).
Thus, changes in the lumbar vertebrae did not appear clearly as neurological
symptoms in these 3 cases. A mild spondylosis of the cervical vertebrae
was also noted in these cases.
A biochemical test of the blood serum was conducted in 42 cases
(Table 19).
Ciin±cai_pict\ire
A review of the combinations of major symptoms making up the clinical
picture showed they resembled those of cases diagnosed as Minamata disease
(Table 20).
144
-------
Among Goshonoura district residents, many cases embrace all of the
symptoms. In one case in Ariake district, involving a fisherman born Nobember
21, 1896, the patient suffered from serious sensory disorder around the mouth
and the tip of upper and lower extremities, and also had a loss of coordina-
tion, constriction of vision, moderate articulation disorders, imbecility,
euphoria, and excitability. He succumbed on November 3, 1971, before he could
undergo a second examination.
.Degree_o_f jiff li_c_tion_arid_reljitionshjLp_ between ±t
and a^gje Qt_onset_and_pTesent_age
In Minamata and Goshonoura districts, those suffering from neuropsy-
chological disorders numbered: serious degree, 0 and 3; moderate degree, 8 and
17; mild degree, 9 and 11, respectively. Out of the 19 Minamata district
patients, 7 having a moderate degree of ailment were aged 40 or over at the
time of onset, and 7 with a mild ailment — under age 39. As for present age
and degree of affliction, 6 cases aged 60 or over were moderately affected, 4
cases aged 40-49 mildly affected, and 6 cases aged 39 of under were also mildly
affected.
In the two districts above, those requiring hospitalization numbered
0 and 1; those requiring regular hospital visits, 5 and 1; those requiring
periodic visits, 5 and 22; and those not requiring therapy, 7 and 7,
respectively.
Section 5. Deferred Diagnosis
Cases where diagnoses are deferred are those in which we cannot find
reasons for completely denying the effects of organic mercury poisoning. For
example, one patient in the Minamata area has a patient suspected of Minamata
disease within his family, but he shows only a minor loss of balance and
speech problem. There is another case where, although he has a Minamata
disease patient in his family, he shows only a sensory disorder on the right
145
-------
side of his body; a case where, although he shows a mild sensory disorder, he
does not have any speech problem and does not have any Minamata disease
patients in his family. Some examples of cases whose diagnoses are deferred
in the Goshonoura area are: a case where a member of his family is a Minamata
disease patient, but he has limited vision and hearing difficulties and does
not show loss of balance; a case where, although limited vision is observed in
his right eye, he is the only one who escaped loss of sight and a medium degree
of hardening of the arteries at the bottom of this eye; no sensory disorder
was observed; a case where sensory disorder, loss of balance, and noticeable
limited vision are accompanied by deformation of retina pigments; a case where,
although mild loss of balance and narrow vision are observed, the patient is
over 80 years old. Cases of deferred diagnoses in each area are 0.7 - 1.7% of
examined residents (Table 3). Occurrences of Minamata disease patients or
suspected Minamata disease patients among members of families of diagnostic
deferred patients are especially high in the Minamata area, and are 20% -
53.3% (Table 7).
Among these cases, similar symptoms seen in the cases which were diag-
nosed as Minamata disease were observed (Table 10), The frequencies of sen-
sory disorders and hearing difficulty are high, and cases of narrow vision are
also noticed. Many cases of sensory disorders exhibit a higher degree of
disorder closer to the extremities of the four limbs (Table 11). Various
kinds of loss of balance which are similar to those observed among Minamata
disease patients are seen (Table 12). Biochemical examinations of serums
were performed on 34 cases (Table 19).
As far as symptoms which are a combination of basic clinical symptoms
are concerned, a few types of symptoms comprise a majority at the Minamata and
Goshonoura areas (Table 20).
146
-------
Section 6. Other Diseases
Table 23 illustrates the number of patients of other diseases and their
frequencies, observed in each of the investigated areas.
Neuropsychiatric disorders due to high blood pressure and hardening of
the brain arteries are 6.60 + 1.17%, 14.70 + 1.27%, and 17.70 + 1.80% in the
Minamata, Goshonoura, and Ariake areas, respectively. The differences between
the Minamata and Goshonoura areas ('/.->'i^.25, P<0.001) and the difference between
the Minamata and Ariake areas u*~>25.25. P-CO.OOl1: are both significant. On the
other hand, the differences between the Minamata area and Heianza Island,
Okinawa <-t-~'~'2. i2*< t and the difference between the Goshonoura and Ariake areas
and Heianza Island !2v-l.9-0 are not significant [15].
Icliotism in Table 23 is observed among people over 40 years old. These
cases, from our experience, are mostly due to hardening of the brain arteries.
If we include these cases, the frequencies of neuropsychiatric disorders due
to high blood pressure and hardening of the brain arteries are 7 70-1 T-\-'0 ,
15.01±1.3l*o, -1.05±1.92-^ , at the three areas, respectively. The difference
between the Minamata area and the Goshonoura and Ariake areas is significant
(X:>l7.o2, P<0.001) _ Tlie difference between the Goshonoura and Ariake areas is
significant " . T " o:'0 .
Two cases of progressive paralysis •'<*. :7j/0.:r,••:/• were discovered. This
has been considered a rare disease in recent years. Both of them are in area
mental hospitals.
Epilepsy is O..~5±0.2e'o, , 1 .:;i: 0.:!2^-, ].13±0.-10% in the three areas, respec-
tively. The value at Heianza Island is 0. llr:0.12?&. The difference between
the Minamata area and Heianza Island (x'>32-1.8S. P<0.001 ; Yates' modification)
and the difference between the Goshonoura area and Heianza Island are signi-
ficant (;r>]0.li. P<0.01). However, differences between the Minamata and the
Goshonoura areas Cx2~"--02), and between the Ariaka area and Heianza Island
(/•\-:O.S7;t'are not proven to be significant (/:>;;.77, F
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-------
TABLE 23. (continued)
Disease
Minimum and maximum for contrast (investi-
gated area)
Corrected frequency (%)
a
b
a + b
Head injury aftereffects
Progressive paralysis
Epilepsy
c
d
c -I- d
Depression
Nervous disease,
hysteria
Alcoholism
Weak mind
ii ii
Parkinsonism
Spinal cord deformatn.
disorder
SMON
Injury aftereffects
8.24 (Heianza Island, Okinawa [3])
0.13 (Heianza Island, Okinawa)
0.33-0 (Ikebukuro, Tokyo - Miyake Island [9, 14])
0.89-0.12 (Imazumi village, Saitama - Gokeso,
Kumamoto [9, 14])
2.47-0.49 (Kurao, Saitama - Ikebukuro, Tokyo [9, 14])
0.87-0.14 (Komoro town, Nagano
Saitama [9, 14])
0.39 (Heianza Island, Okinawa)
0.71 ( " " " )
2.38 ( " " " )
2.19 ( " " " )
- Imazumi village,
Revised frequencies of schizophrenia are 1.39 _> 0. !!>•*, 0.0l±0.31?'i, 0.06±0.-J3%
at the three areas respectively. These values are between the maximum and
the minimum values for residents of other areas in Japan. The value at Hei-
anza Island is 2.11±0 V'^o, The differences between the Minamata and the
Goshonoura areas (jX?S0.32 and j/.!sl0.13 ), between the Goshonoura area and Heianza
Island (2^0.67), between the Goshoura area and Heianza Island (??>^.70, I'\, are not proven to be
significant.
149
-------
Among manic-depressive psychoses, only depression was found in this
examination. Its frequencies are 0.21 ;!<>.::> , ().7^±0.30??. !..~>i± 0.5i>% at the
three areas, respectively. No significant dif ference (z'l~-1.12) is seen between
the Minamata area and Komoro town, which is selected for comparison and whose
frequency is O.S7 ±0.'21'0 . Also, no significant differences are seen between
the Minamata and the Goshonoura areas (r'^1.18; and between the Ariake area and
Komoro town.
Alcoholism is 0.76x 0. \\->-0, '2.id±-(}.<-f,_,, (>._:ii0.2i?o at the three areas, re-
spectively. Significant differences are seen between the Minamata and the
Goshoura areas '/? !.";. r-^0-1^ , between the Goshonoura and the Ariake areas
v -i .."'. 1> j'.'.''2; , and the Goshonoura area and Heianza Island '-"/ !">- ^x"-^'. .
However, no significant difference is proven between the Minamata area and
Heianza Island Cz!£0.(fc).
Ratios of people who are mentally disturbed and are over 5 years old and
total residents over 5 years old are 2.t>i±0.r.o-n, .''.U2±0.-i.;•';,, i.G9 ±0.68% at the
three areas, respectively. Ratios of mentally disturbed people and total
residents over 0 years old are '/..7l +0.5:]';,. '2.79:j.:o. !0", ::. P7.'lO.iji•-„ , respec-
tively. The frequency of mentally disturbed people against total population
is said to be 2 - 3%. The values for the Minamata area and Heianza Island
are close. In the ratios of the population over 5 years old, no significant
differences are recognized between the Minamata area and the Goshonoura and
Ariake areas xj"^0:rr, and between the Goshonoura and the Ariake areas v'/^l 97).
Among other diseases, x-ray examinations were performed on 23 cases,
excluding inherent mental disease patients (Table 17), and biochemical
examinations of serums were performed on 35 cases (Table 19).
150
-------
Section 7. Death Rate of Minamata Disease Patients
and Suspected Minamata Disease Patients
There are 275 Minamata disease patients who have been recorded as a re-
sult of this investigation and 26 confirmed patients who died before the in-
vestigation, totaling 301 patients in the Minamata area. According to Table
24, 36 of them, i.e., 12%, were dead by the end of March, 1973. Among the
TABLE 24. DEATH OF MINAMATA DISEASE PATIENTS AND SUSPECTED MINAMATA
DISEASE PATIENTS
1) Numbers without parentheses are confirmed cases; numbers in
parentheses are unconfirmed cases who died between August,
1971 and to date.
2) Investigation up to the end of March, 1973.
Age
- - it
i:> •1i>
•o- HO
10-- I1.'
f,0 59
ti() - 69
70- 71-'
,-() -iSS
'> - ,- S
Minamata disease
Minamata area
M
l
1 J
it
9
II
3(1)
9
D
1
i: (r,
F
3
3
2
0
1
2 (i)
.'•i (2)
1
0
1.- (3)
T
4
6
9
9
1
5(2)
5(2)
0
1
32 (4)
Unexamined areas M
M
i
0
i
2
4
4
/
S
1
23
F
9
0
0
0
0
o
0
0
9
9
T
3
0
1
9
4
9
~
S
S
37
-
ti
X
4
r>
1J
12
1!
4
fi9
Suspected Minamata
disease
inamata A
area
M
..
rn
( i .'
F
-
—
(1)
—
—
--
—
('-)
(°)
riake
area
M
—
—
—
—
—
—
(i)
—
~
M — male; F — female; T — total.
dead, many were youngsters under 14 years old or elderly persons over 50.
This phenomenon is similar among patients in areas not investigated. As
stated before, 38 patients who showed Minamata disease-like symptoms were dead
before the investigation in the Minamata area. Also, three patients who were
suspected of Minamata disease were dead after the examination but during the
investigation. Therefore, 77 out of 342 patients, i.e., 22.5%, of the
151
-------
Minamata disease and suspected Minamata disease patients from the Minamata
area were dead between 1941 and March, 1973, During this 20-month investiga-
tion, 10 Minamata disease patients (6 are confirmed patients) and 3 suspected
Minamata disease patients, totaling 13, were dead.
From the investigation of family history of residents of the Minamata
area, 39 persons (24 males) were recorded dead before our medical examination;
Minamata disease was unconfirmed, but they had Minamata disease-like symptoms.
According to the description of these families, they showed symptoms such as
numbness of hands and feet, shaking, speech difficulty, loss of strength, loss
of balance, difficulty in walking, difficulty in moving hands and feet, and
vision difficulty. Some reported that they even destroyed a paper sliding
door by losing their balance and falling. During the investigation, 30 of
them (79%) were proven to have 1-4 Minamata disease patients who lived with
them. Two of them have suspected Minamata disease patients, as well as Mina-
mata disease patients who lived with them. Also, five of them have suspected
Minamata disease patients among members of their families who lived with them.
The years of their deaths are: 32 between 1941 and 1971, 6 unknown; 27 between
1954 and 1971. Their ages at death are: 27 persons over 50 years old
(71%), 5 persons — age unknown.
Section 8. Amounts of Mercury in Hair and the Disease
Measurements of amounts of total mercury in the hair of fishermen, pri-
marily along the shores of the Shiranui Sea, were performed in 1960, 1961,
and 1962 [11]. Among people who were examined at this time, 42 males and 27
females in the Minamata area and 2 persons (both females) in the Goshonoura
area were measured for the mercury content in their hair at that time. At
the examination, 35 persons had not had the Minamata disease or were not
suspected of it; 5 persons became ill in the same year, and 18 persons
already had the disease.
152
-------
Among those examined, 34 males and 24 females had Minamata disease;
1 male and 1 female were suspected of having the disease, and 7 males and 4
females had other diseases.
A table was constructed in order to examine the relationships between
amounts of mercury in hair and occurrences of the Minamata disease, degree of
illness of the disease, and narrow vision (Table 25). The amounts of mercury
were primarily obtained by measuring the materials collected in 1960. As is
TABLE 25. RELATIONSHIPS BETWEEN AMOUNTS OF MERCURY IN HAIR AND VISION.
MINAMATA DISEASE, CONDITIONS OF MINAMATA DISEASE, AND POOR VISION
NUMBERS WITHOUT PARENTHESES ARE FOR MALES, AND NUMBERS IN PAREN-
THESES ARE FOR FEMALES
I'l'M
- 0
-l"
— f>
-10
-20
— ,-;o
-40
— ,V)
-60
- 70
-SO
-90
- mo
-l.'fi
-200
200 —
Total
Minamata
Total
no. ,
1HD -
CD (l)
2 (<>) 1
3 (-) —
6 (5) -
4 (LO 1
2 (2) -
8 (D -
1
1
. 0) ~
1 CD CD
l CD -
31(23> 2 (2)
+ suspected Minamata disease Other diseases
Conditions poor vision Total Conditions v°°ion
2 .; 4 :>
- i CD - !
_ _. _
CD CD l CD
l CD -' CD -
1 (2) .? (L-) (l) •'
CD 3 (1)
- ' (i) 1 (l) -
- ._ 3 (1) 2
- l - -
j
i--
ii l
l
_____
_
(l) 1
3 (4)11(11)11 (4) 7 (2)
ir
l CD
(3)
—
(1)
_
1
3 CD
l
_
__
2
__
-
, (6)1
no.
_ _ i i
(1) ..
1 (2) - ' CD (!) -
3 (2) - - 1 (2) -
3 (D CD 3 CD . (D -
1 (2) - 2 t 1
1 (i) _ O) _
o _ 3 _ _
j
j __ __
— — (P — —
_ ] _
1 _______
_
._
1 (!)___
4 (9) 1 (2)10 (4) 7 (0 1
4 ;.
i - l
_
(n rn
- 1 CD 4 (2)
(D (D
_
_ _ _
__ _ _
- l l
— _
_____
.
_____
_
i 3 (..) C> (4)
*
We could not prove poor vision for two cases of Minamata disease
and one case of suspected Minamata disease, and for one case of the
other diseases. Therefore, the number of cases for poor vision is
33 (21) for the former and 6 (4) for the latter. Underlined number
— cases of suspected Minamata disease (2 cases).
clear from this table, 13 out of 18 males (72%) whose hair contained less
than 20 ppra mercury, and 10 out of 13 (77%) females whose hair contained less
than 10 ppm mercury had Minamata disease. Based on data by Ukita [4], it is
153
-------
considered to be normal if a male has less than 20 ppm mercury in his hair,
and if a female has less than 10 ppm. What can be observed from the next
table is that 9 out of 11 persons who were diagnosed as having other diseases
had less than 20 ppm mercury in their hair. Among those whose hair contained
0-10 ppm mercury, 7 out of 34 males (20.6%) and 10 out of 23 females (43.5%)
had Minamata disease, and it is slightly higher among females (z2>o.13. P^'O.OT') .
M.d : 55 1 Total
SM.d: 2J cases
M and
PPM
200-
- 200
- 150
- 100
- 90
- 80
- 70
- 60
- 50
- 40
- 30
- 20
- 10
- 3
- 1
- 0.5
0
Cone
tl
• •
•
• • •
•
•
•
•» K r
00 ••
- . v •
•f 0 OO **•
s V •
• 0 «•• 0
• ••
j__ 5 4 3 2
on
57
»
F
•
•
*
•
1
SM.d: ij cases,
male
M.d: 22]
SM.d: l)
Total Other
23 diseases;
cases, 11 cases,
F M and F
o
V
800
o
Figure 1. Relationships between amounts of mercury in hair and oc-
currences and conditions of Minamata disease:
• — materials in 1960; o — materials in 1961 - 1962; M.d — Mina-
mata disease; SM.d — suspected Minamata disease; F — male; F —
female
In order to facilitate the analysis of relationships between amounts of
mercury in hair and conditions of the disease and poor vision, a graphical
representation of the table is made (Figure 1). We cannot prove a fixed
relationship between mercury content and conditions of the disease, even from
this figure. However, the figure shows the various above-mentioned facts
obtained from Table 25 more clearly.
154
-------
Minimum jind_ maximum £as_es_p_f me_rcury_
COQtent in_haij:
(i) The first case is a female born in Tsukinoura in March, 1951. She
is a farmer, and her husband is an office worker. She ate fish 2-3 times
a week. She started showing symptoms of twitching of her muscles in 1957,
and of numbness of her hands and feet in 1960. The amount of mercury in her
hair was 0 ppm in December 1960. Her condition on November 1, 1972 was:
speech problem (+) , loss of balance (+) , poor vision (-H-) , sensory disorders
of all of her body, loss of sense of touch, aches, coldness, and warmness from
her lower limbs to her feet (III), hearing problem (MI), mental redardation
(+), positive serum syphilis reaction (+); the condition of her disease: 3.
Confirmed as having Minamata disease in April, 1973.
(ii) The second case was a fisherman (single rod fishing) of Yudo, born
in March, 1914. He wife and 3 younger of his 6 children were Minamata disease
patients. He showed symptoms of numbness in his hands and fever in April,
1954. He could not keep his slippers on in 1965. Loss of sight and a speech
problem occurred in 1968. The amount of mercury in his hair was 302.5 ppm in
November, 1960, 18.33 ppm in July, 1971, and 147.5 ppm in December, 1960. His
condition on February 14, 1973 was: loss of balance (++), poor vision (+),
sensory disorders (++), hearing problems (+), mental retardation (+), shaking
of his body (++), weakness of muscles on the backs of his hands (2), deforma-
tion of spinal cord; blood pressure: 174/110; albumin in the urine (+);
the condition of the disease: 3. Confirmed having Minamata disease in
January, 1973.
155
-------
PART 2
TREATMENT
Treatment by drugs was tried for subjective symptoms, which are one of
the worst sufferings among Minamata disease patients. This was done for the
patients who visited a mental hospital in the examined Minamata area and who
had illness conditions of 3 - 4. Ages and sex of the patients are: 30 - 39
years old, 0 (male) - 1 (female); 40 - 49 years old, 2 (male) - 1 (female);
50 - 59 years old, 1 (male) - 3 (female); 60 - 69 years old, 5 (male) - 10
(female); 70 - 79 years old, 4 (male) - 3 (female); total 30 persons (12 male).
The treatment periods were: 2 months, 11 persons (5 male); 4 months, 4 per-
sons (3 male); 6 months, 5 (1 male); 8 months, 3 (no males); 10 months, 6
(2 males); 12 months, 1 (male).
Table 26 summarizes the effect of treatment performed. According to the
table, some symptoms are relatively easily improved by the treatments: some
examples are insomnia, headaches, aching of limbs and body, and irritations.
On the other hand, the following symptoms are difficult to cure; forgetfulness,
hearing difficulty, poor vision, loss of strength, blackouts, etc.
The summary of the effects of treatments is shown in Table 27. According
to the table, 15 out of 30 examined cases showed improvement in their symptoms.
In the case of improvement, 8 cases showed partial reduction or partial im-
provement of subjective symptoms, and 7 cases showed improvements in every
symptom. Fourteen cases, which is a large number, showed improvement of some
symptoms and deterioration in other symptoms.
Finally, Table 28 illustrates drugs which are considered to be effective
for these symptoms. For insomnia, various drugs have proven effective. Among
them are tranquilizers (Dichlotride, Selpasel, Apresoline), Contamine, pheno-
barbital. These three drugs are also effective for headaches. Phenobarbital
and Contamine are effective for crow bend and aching of limbs and body, and
these two drugs and Contole are slightly effective for irritation.
156
-------
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157
-------
TABLE 27, EFFECTS OF TREATMENTS
Improvement
Disappearance + better
Better
Partial improvement and partial
deterioration
Unchanged
Deterioration
Total
Male
6
2
4
6
0
0
12
Female
9
6
3
8
1
0
18
Total
15
8
7
14
1
0
30
TABLE 28. RELATIONSHIPS BETWEEN IMPROVED SYMPTOMS AND DRUGS
Nelbon
Phenobarbital
Netobal
Contamine
Horizon
Contole
Selnale
Triputanole
Calicrane
Hexanisset -
Capilon
Pontal
Tranquilizer
Sularon
Neobitacane
insomnia
* * *
D I U
13 11 2
22-
7 7 1
j <> _
882
'-{ ,
46-
20-
3 1 -
T> \ -
62-
63-
c o i
10 5 1
5 3 1
2 1 -
*
Head-
ache
D I U
1 12 11
1 2
-67
- 2 1
1 9 6
- - 2
- 6 3
-53
-22
-32
- 3 5
1 5 4
101
i — i
1 d ' 5
- 2 6
- 1 2
Drow
send
D I U
6 7 13
1 1 i
T .i in
- i -
568
1 1 1
2 i ;
2 2 Z
O
1 2 2
- 5 ti
245
- ?, 3
3 7 S
1 1 6
I - 1
Limb ,
body
aches
D I U
; 10 IS
- i .-;
- s ;n
i y n
1 2 7
- r f
i -i
- \ 3
1 3 s
- 5 6
1 3 ?,
1 6 12
1 2 S
__ •>
Irrita-
tion
D I U
0 j. 1 -
- 2 2
- C. I'l
- 1 L>
2511
— 1 2
254
3 -
- 2 1
- 3 2
1 4 6
- 3 6
i i i
268
- 1 H
Despres-
sion
D I U
- 4 18
2
£ U
1
- 2 11
1
- 2 6
- 2 3
- .5 2
- 1 4
- 1 5
-26
I 5
- 3 11
- i S
0
D — disappearance; I — improvement; U — unchanged
158
-------
Triputanole or tranquilizers are sometimes effective for
depression.
As a summary, phenobarbital, Contamine (chlorpromazine), and tranquili-
zers are, in general, effective for subjective symptoms of Minamata disease
patients.
PART 3
INVESTIGATION OF HEALTH CONDITIONS OF EMIGRANTS
TO OTHER PREFECTURES
Introduction
The health conditions of 22 persons who emigrated from the Minamata area
under investigation to other areas were examined neuropsychiatrically. All
of them were those who came back temporarily to the Minamata area for New
Years Day, Bon Festival, or memorial services. Years when they left Minamata
were as follows: 1950 - 1961, 11 persons; 1962 - 1968, 7.persons; 1970 - 1971,
4 persons. Their current addresses are: 2 in Tokyo, 2 in Chiba City, 6 in
Gifu, 1 in Nara, 6 in Osaka, and 5 in Kitakyushu City. Males (13 persons) and
persons under 39 years old (15 persons) are in the majority. Their current
occupations are: 4 plasterers, 4 construction workers, 3 businessmen, 2
drivers, 1 engineer, 1 carpenter, 1 clerk, and 5 housewives.
Twenty persons belong to 16 families in the Minamata area, and all of
these families have other Minamata disease patients within them.
Condition Before This Examination
Twenty out of 22 persons complained of symptoms, such as numbness, head-
aches, aches in joints, dizziness, insomnia, dullness, early fatigue, and
forgetfulness, and have received treatments at many hospitals. However, in
159
-------
all cases, they were diagnosed as unknown or nervous disorders, and no cases
were diagnosed as Minamata disease or suspected of it,
Fourteen persons experienced the subjective symptoms mentioned above
before they left the Minamata area, and 6 persons did so after they left
the area.
Results of Investigation
a. Overview of diagnoses
i) Minamata disease: 20 persons
?.i) Suspected Minamata disease: 1 person
iii) High blood pressure: 1 person
b. Cases which were diagnosed as Minamata disease
i-_ J3ymp_tpms
The following symptoms: subjective symptoms, 20; speech problem, 16;
loss of balance, 20; loss of strength, 13; poor reflexes, 3; shaking, 7; poor
vision, 7; sensory disorder, 20; hearing difficulty, 16; olfactory disorder, 6;
epilepsy, 1; dizziness and other disorders of the conscience, 15; mental
disorder, 19; emotional disorder, 18; high blood pressure, 4; low blood
pressure, 1.
2.._ Cpniti.ns_o_f the_ ^iise:ase^_neej. for _treatmen_t.
High: 2 cases; medium: 15 cases; low: 3 cases. Need to be hospital-
ized: 0; need to visit a hospital regularly: 7; need to visit a hospital
occasionally: 10; no need for treatment: 3.
160
-------
c. Case suspected of Minamata disease
The patient is a female, born in January, 1946, in the heavily mercury
contaminated area, married in January. 1971, and moved to Chiba city. Al-
though she showed a hearing difficulty in 1958, she did not show any subjective
symptoms in May, 1972. However, she displayed dullness in the sense of touch,
aches, and warmth in parts of her lips, right leg, disorder of vibration
senses, loss of balance in knee bend test, and a medium degree of mental re-
tardation. Both parents and two of her siblings are Minamata disease patients,
and her other two siblings are suspected of the disease. This case can be
actually considered as Minamata disease. The degree of disorder is light,
and no medical treatment is considered to be needed.
d. Case of high blood pressure
The patient is a carpenter born in August, 1950, and moved to Osaka in
April, 1959. In December, 1971, his blood pressure was 170/90, although no
neurologically noticeable events were observed. His grandmother, with whom
he lived before he moved to Osaka, is a Minamata disease patient, and his
grandfather died from Minamata disease-like causes.
PART 4
MERCURY CONTENT IN HAIR OF RESIDENTS ALONG SHORES OF
THE SHIRANUI SEA AND IN FISH IN THE SAME AREAS
Introduction
This simultaneous examination brings up a question that mercury contami-
nation in the Shiranui Sea may still affect the health conditions of residents
today. This research was carried out to measure the amounts of total mercury
contained in the hair of residents in the Minamata and Goshonoura areas,
161
-------
where simultaneous examinations were performed, and in Kumamoto city for the
purpose of comparison. Many residents in the Minamata and Goshonoura areas
who were subjects of the measurment were either Minamata disease patients or
suspected Minamata disease patients. Residents in Kumamoto city were selected
randomly. Also, the amounts of mercury were determined in fish from Minamata
Bay, the eastern short of Amagusa which includes the Goshonoura area, and the
western shore of Amagusa which includes the Ariake area. These fish were
obtained between February, 1972, and March, 1973.
Method and Data
The amount of total mercury was measured. Using instruments and methods
described by AOAC [1], the hair was turned into wet ashes, all mercury was
changed into inorganic mercury, reduced to metal mercury using tin monochlor-
ide, and measured by the mercury vapor ultraviolet absorption method (Hira-
numa mercury gauge). Reagents used were either manufactured by Wakojunyaku
or by Katayama Chemical for analytical purposes.
Approximately 100 - 200 mg of hair were used for measurement. The reason
for choosing 100 - 200 mg of hair is that a full scale of the Hiranuma mercury
gauge is 0.5 yg, and the amount of liquid required for each measurement is
100 ml. In order to use the central part of the scale for a measurement,
it is appropriate to adjust so that the amount of mercury in 100 ml of test
oxide liquid is about 0.25 yg. Theoretically, 100 ml of liquid for measure-
ment is sufficient. However, it is difficult to keep the reaction liquid to
100 ml, considering the amount of oxidizing and deoxidizing materials used.
Also, if we consider the possibility of measuring several times, using the
same oxidizing liquid, 500 ml of oxidizing liquid would be appropriate. Cal-
culating from the concentration described above, 1.25 yg of mercury is con-
tained in 500 ml oxidizing liquid. In order to attain this value, about 150
mg hair containing 8 ppm mercury are sufficient. Eight ppm is close to the
average amount of mercury in the hair of a Japanese, and major portions can
be measured using the central part of the scale; thus, more precise values
can be expected. For actual measurements, the amount of mercury in hair is
162
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computed by subtracting a comparison value (using an equal amount of a re-
agent used in the experiment, the oxidizing liquid is obtained by performing
the identical operation without adding hair) from the actual reading. In
order to confirm the effectiveness of this method, the results from residents
in Kumamoto city measured by this method were compared statistically with
the results obtained in Tokyo in 1966 by Fukada et al. [4]. Both variances
(P < 0.5) and averages (P < 0.1) are similar, and no significant differences
are found. At the same time [3], a variance of the logarithm of amounts of
mercury in hair (9 subjects) which was taken from various parts of the same
person's head, and were measured by this method, is 0.0028. Considering that
amounts of mercury measured from one person vary, depending upon collection
places and locations of hairs on one's head, this variance is very small, and
the amount of mercury measured by this method is considered to be reliable.
Therefore, the amount of mercury in one person's hair, measured by mixing
the hair from different parts of his head and sampling 100 - 200 mg of it,
can be considered to represent an adequate measure [6]. For small size fish,
the entire fish is used, and for large size fish, 1-10 grams of primarily its
muscles are used. The mercury concentration is expressed as ppm (per wet
weight).
Results
i-_ Amountj^ ^f_roe_rc_ury_co_nt_aine_d_iri hair
As illustrated in Table 29, information obtained from 16 males and 15
females who live in Kumamoto city is a maximum of 10.00 ppm and a minimum
of 0.91 ppm. Eighteen males and 17 females who live in the Minamata area
show a maximum of 19.40 ppm, and a minimum of 0.94 ppm. Nineteen males and
30 females from the Goshonoura area show a maximum of 19.69 ppm, and a mini-
mum of 1.10 ppm. It is known from a previous report [15] and from our in-
formation [6] that the amount of mercury in hair has a log-normal distribution.
Therefore, if a logarithm of mercury content in hair is taken, it will have
a normal distribution. Using this fact, the variance and average of mercury
163
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content were computed. A statistical significance test was done by the vari-
ance analysis method [13], In the following test, the amount of mercury in
hair is indicated by a logarithm of mercury concentration (ppm).
In the previous literature [2, 4, 5, 11], mercury amounts are compared
without segregating males from females. However, according to our study [6],
the variances of amounts of mercury in hair grouped by sex are almost identi-
cal if subjects are in the same area. On the contrary, a very significant
difference between male and female is found (P < 0.001) in terms of their
average values. No significant differences in variance and average are ob-
served when subjects are grouped according to their ages [6], Therefore, it
is considered necessary to group by sex, but not by age, in comparing amounts
of mercury in hair.
Based on Table 30, which was produced based on the above observations,
the variances in three areas are almost identical between male and female in
each area, and no significant difference in average values is observed
(P < 0.005).
Comparison of values for the same sex among these areas show that no
significant difference of averages for females is observed. However, for men,
as shown in Table 31, a significant difference is observed between Kumamoto
and Goshonoura (P < 0.025). However, no significant differences are seen
between Minamata and Kumamoto or between Minamata and Goshonoura.
2_._ Amount_of_ mercury^ in_fish
A total of 61 subjects were examined. Eighteen subjects were collected
from Minamata Bay, 9 from the southern shore of Kyushu other than Minamata,
18 from the eastern shore of Amagusa, and 16 from the western shore of Amagusa
(Figure 2, Table 32).
164
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TABLE 29. AMOUNTS OF MERCURY (ppm) IN HAIR OF RESIDENTS IN THE
KUMAMOTO, MINAMATA, AND GOSHONOURA AREAS
Kumamoto
Minamata
Goshonoura
Male Female' Male Female Male Female
AgeHg cone.AgeHg conc.AgeHg cone.AgeHg cone.Age Hg cone.Age Hg. cone.
S.98
1C), fill
- ...
S ill
li.'iiS
3.3S
2.46
5.36
2.70
5.58
5.30
3.61
6.85
2. an
; 2;
4 47
21
2S
21
21
21
21
36
30
1
28
27
4
2
',
0.78
3.55
1.82
1.83
3.57
1.94
3.22
4.07
0.91
1.90
3.27
-1.38
3.00
3.14
1 96
5<>
50
52
54
41
5
62
67
37
31
2
53
74
39
56
54
25
30
7.23
t" 91
2.10
CS 80
"19.40
4.95
Q7.40
O8.54
Q7.87
8.06
4.30
O".03
2.94
2.70
'"" r> J ->
4.50
l.SJ
9 Q3
1 50
5!
19
53
43
38
1 16
1 31
4
9
64
83
33
n
4
21
25
1
CJ-S-!
4.PO
G3.44
C3-'ii
1.15
70
12
iiO
41
11
47
OS
66
/>;
.49
.6?
.il
.06
.69
41
74
85
15
60
59
59
61
59
Note. O — Minamata disease; 1 — suspected Minamata disease;
with no mark — only healthy persons in Kumamoto, healthy per-
sons and persons having other diseases in other areas.
A histogram of mercury contained in fish is illustrated in Figure 3,
and from it, it can be estimated that the amount of mercury in fish is ex-
ponentially distributed. That is, it is expressed as [19]:
F (x) -
1-e /
x <: 0
* < 0
Here, F(x) indicates the frequency of x (mercury concentration in fish);
A is the average value.
165
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TABLE 30. STATISTICS OF AMOUNTS OF MERCURY IN HAIR OF
RESIDENTS IN THE KUMAMOTO, MINAMATA, AND GOSHONOURA AREAS
Male
Female
Variance
Average value
(Converted to ppm)
Number of data
Variance
Average value
(Converted to ppm)
Number of data
Kumamoto
0.030
0.717
(5.21)
16
0.030
0.429
(2.68)
15
Minamata
0.073
0.743
(5.51)
18
0.064
0.441
(2.76)
17
Goshonoura
0.037
0.875
(7.50)
19
0.059
0.448
(2.80)
30
Note. Variance and average values are computed on the logarithm
of mercury concentration (ppm).
Let us assume that this equa-
tion holds. Then, if we plot the
logarithm of frequency on the y-
axis and the amount of mercury on
the x-axis, log F(x) for its cor-
responding x should be a straight
line. As shown in Figure 4, those
points are approximately on a
straight line. This result can be
confirmed from the values in the thesis by Kitamura [8].
TABLE 31. A SIGNIFICANT TEST OF
MERCURY CONTENT IN MALE HAIR IN
KUMAMOTO, MINAMATA, AND GOSHONOURA
Kumamoto
Minamata
Minamata
Insignificant
Goshonoura
Significant
(l' "-.v
Insignificant
Table 33 illustrates the maximum, minimum, and average values of total
mercury in fish from each area. In order to determine the significance of
differences in those four areas, by letting ^/^ = L, a F-test is used to
166
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TABLE 32. MERCURY CONTENT IN FISH FROM EACH AREA ALONG THE SHIRANUI
SEA (IN ppm)
Minamata Bay
Western shore of Kyushu (excluding
Minamata Bay)
Subject name
Hg
cone.
Subject name
Hg
cone.
Bina
Bina
Hibarigai modoki
Short-necked clam
Hibarigai modoki
Hibarigai modoki
Hibarigai modoki
Bina
Crab
Sea bream
Prawn
Garakab-j
Conger
Flatfish
Kuchipoko
Gray mullet
Bina
Scabbard fish
o :>M
0.5)3
0.3?6
O.lsG
0.356
(1.013
Bina
Bina
Clam
Clam
Clam
Bina
Hibarigai modoki
Bina
Hibarigai modoki
O 000
0.009
I) |YK)
o.oeo
0.006
O.IKS
0 038
0 116
0.173
Western shore of Amagasu
Eastern shore of Amagasu
Bream
Bream
Halfbeak
Garakabu
Short-necked clam
Bina
Scabbard fish
Flatfish
Kurio
Kawahagi
Stingfish
Turbot
Kuroio
Bina
Garakabu
Tilefish
Kusabi
Unknown
0 u.J7
0 000
0.1 l-i
0 17)p
Bina
Bina
Abalone
Short-necked clam
Gray mullet
Bream
Sea bream
Short-necked clam
Short-necked clam
Bina
Bina
Bina
Garakabu
Lobster
Octopus
Swellfish
0 00(1
0.051
o i
167
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Shimabara peninsula
Sankaku town
^hiranui town
Goshonoura town
Ushihuka cityS
Minamata city
Fre-
quency
o.i 0'2
Hg cone, in
fish (ppm)
Figure 3. Histogram of mercury con-
centration in fish (wet weight ppm)
along the Shiranui Sea (excluding
ones from Minamata Bay)
Demizu city
Figure 2. Fish collection sites:
o — Minamata Bay; A — western
shore of Kyushu; + — eastern
shore of Amagusa; " — western
shore of Amagusa
find whether L = 1, i.e., A = A , or
A Jj
not [13], Here, A and A are the average
I.O
0.5
0.05
0.1
Figure 4, Mercury content in
fish and adjustment of their
frequencies to log [F(x)] =
Ax + B, where F(x) — frequency
of x, x — mercury content (ppm)
mercury amounts in fish (wet weight) from
two areas respectively. Table 34 illus-
trates the result. From the table, sig-
nificant differences are recognized be-
tween Minamata Bay and three areas: the
western shore of Kyushu, eastern shore of
Amagusa, and western shore of Amagusa (P < 0.002), This result shows that the
mercury in Minamata Bay is still higher than that in other areas. No signi-
ficant differences are seen among other area.
168
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TABLE 33. MAXIMUM, MINIMUM AND AVERAGE VALUES OF MERCURY
CONTENT IN FISH (WET WEIGHT ppm) FROM EACH AREA ALONG THE
SHIRANUI SEA
Maximum value
Minimum value
Average value
(ppm)
(ppm)
(ppm)
Mina-
mata
Bay
3. DO
0.013
0. 175
18
Kyushu
western
shore
0.173
0.000
0.060
9
Amagusa
eastern
shore
0.331
0.000
O.OGG
19
Amagusa
western
shore
0.0%
0.000
0.033
16
No. of examined fish
TABLE 34. A SIGNIFICANCE TEST OF MERCURY CONTENT IN FISH (NET
WEIGHT (ppm) FROM EACH AREA ALONG THE SHIRANUI SEA
Western shore of Kyushu
Eastern shore of Amagusa
Western shore of Amagusa
Minimata Bay
Significant
(!•<-',: (.•>.')
Significant
(!'<' M'J
Significant
Western shore of
Kyushu
-
Not significant
r-.-o
Not significant
Eastern shore
of Amagusa
-
-
Not significant
It should be noted that the mercury contained in Bina fish caught from
the Ariake shore in the Ariake area was nearly zero. This fact was previously
stated in Chapter 2, Section 3, II.
Qbseryattpns
The amounts of mercury in hair do not indicate clear differences from
one area to another, as long as hair of the same sex is compared. The dif-
ference in the amounts due to sex is larger than the difference due to areas.
169
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The mercury content in hair of Minamata disease patients, reported by Kita-
mura [5] in 1960, also shows a significant difference in the average values
between the sexes. It is under investigation whether the reason for this dif-
ference is food, especially the consumption of fish, between male and female,
or whether it is related fundamentally to the difference of sex [6], The in-
vestigation of the relationship between the difference in the amounts of mer-
cury contained in male hair and female hair and the disease rate of the Mina-
mata disease between males and females may provide a clue for the structure of
occurrences of the Minamata disease or its treatment.
The amount of mercury in fish from Minamata Bay is significantly higher
I'-. iMW' » compared with that from other areas. However, compared with the
value of 14.47 ppm (average value) [8] reported by Kitamura in 1960 on the mer-
cury content of fish from Minamata Bay, the current value can be said to be
remarkably lower. The current value is equal to 0.5 ppm, which is the standard
set by the FDA.
The amounts of mercury in fish and in the hair of residents in the sea-
shore areas of the Shiranui Sea were discussed. The mercury content of fish
from the Minamata area showed a higher value, compared with that from other
areas. Goshonoura residents (males) showed a slightly higher mercury content
in their hair.
PART 5
EXPLANATION
From August, 1951, to March, 1973, in order to determine the effects of
organic mercury poisoning on human health conditions, direct neurological
and psychiatric examinations were performed on a total of 3589 persons, 965
from the Minamata area whose bay was heavily contaminated by organic mercury,
170
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1723 from the Goshonoura town, Arashiguchi area, which was lightly contaminated,
and 901 from Ariake town, Amagusa county. Moreover, direct examinations of
people who moved out of the prefecture from the Minamata area were undertaken,
and the mercury content in fish from the nearby sea and in the hair of resi-
dents in the above-examined areas was measured. Major conclusions obtained and
worth noting are as follows: establishment of percentages of Minamata disease
patients (disease rate) among residents of examined areas; confirmation of
the existence of Minamata disease patients in the Ariake area; establishment
tha t high blood pressure and blood circulation problems will occur from or-
ganic mercury poisoning; discovery of a high ratio of the suspicion of liver
problems among residents in the Minamata area; findings of many Minamata
disease patients among people whose hair contained 20-0 ppm mercury in 1960;
findings of frequency of patients who need to enter hospitals or to visit
hospitals for medical treatment.
I. DISEASE RATE
1. Percentages of people who have neurological and psychiatric disorders
in each area are as follows: Minamata area, 59 48±1.5H%; Goshonoura area
27.G.'}±1.08';i; Ariake area^i 29±1.5I<^. It should be noted that nearly 60% of the
residents in the Minamata area have some sort of disorder.
2. The number of Minamata disease patients and the number of suspected
Minamata disease patients plus Minamata disease patients (in parentheses) are
as follows: community A in the Minamata area, 44 (49); Tsukinoura, excluding
community A, 56 (69); Yudo, 130 (141); Detsuki, 45 (54), Goshonoura area,
34 (65); Ariake area, 8 (10). The frequencies of Minamata disease patients
relative to the total examined residents are, respectively: 71 -• "«';i
L<;; -,7 ±3.00-;, :v> ::i -•> ?:.'.- \:> :,>±2.1.>i f I.97±0.:^, O.M^O.ol-v, . The frequencies
of both Minamata disease and suspected Minamata disease patients are:
M. (i:>.-_ : ??".;. 32 2\±}.2'i">0. TO 07-J.:;v,;, \>>M^I.^',,, .-, 77^0. it>5, 1.11-0 :)">•,,
&
tively. However, in this investigation, there is a possibility that some
cases of organic mercury poisoning, which show few basic symptoms for clinical
judgment, may be overlooked. This is based on our observation, as previously
171
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mentioned (Part 1, Chapter 2, Section 3, VII, A, 10), that the majority of
cases which are diagnosed as Minamata disease display many basic symptoms.
Community A is located closest to the sea, which is contaminated by
mercury. Residents, fishermen or non-fishermen, are — in general — poor,
and they have no choice but to eat only the fish that they catch. Detsuki is
close to the shore of community A, but does not face the sea, and many people
there engage in non-fishing work, such as farming. The other two areas in the
Minamata area are located between these two areas. The Goshonoura town,
Arashiguchi area, is 16.5 km away from the source of mercury contamination,
and is located on the other side of the mercury contaminated source relative
to the Shiranui Sea. Sixty to seventy percent of the residents engage in
fishing. The Ariake area faces the Ariake Sea, and contains a number of fish-
ermen. The area is selected for the purpose of comparing it with the examined
areas mention above.
In the Minamata area examined, 301 Minamata disease patients have been
confirmed to date. The number of patients recognized by Kumamoto Prefecture
was 40; 21 up to 1962; 0 from 1963 to 1968; 1 in 1969; and 18 from 1970 until
this examination. Until this examination, the remaining 261, with some excep-
tions, already had the disease, but were not detected. The situation is
similar among patients in the Goshonoura area. Many reasons can be considered
for this situation: for instance, a lack of knowledge among residents, includ-
ing patients, from a hygienic standpoint, reserved attitude of people toward
the disease, poverty which prevented the treatment financially. At first,
among doctors — including us, the difficulty in precisely diagnosing the
disease was also one of the most important factors. The lack of cooperation
from the government, local society, fishermen, and related enterprises in
finding patients and in simultaneously examining residents was also important
in creating the above situations.
In the Minamata area, 38 persons who exhibited Minamata disease-like
symptoms were recorded dead prior to this examination.
172
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II. MINAMATA DISEASE PATIENTS FOUND IN THE ARIAKE AREA
In the Ariake area, 9 patients whose symptoms could not be distinguished
from those for Minamata disease and 1 patient suspected of the disease were
found. One of them is considered to be a patient of organic mercury poison-
ing from fish in the Shiranui Sea. However, the fishing grounds for other
patients are the Ariake Sea0 Therefore, it is necessary to investigate the
source of organic mercury poisoning for the sea in this area. This seems
to suggest that we should consider whether the effects of mercury contamina-
tion on the health conditions of residents can be seen not only in the Ariake
seashore, but also in Japan's inland seas and bays beside which factories
are built. In this examination, the amount of mercury in shellfish from the
seashore of the Ariake area was nearly zero ppm.
III. MINAMATA DISEASE PATIENTS FOUND AMONG PEOPLE MOVING
TO OTHER PREFECTURES
Nineteen Minamata disease patients and one suspected patient were found
among 21 persons who moved to other prefectures, such as Gifu and Osaka, from
the Minamata area, which was under this investigation. These patients were
not diagnosed properly at medical facilities in their new areas, or were
diagnosed as having nervous disorders and treated accordingly.
Many residents along the shores of the Shiranui Sea also moved to other
prefectures, and it it estimated that many of them might be Minamata disease
patients. We should consider methods of diagnosing them, and plans for
helping them.
IV. EFFECTS OF ORGANIC MERCURY ON HUMAN HEALTH
This investigation has proven that, among organic mercury poisoned
patients, almost all of the cases showed not only various types of neurotic
conditions due to peripheral nerve, cerebellum, and thalamus damage, but also
various kinds of mental disorders. It was also proven that this poisoning
173
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could be a cause of convulsive and neurotic conditions due to high blood pres-
sure, damage to the heart vessels, and blood circulation problems. The high
frequency of abnormal values of GOT and GPT, which indicate the suspicion of
damages to the liver among residents in the Minamata area, shows a significant
difference from that in the Ariake area. As a summary, it can be said that
the number of types of symptoms for organic mercury poisoning is remarkably
increased from what the number used to be.
V. DIAGNOSIS OF ORGANIC MERCURY POISONING
Diagnosis of organic mercury poisoning is made from the combined judgment
of the following items: existence of contaminated areas, outbreak of the
disease within a family, basic symptoms — such as sensory disorders, loss of
coordination, mental retardation, hearing problems, speech problems, and cen-
tric vision constriction,. When the area organic mercury contamination is
light or unknown, if there is no patient in a family, then the diagnosis of
the disease must be done cautiously, even if the various symptoms mentioned
above are observed. On the other hand, if many members of a family are Mina-
mata disease patients and a subject is young, sensory disorders alone are
sufficient to diagnose the subject as a Minamata disease patient.
Conditions of organic mercury poisoning may be controlled by conditions
such as development of high muscle tension in the lower half of the body,
sensory or motion paralysis on one side of the body, epilepsy, mental retarda-
tion, nervous disease, nervous breakdown, illusions, and fantasies. There-
fore, these conditions must be brought to mind in diagnosing the disease.
We examined 17 old men aged between 65 and 80 (7 males) living in
Kumamoto city for the purpose of comparison. According to this, it was ob-
served that some of them also had symptoms such as sensory disorders at the
tips of the extremities, loss of balance, mental retardation, hearing problems,
speech problems. According to Kameyama [7], 118 out of 190 persons over 60
years old were found to have abnormal degeneration in the spinal cord. Also,
according to Tog [19], the density of the total nerve fibers in intestinal
174
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nerves rapidly decreases until the age of 10, and then gradually decreases„
For the purpose of comparison, we examined r. (7 males) healthy persons aged
20 - 50, primarily between 20 and 30, living in Kumamoto city. We could find
neither any loss of balance nor sensory disorders. However, for the sense
of touch and pain, 5 and 12 subjects, respectively, showed low sensitivity
around their mouths and at the extremities of their four limbs. In order to
diagnose MinamatT disease, we must take the observations mentioned above
into consideration.
Many patients who were diagnosed as having Minamata disease showed an
abnormality in the spinal cord. However, the possibility that the spinal
disease may be diagnosed as Minamata disease has not been disproven. At the
same time, no proof has been obtained that the spinal disease will signifi-
cantly affect the Minamata disease. If we review Minamata disease patients
having spinal abnormalities, it is revealed that the diagnoses of the Minamata
disease were based on the following symptoms which were not related to the
spinal abnormality: sensory disorders around the mouth, speech problems, poor
vision, other patients in a family. However, in the case of changes in the
lumbar vertebrae, about half the subjects showed sensory disorders and muscle
tension in the lower limbs more than in the upper limbs.
VI. PLANS
1L._ Relief of Patients
Relief of patients has already partially started. However, it is desir-
able to provide not only medical assistance, but also assistance in living,
occupation, and education. Its implementation must be carried out quickly.
Among Minamata disease patients, many are old and their death rate is high.
175
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2. Medical Treatment
a. Creation of environment for treatment in
area society
Minamata disease patients not only have physical disorders, but also
mental disorders. Many of them especially show mental reactions such as
anxiety, melancholy, and offensiveness. In general, in order to examine
patients such as these, it is most important to create an atmosphere such that
the family and area society cooperate with the patient's treatment. The fol-
lowing are considered to disturb such an atmosphere for treatment: adminis-
trative, social, and industrial prejudice against patients, heretic treatment
of patients, criticism, jealousy, difference of opinion among patients. It
is necessary for the administrative staff and the medical staff to correctly
understand Minamata disease patients in the same way as patients of other
diseases, and guide the area society in creating an atmosphere for promoting
and assisting medical treatment of patients. The reason that many Minamata
disease patients show nervous conditions, depression, anxiety, melancholy, and
offensiveness is considered to be because of their disease and the disease
among their families, as well as because of abnormalities in the environment
surrounding them.
b. Establishment of a center for medical treatment
Since there are many patients, it is desirable to establish centralized
facilities which can accomodate diagnoses, treatment, and rehabilitation of
patients primarily for this disease.
c. Methods of treatment
Eighty percent of Minamata disease patients are considered adequately
cared for by merely having them visit hospitals. Therefore, methods of treat-
ment should focus on treatment by visiting hospitals. On the other hand, the
rate of patients who need to be hospitalized increases with the patients"s age,
176
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and thus increases in the future. Families just consisting of old patients
whose children have moved to other prefectures are sometimes seen.
Currently, many patients receive treatment from physicians practicing
nearby. In the future it will be necessary to obtain the cooperation of local
medical facilities in treating the patients. Minamata disease patients re-
quire not only neurological treatment, but also treatment from many directions,
such as from a psychiatric view, from the standpoint of the heart, blood ves-
sels, and liver diseases.
From actual experience,some of the subjective symptoms, such as insomnia,
headaches, crow bend, body aches, and irritation, are improved fairly well by
drugs such as phenobarbitol, chlorpromazine, and tranquilizers. However, many
patients still rely on moxa cautery to cure subjective symptoms. A systematic
study on treating the disease is seen to be difficult at present.
3. Prevention Plans
a. Prohibition of fishing in the Shiranui Sea
Amounts of mercury in fish from the Minamata Bay and in the hair of resi-
dents in the Goshonoura area still showed high values in this investigation.
Fifty-five percent of the patients described their condition as deteriorating
and, in some cases, deterioration of the patient's condition was confirmed.
In 1972 and 1971, new patients suddenly appeared. Also, on May 19, 1973, a
34-year-old housewife from Morimichi exhibited a violent attack of symptoms
during her examination. Sudden sensory abnormalities which are hard to
describe, such as bone grinding aches, numbness, no feeling, heavy feeling,
dullness, and loss of muscle strength, occurred in the lower half of her body
beneath her waist. She could not even sit in a chair. She lay on the floor,
supporting her upper body with her hands, stretching her lower limbs, and
suffered from pains in the four limbs, joints, and bones. After about 20
minutes, she left the examination room, held by her husband. From the violent
reaction to conditions, the phenomenon mentioned above is not due to sequela
177
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of poison invasion of her body in the past, but is assumed to be due to the
poison invasions of her body which she still had at the time of the examina-
tion. The family occupation was fishing, and the main dishes were fish, and
no changes had been observed until then. The floor of Minamata Bay also
contains a large amount of mercury [10], From the above, it cannot be denied
that fish in the Shiranui Sea are still possibly poisonous. Therefore, we
should consider prohibition of fishing in the Shiranui Sea. In this case,
unless those who are affected by the prohibition of fishing are compensated
for their loss, it is difficult to execute this effectively. For example,
those whose only income is from fishing may fish for themselves and for sale,
even if fishing is prohibited.
b. Avoidance of consumption of food containing
mercury, especially among pregnant women,
infants and the aged
Those younger than 5 years old, especially zero years old (i.e., heredi-
tary or fetus Minamata disease), or those older than 40 years, and especially
over 60 years, have a higher frequency of serious illness if they become
patients. There is a high possibility that the brain of such a patient will
be damaged by organic mercury. Therefore, pregnant women, infants under 5
years old, and old persons should avoid consuming such food, even though the
mercury content is low.
c. Mercury content in the hair of many Minamata
patients is 20 - 0 ppm
Thirteen out of 19 men whose hair contained less than 20 ppm, and 10 out
sf 15 women whose hair contained less than 10 ppm, in 1960, were diagnosed as
having Minamata disease,, That is, small mercury content in the hair does not
preclude occurrences of Minamata disease. According to an outline for plans
against environmental contamination by mercury issued by the Ministry of Public
Welfare (August 17, 1968), normal mercury content in human hair is, in general,
less than 20 ppm. Mercury content in the hair of residents in the Minamata area
178
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decreased remarkably in 1961, as compared to 1960, and further decreased in
1962 [11]. On the other hand, it is reported that a resident in an area not
included in this examination, whose hair contained 630 ppm mercury in 1961,
does not currently show any sign of symptoms. In either case, it suggests
the necessity of reexamining the significance of the mercury content in hair.
4. Health Examination of Residents in Other Areas Along
Shores of the Shiranui Sea and the Ariake Sea
From the illness rate stated at the beginning, it is estimated that many
unconfirmed Minamata disease patients exist among residents along the Shiranui
Sea. We often found that many patients were unaware of symptoms, although
they showed symptoms, such as a high degree of sensory disorder and poor
vision. Therefore, unless we examine each resident one by one directly, an
investigation of health conditions of residents cannot be said to be complete.
It will take time to do an investigation of health conditions of all residents.
Before doing so, it will be necessary to investigate the health conditions of
residents in urban areas of Minamata city, its suburbs, Tsunaki town, Taura
town, Otabi, Amagusa county. From the illness rate of the Minamata disease
obtained from the investigation, we can estimate the approximate number of
Minamata disease patients among residents along the shores of the Shiranui Sea.
In a similar manner, an investigation of health conditions of the resi-
dents along the shores of the Ariake Sea should be planned.
5. Examination and Treatment of Emigrants to
Other Prefectures
A number of people moved to other prefectures from the shores of the
Shiranui Sea, and many of them are estimated to be poisoned by organic mercury.
Methods of treatment and plans for their relief are an important future
problem.
179
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6. Medical Studies on Organic Mercury Poisoning
From the results of this investigation, the following are considered to
be important in treating and preventing this disease: methods of treatment,
development steps of subjective symptoms seen among organic mercury poisoned
patients; mechanisms of symptom development; relationships between organic
mercury poisoning and blood pressure, heart-blood vessel system and blood
circulation, stages of developing diseases due to organic mercury poisoning —
such as epilepsy, sensory disorder, and half body paralysis, relationships
between organic mercury poisoning and organ functions — such as the liver,
stages of developing mental diseases, relationships between the mercury con-
tent in hair and appearance of poisoning symptoms, effects of mercury passed
from the mother's body to the brain of a fetus, relationships between occur-
rences of organic mercury poisoning and age»
7. Establishment of a Medicaland Research Center for
Organic Mercury Poisoning
The establishment of such a center has been already planned by the
Environmental Bureau. From out experience in this investigation, we consider
such a facility essential, and its realization most urgent. Its functions
include: treatment of patients; guidance for patient rehabilitation to society;
guidance for life and occupation, and information gathering of patients
staying at home; examination of confirmed patients; simultaneous examination
of people in mercury contaminated areas; communication with related medical,
welfare, and government facilities; basic research, such as treatment and pre-
vention of diseases caused by poison; and elucidation of outbreak stages.
It is necessary to have a staff not only of doctors and nurses, but also many
paramedical staff members and researchers in areas other than medicine. It is
desirable that the center be nationally administered, and that it be located
in the Minamata area. Considering the great number of patients, wide func-
tional field, nearly permanent lasting problems, and international responsi-
bility, the plan should proceed on a broad scale.
180
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VII. OTHER DISEASES
In order to simplify the discussion, the following abbreviations are
used: Minamata area — M, Goshonoura area — G, Ariake area — A, Heianza
Island [3] — H. » indicates a significant difference from the statistical
estimate standpoint, > — a minor difference, = — no significant difference.
What is striking in comparing frequencies of each disease in examined areas
is that no significant differences are seen among the areas for diseases, such
as mental diseases for internal causes. That is, for nervous breakdowns,
M = G = A = H; for depression — M = G = A = Komoro town, Nagaro [9, 14];
for epilepsy, M = G = A = H; and for mental disorders, M = G = A = H. How-
ever, if neuropsychiatric disorders are related to these diseases, then con-
siderable differences in values among these areas become apparent. For example,
for the total number of patients who have some sort of neurological or psy-
chiatric symptoms: M > A > G » H; for the Minamata disease: M > G = A
for the Minamata disease and its suspects: M » G > A; for other diseases:
A > M = G. By assemblyng the facts described above, we can conclude that a
significant effect of organic mercury on health conditions of residents in the
examined areas, especially the Minamata area, is proven from the values
mentioned above.
However, for alcoholism, G > M = H > A, and for high blood pressure and
neuropsychiatric disorders due to hardening of the brain arteries — A > G >
M = H. For the latter, it is possible that cases of high blood pressure and
hardening of the brain arteries may include some which are related to organic
mercury poisoning.
181
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PART 6
SUMMARY
The following results are obtained from direct examination of 3589 per-
sons, mainly the residents along the Shiranui Sea, held from August, 1971,
to March, 1973.
1. Occurrences of neuropsychiatric disorders among the examined resi-
dents of Minamata, Goshonoura, and Ariake were approximately 59%, 28%, and
31%, respectivelyo They are remarkably high compared with the 10% at Heianza
Island, Okinawa. However, if we exclude the cases of organic mercury poison-
ing and its suspected cases from them, then the occurrence of other diseases,
especially of inherent mental disorders and mental breakdown, is similar to
those in other areas of Japan in these three examined areas.
2. Among the examined residents along the Shiranui Sea, the percentages
of Minamata disease patients in the examined areas are as follows: 71 j8±3.(>7<^,
, 12...17 "i.oo-^, ir>.r,2j_2.i;; .. '•.,., . if suspected Minamata disease
patients are added to them, then these figures become approximately 83%, 35%,
32%, 19%, and 4%, respectively. Figures for people in other areas will be
somewhere between or close to these figures. Frequent occurrences of patients
are seen in areas and among families that have the following conditions:
their homes are very close to the sea which is close to the contaminated area,
shellfish can be caught at the seashore, they are dependent only upon fishing,
and they are poor.
The Minamata disease remarkably displays the tendency of concentrated
outbreak not only in geographical areas, but also in families, especially in
the Minamata area0
3. Even in the Arike district, 8 patients, about 1% of the examined
people, showed symptoms which could not be distinguished from those of Minamata
182
-------
disease. It is necessary to investigate their cause or the source of
mercury contamination.
4. Twenty-one out of 22 persons who moved out of the prefecture, away
from the organic mercury contaminated Minamata area, and who were examined
when they came home temporarily, either had the Minamata disease or were sus-
pected of having it. There are many people who moved from the Minamata area,
and many of them are considered to be Minamata disease patients. We should
plan methods of examining and treating them.
5. Minamata patients show not only nervous diseases, but also various
kinds of mental disorders. High blood pressure, half body paralysis, epilepsy,
and other sensory disorders may also result from organic mercury poisoning.
Liver problems are also considered to result from organic mercury poisoning.
6. Diagnoses of the Minamata disease are with combined judgements,
reached from medical views, as well as patients in the family, a combination of
of basic symptoms, and characteristics of sensory impediments. It must be
taken into consideration that Minamata disease is similar to other kinds of
nervous disorders and mental diseases, and that aged persons sometimes show
similar symptoms, even if they are healthy.
7. From the results of this examination, it becomes necessary to examine
directly all the residents in areas along the Shiranui Sea and the Ariake Sea
which were not examined.
8. Relief for Minamata disease patients should proceed, as it does now,
not only from a medical standpoint, but also from living, occupational, and
educational viewpoints. Since many patients are old and the death rate among
them is high, it is necessary to speed up relief plan. As a medical
treatment plan, it is necessary to form an environment suitable for treatment
in these area societies: medical treatment by patients visiting hospitals
and by visiting patients in their homes.
183
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9. We cannot deny that there is still a possibility that fish in the
Shiranui Sea are poisoned. Therefore, fishing in the Sea should be forbidden.
10. Effects of organic mercury poisoning are especially heavy on
fetuses, infants under 5, and the agedo Consumption of food containing mer-
cury should be avoided among people in these age groups, including pregnant
women.
11. Many people whose hair, measured in 1960, contained mercury less
than the normal value — i.e., 20 ppm determined by the Ministry of Public
Welfare, or less than 20 ppm for males and 10 ppm for females, determined
from the data by Ukita [16] —were diagnosed as having Minamata disease.
The rate of Minamata disease patients having less than 10 ppm was higher in
females than in males. From these observations, we cannot assume that small
amounts of mercury in hair indicates less outbreak of the disease. In the
examination, no male Minamata disease patients and suspected patients showed
over 20 ppm total mercury content in their hair. The majority of male and all
female patients was less than 10 ppm (refer to Chapter 6).
12. We consider the following research subjects important for the treat-
ment of, and the prevention of, this disease: establishment of systematic
treatment methods for Minamata disease; elucidation of outbreak steps for
subjective symptoms, occurrences of sensory impediments, symptoms on only one
side of the body, and mental disorders; effects of organic mercury on infants
and brains of fetuses; and the relationship between organic mercury and blood
pressure and heart-blood vessels.
13. Approximately 22 - 30% of the residents examined in the areas had
neuropsychiatric disorders unrelated to organic mercury poisoning. It is
equally important to medically treat these patients as we do Minamata disease
patients. Unbalance in medical treatment for these two groups of patients will
disturb the environment for medical treatment in these areas.
184
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14. As is understood from the above descriptions, there is a wide range
of important problems concerning the Minamata disease, such as its treatment,
simultaneous examination of resident, examination of applicants for diagnoses,
and research on its treatment and prevention. In order to cope with these
problems, the need for facilities for the center of these activities is urgent,
and its prompt implementation is desired. The site of the facilities should
be in the Minamata area.
REFERENCES
1. AOAC; 9th Edition, 1960, p. 438.
2. Hiroshi, Aoki. Studies on Environmental Pollution by Mercury, Report
No. 3; Japan Hygiene Journal, Vol. 24, Nos. 5, 6, 1970.
3. Hirayasu, Tsunetoshi. Epidemiological and Social, Psycho-Medical
Studies on Psychoneurotic Patients on a Remote Island in Okinawa.
Journal on Psychoneurosis, Vol. 71, 1966, p. 466.
4. Hoshinu, Otomatsu, Keiko Tanzawa, Yoshinari Hasegawa, Tadanoshin Ukita.
Differences in Mercury Level in Hair of Healthy Persons Due to
Residential Environment. Hygiene Chemistry, Vol. 12, 1966, p. 90.
5. Hoshino, Otomatsu, Keiko Tanzawa, Mitsuo Terao, Tadanoshin Ukita.
Determination of Mercury in Hair thru Radiochemical Analysis; Hygiene
Chemistry, Vol. 12, 1966, p. 94.
6. Inoue, Takeshi, Aoi Teraoka, Shozo Egami. Unannounced Essay.
7. Kameyama, Masakuni, Eiichi Otomo, Shoichi Maruyama, Toru Mannen,
Kazuo Takahashi. Degeneration of Posterior Fibers in the Spinal
Cord of the Aged. I: Its Frequency, Origin and Clinical Signifi-
cance; Clinical Neurology, Vol. 5, 1965, p. 709.
8. Kitamura, Seija, Kyoji Ueda, Jitsuko Niino, Irei Ujioka, Hdkoji Misumi,
Toshiyuki Kakita. Results of Probe into Chemical Toxins relative
to Minamata Disease (Report No. 5); Kumamoto Igakusha Journal,
Vol. 34, Supplement 3, 1960, p. 593.
9. Public Hygiene Bureau, Ministry of Welfare. Present Conditions of
Psychiatric Patients in our Nation; Survey of the Mental Hygiene
Situation for 1963; 1965.
10. Kumamoto Prefecture. Pollution White Paper; 1972 Edition.
185
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11. Hygiene Research Institute, Kumamoto Prefecture. Survey of Mercury
Level in Hair Relative to Minamata Disease; Report No. 1 of May 1961;
Report No. 2 of May, 1962; Report No. 3 of May, 1963.
12. Masuyama, Motosaburo. The Road to Sampling. Tokyo University Publica-
tions Association, 1957.
13. Masuyama, Motosaburo. The Method of Consolidating Minority Cases;
Takeuchi Bookstore, 1964.
14. Muramatsu, Tsuneo. Mental Hygiene, 6th Edition, Nanzando, 1960.
15. Noushi, Hiroshi, Taichiro Nishima, Uko Tada, Mamoru Nagasaki.
Mercury, Lead and Cadmium Levels in the Hair of Tokyo City Residents.
Japan Hygiene Journal, Vol. 27, No. 1, 1972, p. 50.
16. Tatezu, Seijun, et al. The Wartime Mortality Rate of Inmates of
Matsuzawa Hospital. Journal on Psychoneurosis., Vol. 60, 1958, p. 596.
17. Tatezu, Seijun, Akatsuki Azumaya, Koichi Mimura, Masazumi Harada,
Tsuycchi Tsukayama. Clinical Studies, Based on Follow-Up Surveys of
Mass Carbon Monoxide Poisoned Persons as a Result of Mine Explosion
Covering a Four-Year Period. Progress in Neurology, Vol. 13, 1969,
p. 11.
18. Tatezu, Seijun, et al. Psychoneurotic Studies on Minamata Disease and
Clinical Epidemiclogical and Symptomatic Studies on Minamata Disease.
Post 10-year Minamata Disease Research Team of Kumamoto University
Medical Department. Epidemiological, Clinical and Pathological Studies
on Minamata Disease at the End of 10 Years. 1972, p. 41.
19. Togi, Hideo. Metrologic Studies on Age Differences in the Gastrocnemius
Nerve of a Normal Person. Clinical Neurology, Vol. 12, 1972, p. 484.
20. Omura, Taira, Naotaka Imada. Fortran of Conjectural Statistics.
Omusha, 1972.
186
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5. HEALTH SURVEYS IN THE AREA OF PEDIATRICS, RESULTS OF EXAMINATIONS OF
MINAMATA DISEASE-STRICKEN CHILDREN, AND CHROMOSOMES OF CONGENITAL MINAMATA
DISEASE STRICKEN CHILDREN
Department of Pediatrics, Research Institute of Internal
Medicine, Kumamoto Univeristy
Team member: Yoshitaka Harada
Research assistants: Ryoko Miyamoto, Hiroyuki Moriyama,
Midori Takahashi, Sachio Takenaga,
Toei Ishizu, Nobumasa Suetsugi
Preface
The majority of congenital Minamata disease-stricken children were born
prior to 1960. No surveys or examinations have been performed on their
brothers/sisters born subsequent to that year0 Not a few Minamata disease-
stricken patients have subsequently given birth to offspring. It is unknown
whether the effects of organic mercury are confined solely to the patient
or continues to persist in succeeding generations„ The purpose of this study
was to conduct various surveys and health examinations in conjunction with
efforts to clarify the correlation of chromosomes and Minamata disease through
an examination of chromosomes of congenital Minamata disease-stricken symp-
toms, neurological abnormalities, in particular, of children subsequently
born to patients and of brothers/sisters of congenital Minamata disease-
stricken children.
187
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Survey of Households of Minamata Disease-
Stricken Patients
1. Object of survey
Examination of record of growth and determination of bodily disorders,
especially neurological abnormalities, of children of 29 households or
patients born subsequent to the affliction of disease, and of brothers/sisters
of 11 cases of congenital juvenile patients.
2. Results
Of a total of 76 individuals, above, 36 cooperated and 36 consented to
submit to examination, the results of which are indicated below. Table 1
reflects the age group, sex, and the number of abnormalities.
TABLE 1
Age group
(years)
0~5
6~10
11~15
16 ~
Total
Male
l
8
8
17
Female
4
4
9
2
19
Total
5
12
17
2
J(3
Abnormalities
n
/
4
2
l.i
The heading "abnormalities" includes those individual with proprioceptive
symptoms, a suspicion of disease by family members, or even the slightest
indication of abnormality, exteroceptively, in movement, in behavior, or in
perception. It does not include cases where there is no physical abnormality,
despite deterioration of mental faculties.
188
-------
The number of persons in the above category (those subjected to examina-
tion) totalled 13 out of 36. The 13 persons adjudged abnormal were classified
according to proprioceptive symptoms or primary grievance, perception, move-
ment, behavior, and intellect to indicate abnormality or disorder, if any.
This is shown in Table 2.
TABLE 2
Case
no.
1. Ishi-
2. Ishi-
3. Ina-
4« Shiirt,-i-
5 . Fuku-
6. Sa-
7. Sa-
8. Kawa-
9. Ta -
10. Yama-
11. Ta-
12 . Ta-
13. Oni-
Aee
^^O
10
17
7
18
8
14
7
14
8
15
13
10
9
Propriocep-
tive symp-
toms or
primary
grievance
Perception
Perception
-
Intellect,
movement
Perception
Perception
Perception
-
Intellect
Movement
Intellect
-
-
Exteroceptive symptoms
Perception
abnormality
_
+
-
-
+
+
+
-
-
-
-
-
+
Impairment
of movement
_
-
+
-
-
-
-
+
-
+
+
+
-
Abnormal
behavior
_
-
-
-
-
-
-
-
-
+
-
-
-
Intellect
abnormal .
_
-
-
IQ = 89
-
-
-
-
IQ = 99
-
-
-
-
Re-
marks
polio
Excluding the cases of abnormal perception without any exteroceptive
symptoms (No. 1), mental deterioration amid perfectly normal bodily conditions
(No. 4), alleged mental deterioration but no particular disability (No. 9),
and clear diagnosis (No. 10) , there were 9 cases involving abnormality of per-
ception and impairment of movement. In case no. 8, involving impairment of
movement, disability consisted of flaccidity of the lower left leg, character-
ized by slight spasmatic resistance, without any other movement disability.
Case no. 12 could not move her tongue rapidly, but had no difficulty in speech
or articulation, nor did she have any difficulty while being nursed as an
infant. Thus, a total of 7 cases were considered to pose a problem: five cases
of impairment of perception, one of movement, and another of both intellect
189
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and movement. These cases are briefly described according to symptoms,
as follows.
Case 1 (No. 2): Ishi-, 17 years of age, female.
Development from the period of conception, birth, suckling, and childhood
was normal. Complained of fatigue in the right shoulder from around the age
of 12 (1967). Began to experience pain in right forewrist and twitching of
muscle from one year ago. Pain alleviated by massage. About the same time,
began to sense numbness in the area below the right lower thigh; numbness
still persists to date.
Deterioration of sense of touch, pain, and temperature was observed in
the right upper limb. Weakening of the sense of pain and temperature was
noted in the left hand and on the left lower thigh as well. Weakening of the
sense of temperature was seen in the left and right lower thighs. Weak sense
of sensation; normal physical function in upper and lower limbs; abnormality
involved only perception.
Case 2 (No. 3): Ina-, 7 years old, male.
Normal development from time of conception, birth, and suckling. No com-
plaints by individual. Tensile tremor noted on left hand. Maladroitness in
movement of fingers (finger test), heels (knee test) , and in changing positions
were noted. Writing ability was relatively satisfactory.
Case 3 (No. 5): Fuku-, 8 years of age, male.
Development through the periods of conception, birth, and suckling was
unknown, but thought to be almost normal. Has complained since last year of
of fatigue and pain in right upper shank. These symptoms were included in
the column on abnormality of perception, but they are not abnormality of per-
ception as such — rather, a case of muscular pain.
190
-------
Case 4 (No.6): Sa-, 14 years of age, male.
Development through the periods of conception, birth, and suckling unknown,
but believed to be almost normal. Has complained of numbness in the left hand
since age 12 (1970). Some weakening of perception was noted following examina-
tions to determine touch and pain reactions, but there was no dullness or loss
of such perception. Movement functions were absolutely normal.
Case 5 (No. 7): Sa-, 7 years of age, male.
Development through the periods of conception, birth and suckling was un-
known, but is believed to be normal. Complained of abnormal sensation since
around age 3 in left lower limb, at times accompanied by pain. Abnormal sen-
sation and pain in entire left lower limb, frequently during middle of night or
after a noon nap. Occasionally quivering of the same area.
Senses of touch and pain differed between left and right sides of the
body. No loss of sensation was noted. Hypersensation was observed in the right
limb at the upper and lower shank, while a moderate degree of hypersensation
was noted on the left limb at the instep. No abnormality was detected in move-
ment functions and deep sensation.
Case 6 (No. 11): Ta-, 13 years of age, female.
Development through the periods of conception, birth, and suckling was
normal. Intellectual deterioration was noted, with IQ of 62. Some maladroit-
ness was observed in the finger test. However, ability to change body position
was normal, and handwriting was normal.
Case 7 (No. 13): Oni-, 9 years of age, male.
No abnormality since the period of conception and birth. Was slightly
underweight at time of birth, but development during the period of suckling
-------
was normal. No proprioceptive symptoms or grievances from family members.
No dullness or loss of senses of touch or pain in area below upper part of
both limbs, although some deterioration was noted.
3. Remarks
Of 76 individuals who were the objects of the survey, 36 were examined.
While it was difficult on the basis of these results to calculate the affects,
if any, of Minamata disease on posterity, 13 or 36.1% complained of or suf-
fered from some physical abnormality. However, inasmuch as these included
individuals who could not be judged as normal, the frequency of appearance of
abnormality could not be determined. We cannot leave the realm of conjecture
because, as can be noted in the aforementioned cases, the guardians of
patients failed to closely observe the letter's record of development through
conception, birth, and suckling, and because of deficient background data
relative to the guardian's knowledge of child rearing or his livelihood.
What is certain is that three cases involved abnormal perception, propriocep-
tive and exteroceptive, devoid of any marked changes such as total loss or
dullness of perception. A further monitoring of such cases is probably
required.
In such movement disability as seen in Cases 2 and 3, the patients,
because of their ages, were unable to fully respond to directions. This in-
ability to comply may be due to maladroitness due to tension of the initial
experience, or weak movement capability due to intellectual deterioration.
At any rate, inability to effect coordinated movement, while not marked, was
observed during the finger test. In other coordinated actions, such as button-
ing clothes, no abnormality was seen. A definite finding probably cannot be
reached unless studies are based on repeated actions. Even though abnormal
perception and physical movement disability were slight, they were discernible
in the cases examined. It cannot be established whether they are linked to
Minamata disease or whether they were transmitted through Minamata-disease-
afflicted parents or congenitally. Today, when there is no outbreak of a
typical case of Minamata disease, no conclusion can be reached on the basis
192
-------
of only one survey. It is apparent that further studies of yet unexatnined
cases and monitoring of cases cited in this report are required.
Conclusion
1. A survey was conducted among children of Minamata disease-afflicted
patients and brothers/sisters of children stricken by the same disease. The
target of the survey was 76 individuals, but only 36 were diagnosed and
examined.
2. Of the 36 individuals examined, 13 showed some form of abnormality
and were either conscious or unconscious of the symptoms or the symptoms had
been pointed out to them by family members.
3. In most cases, the symptoms of which the patients were conscious
were dominant.
4. Those requiring additional studies were three cases of abnormal per-
ception, proprioceptive or exteroceptive, four of impairment of movement —
though of moderate degree, and one of exteroceptive perception abnormality.
Chromosomes of Congenital Minamata Disease-Afflicted
Children
Chromosome examinations were conducted in seven cases of congenital
Minamata disease-afflicted children.
1. Method of examination. The peripheral blood leucocyte culture method
was used. Specifically, 6 - 8 ml of peripheral blood was drawn with a 10 ml
hypodermic syringe containing 0.1 - 0.2 ml heparin sodium. After being put
aside for several hours under sterile conditions, the isolated leucocytes,
along with blood plasma, were removed and cultured for 72 hours, using culture
solution 109. At the same time, 0.2 ml PHA-M was added to the total volume
of 10 ml. Twelve to 15 hours prior to completion of the culture, 2 or 3 drops
193
-------
of korusemido* [sic] were added, upon completion of the culture was centri-
fuged, a hypotonic solution added to the sediment, and water treated. Follow-
ing 15 minutes of water treatment, it was again centrifuged, fixed with
karunoa* [sic] for 15 - 20 minutes, which process was repeated three times,
after which a preparation was formed. The preparation was produced by flame
fixing and by crushing, using the rapid drying method. After it was completely
dry, it was dyed with gimuza* [sic], and examined with a microscope.
2. Results. The results are shown in Table 3. The total number of cells
examined was 301, and the karyotype — 46XY or 46XX. Thirteen reflected the
number of chromosomes as 45, and 4 — as 44, an artificially abnormal number
in producing the preparation. No specific abnormal cell structure was ob-
served. Three were abnormal chromosomes, revealing a chromatid separation.
Such abnormalities did not show any relationship with the gravity of Minamata
disease symptoms.
3. Comments. When considering the effect of organic mercury on chromo-
somes, it can readily be stated that there is presently no effect on the number
of chromosomes. It is clear from animal experiments using organic mercury that
the latter passes through the mother's body to the placenta and affects the
fetus. Although partial physical abnormalities such as hydrocephalus can
occur, there has been no case of abnormality of the entire body attributed to
chromatic changes or so-called physical, multiple deformities apparent in
fetuses undergoing miscarriage, premature birth, or stillbirth. In fact,
deformity seldom occurred, despite the high content of mercury in the fetus.
Even among clinical symptoms such as serious cranial paralysis in infantile
Minamata disease-afflicted children, no physical deformity has been observed,
even though the paralysis either could not be physiologically categorized,
or disclosed mixed symptoms. And since there were no symptoms to suggest that
they were the result of changes in the number of chromosomes, it was not pos-
sible to expect them to reveal any changes in the chromosome count. It can be
said that no abnormal count was detected in the examination of 301 cells in
seven cases.
Translator's note. This is a Japanese compound whose exact English counter-
part is unknown.
194
-------
According to reports available up to now, morphological changes in
chromosomes have been brought forth by various biological chemical and physical
stimulations. Such changes consisted of chromatid separations, chromatid
gaps, fragments, dicentric portions and rings, while in animal experiments
TABLE 3. CHROMOSOMES OF CONGENITAL MINAMATA
DISEASED CHILDREN
XT Degree of
Name
serious-
ness
NAKA, Chi
IWA, Sue 4
HAN, Kazu 4
KANE, Mesu :i
ONI, Yu :;
NAGA-
KA, Kiyo 2
Total
%
Chromosome count
44
2
1
1
4
1.3
45
2
9
2
1
2
4
13
4.3
46
2.1
32
II
.).}
1 '
'> •
43
2? 1
91.1
47
Total
cell
count
•> >
f>t>
::
'•
; ;
2f'
IS
,;o;
'.Oi'.i'
No. of
abnormal
cells
i
-
o
0.9
using organic mercury, morphological abnormalities observed were separation,
gap, and fragment. These changes, however, are known to undergo marked de-
crease as time progresses, following administration of organic mercury.
In our study, we observed three cells with a separation among the 301 cells
that we examined. This was a frequency of 0.9% of the whole. It cannot be
affirmed that such a change was evident until the present time as a result of
the effect of organic mercury. It was not possible from our experiment to
draw sufficient data to compare the frequency of appearance of abnormality
under normal conditions, that is, a comparison with the frequency of appear-
ance of artificial abnormality, to consider the differences. Based on these
results alone, it can probably be stated that the chromosomes of such stricken
children are completely normal at this time.
195
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When discussing these problems on the basis of only a few discernible
chromosomes, there is an apparent danger that some uncovered abnormalities
are still lurking in the background. As for the problem of congenital abnor-
mality attributed to chromosomes, it is considered necessary to conduct suf-
ficient examinations of the offspring of Minamata disease-stricken patients,
and to monitor conditions of such offspring, including brothers/sisters of
stricken children, over a prolonged period.
Conclusion
1. Chromosome examination of seven cases of congenital Minamata disease
patients were conducted.
2. The peripheral blood culture method was utilized for the chromosome
preparation.
3. The cell count of chromosome preparation examined was 301. In the
chromosome count, all indicated a normal karyotype, with no sign of abnormality.
4. As for morphological (structural) changes, three cells revealed sepa-
rations, but not of a frequency to suggest the development of abnormal
chromosomes.
5. No chromosomatic abnormalities were detected in the current examina-
tion; hence, it can be stated that the chromosomes were normal.
196
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6. NEUROOPHTHALMOLOGICAL STUDY OF MINAMATA DISEASE (Part 2)
1) On Patchy, Dark Scotomas Observed in Minamata Disease
Ophthalmological Seminar, Department of
Medicine, Kumamoto University
Team member: Jun Tsutsui
Research assistants: Hiroyoshi Ogata
Fumio Miyamoto
I. PREFACE
Patchy, dark scotomas represent a phenomenon in which numerous
minute dark spots are found in the residual center of field of vision narrowed
by Minamata disease. The development of centripetal field of vision constric-
tion through organic mercury poisoning has been known since the days of
Hunter-Russel. With respect to Minamata disease, however, only centripetal
constriction of the surrounding field of vision has been emphasized, and not
enough research has been completed on the quantitative or static measurement
of the field of vision.
In Minamata disease, a biopsy of cases revealed that patchy fallout of
nerve cells of the brain cortex, especially of the optic area, constitutes
the most unique change. Therefore, a certain kind of statical, quantitative
method was used to carry out a new form of field of vision measurement, known
as patchy, dark scotoma measurement.
II. METHODS AND PATIENTS
Thirty-one cases of confirmed Minamata disease patients were examined.
Excluded were those who, at the time of field of vision tests, evidenced a
197
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lack of understanding or a poor state of fixed vision, which could lead to
unreliable findings. Also excluded were cases where there was a probability
of patients developing a field of vision constriction.
A Goldmann Perimeter 940, manufactured by Haag-Streit, was utilized. The
nature of the test was described to the patients, and checks were made for
abnormality of vision and of the Marriott's blind spot.
Then, 3/0 optometer charts were posted at several places around a fixed
spot, and after making sure that they were visible, a field of vision of 10°
or less at the center (5° or less in some cases) was measured at a total of
40 places. The scotoma area was then counted, and the extent of patchiness
of micro-dark spots was sought. 3/0 was equal to around 2.8* in the angle of
vision, projecting the functions of about 8 optic cell units in the center
where the cones were supreme.
III. FINDINGS
Analysis was conducted on the following five items.
1. Relationship with the degree of field of
vision constriction
Generally, the degree of patchiness increased as the constriction of the
field of vision advanced. Out of 31 cases examined, seven cases (22.6%) dis-
closed no evidence of patchy, dark scotomas, this group having a field
of vision of 50° - 70°. A high maximum degree of 62.5% was noted in cases
where there was no extensive constriction of the field of vision, or where the
average field of vision was 50° or more. Consequently, a relatively wide
field of vision does not mean that functions in the remaining field are com-
plete. Herein lies the significance of patchy, dark scotomas and the
gravitation of the field of vision as explained below.
198
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2. Relationship with gravitation of field
of vision
Observation of the relationship between gravitation of the field of
vision, as measured with a 2/1 Isopter, and patchy, dark scotomas detected
a parallel relationship between both. The greater the gravitation of the
inner Isopter, the more conspicuous was the rise of the degree of patchiness.
Specifically, they constituted both the frontal and rear aspects, revealing
the functions on the same plane.
3. Relationship with visual power
While no definite relationship was noted, the visual power was relatively
sound in most instances where the degree of patchiness was 0.
4. Relationship with degree of seriousness
A direct relationship was not noted when the degree of affliction of
Minamata disease was classified into grave, moderate, and light, and compared
with patchy, dark spots. Patchiness was not necessarily high in patients
with total bodily symptoms. This is only natural, because, in the case of
Minamata disease, perception or hearing disabilities which are one of the
major afflictions do not appear to be attributable to impairment of the
occipital lobe brain cortex alone.
5. Control cases
Virtually no patchy dark scotomas were detected in cases of about
the same age group having no neurological or ophthalmic abnormalities. A
slight degree of patchiness was detected in cases of centripetal retinitis
and in changes affecting the sclera. It can be distinguished from that in
the occipital lobe through visual examination.
199
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IV. COMMENTS
Numerous micro-dark spots called patchy, dark, scotomas were found
in great frequency in the residual area of the field of vision. This was a
phenomenon newly found by us as a type of abnormal field of vision due to
organic mercury poisoning. In this latest study, we avoided cases of which we
possessed little knowledge, carrying out repeated measurements through micro-
optometric charts equal to 2.8' in the angle of vision. The phenomenon is
believed to be valid because of the close relationship with field of vision
constriction and the state of gravitation. Hitherto, these micro-dark spots
were utilized for the detection of vascular dark spots in the retina, involv-
ing primarily the area surrounding the head of the optic nerve, but it is
said to be difficult to uncover such dark spots within 10° of a fixed visual
point. They virtually do not appear in healthy individuals. These dark
spots were detected in some individuals suffering from retinitis, but they
can be clearly distinguished from Minamata disease through eye examinations.
In pathological examinations of the brain relative to Minamata disease, fall-
out of nerve cells, unlike that in the field of vision constriction, was
identified at the tip of the optic center of the occipital lobe. It is pos-
sible that an equivalent will turn out to be patchy dark scotomas.
We hope to continue the study of not only organic mercury poisoning, but
also pathways of vision and optic center deformities.
V. CONCLUSION
Using Goldmann Perimeter 3/0 Isopter with an angle of view of 2.8',
numerous micro-dark spots were detected in the residual area of the central
field of vision in the centripetal field of vision constriction due to
Minamata disease. This occurred in 77% of the cases of Minamata disease
involving constriction of the field of vision, and the presence of many micro-
dark spots was confirmed.
200
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6. 2) Peculiarities of Strabismus in Minamata Disease
Ophthalmological Seminar, Department of
Medicine, Kumamoto University
Team member: Jun Tsutsui
Research assistants: Sakuko Fukai
Hiroyoshi Ogata
I. PREFACE
There is a high rate of occurrence (over 50%) of strabismus in fetal
Minamata disease. This ailment is extremely distinct through cerebral patho-
logical examination, and can be compared with other clinical symptoms from a
pathological standpoint. The following are the findings as a result of exten-
sive analysis of fetal Minamata disease accompanied by strabismus.
II. METHOD AND CASES
Neuroophthalmological examinations, as well as an analysis of constituent
factors of strabismus, visual corrections before, during, and after surgery,
and drug treatment methods, were conducted over different periods. Example:
M.T. age 16, male, IQ 61 (Vinnie Tanaka method), Family record: grandmother,
father and mother are recognized Minamata Disease patients.
III. RESULTS OF TREATMENT
The results of treatment were studied on the basis of three different
periods.
First period: Presurgery (July 18 - August 2, 1972). Strabismus was
detected about 6 months after birth. Visual capacity changed greatly, with
OD-(0.4) - (0.5) OS-(0.4) - (1.0). The field of vision was only outer
isopter, with both eyes having a constriction of 5° - 13°, and disclosing
gravitation. The angle of strabismus was 15/^XT, I5/\XT , at P.C.T.,
201
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characterized by common, alternative outward strabismus. Visual functions
in both eyes were impaired, and some suppression was noted with respect to
altemativeness. In a reaction test, normal conditions were noted (receipt
of afterimage, rod light test). In the afterimage test, an afterimage was
observed, extending to the affected part of the field of vision. The con-
vergence point was 40 - 50 cm or farther, depending on the day. A double
vision perception method was attempted for purposes of pre-operative visual
correction, but was not successful. Cosmetic surgery was then performed, as
the symptoms resembled strabismus which appeared in cerebral infantile
paralysis.
Second period: (August 3, 1972). With respect to iTi/^XT ^cc) , the
muscle in the right eye was shortened 6 mm, and that in the left eye — by
the same length. The remaining angle was at a normal position at P.C.T.,
Alt. P.C.T. A fusion of the image was achieved dramatically with the S.G.
test. The S.G, test was further employed for convergence training during
the surgery. A convergence point of 30 cm was attained, giving hopes for
visual corrections following surgery.
Third period; Post-operative progress (August 4 - October 1, 1972).
One week after surgery, the patients began to complain of insomnia and ner-
vousness, as well as headaches. This was believed due to eye corrections.
Central nerve suppressants were used for various nervous conditions. As such
symptoms decreased, vigorous suppress!on-removal training was conducted. The
method consisted of one week of stimulation of the mid-regions of the objec-
tive angle of strabismus, followed by kinetic biretinal stimulation through
the use of visual slides, which, after five minutes, led to vomiting, head-
ache, and nervousness on the part of the patients. Since the previously de-
scribed symptoms of nervousness reappeared, the administration of central
nerve suppressants and orthoptics was suspended. After an active agent only
was used for a while, the field of vision enlarged, and the inner isopter
emerged. There was also a period, following surgery, of complaints of double
vision outside the area of Panum's image fusion. This, however, was put to
counter use and applied for indoor training. Orthoptics was performed as the
202
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symptoms of nervousness diminished. A day later, a fusion function appeared
and vigorous training was performed to enhance it, resulting in a reading of
+10° - —4°. Convergence point also improved to 10 cm - 7 cm. Monitoring
is being continued at present.
IV. COMMENTS AND CONCLUSION
Minamata disease is a typical affliction responsible for organic changes
of the brain, and produces fallout, obliteration, or degeneration of nerve
cells. Some activity of degenerative cells is believed to have occurred in
the cases we have examined. This is thought to be a case of outer strabismus
attributed to congenital fusion deficiencies. The fact that orthoptics,
central nerve activating agents, and surgery for strabismus have led to some
improvement of functions in both eyes should revise the opinions that these
ailments are not in the realm of orthoptics because of their organic nature.
Address before the Second Research Meeting
of the Visual Function Trainers' Association
(Yokohama). Japan Ophthalmology Bulletin 24:
No. 2, 1973, p. 174
203
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6. 3) Cerebral Pathology of Visual Association Area of Minamata Disease
Second Pathology Seminar, Department of Medicine, Kumamoto
University
Team member: Tadao Takeuchi
Research assistant: Mitsuaki Eto
Ophthalmological Seminar, Department of Medicine, Kumamoto
University
Team member: Jun Tsutsui
Research assistants: Kimiko Mayuzumi, Fumio Miyamoto,
Hiroyoshi Ogata, Junko Takenaka
I. PREFACE
Centripetal constriction of the field of vision has been known since the
days of Hunter-Russell to be a major neuroophthalmological symptom of Mina-
mata disease. We, a group at neuroophthalmology of Kumamoto University, have
successively reported on findings not previously known, such as abnormality
of eye movement in both eyes, reflex disturbance of pupils, and on the resi-
dual field of vision and patchy, dark scotomas. Accordingly, it was
necessary to confirm our findings through a comparison of cerebral, patho-
logical findings with neuroophthalmological symptoms. We were able to direct
our studies to an appropriate specimen derived from numerous anatomical
studies of Takeuchi and his associates of the Second Pathological Seminar,
Kumomoto University. While it would be necessary ultimately to delve into
the aspects of the brain related with visual functions, our latest study was
centered on the occipital lobe, which showed the greatest changes. Since the
reports of Takeuchi, Eto, and their associates are available concerning falx
cerebri, we shall turn our attention to the visual association area, as it
has not yet been reported on in detail.
204
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II. METHOD AND MATERIALS
Five specimens were selected from among the cerebral specimens pre-
served at the Second Pathology Seminar, Kumamoto University, for microscopic
examination. A series of optical microscopic photographs, taken from one
these specimens, was pasted together (for a panoramic view) to conduct a study
of extensive cell disorders.
The case under study was stricken on October 7, 1960, and after having
gone through chronic Minamata disease, died on January 15, 1965, of dysphagic
pneumonia at the age of 79. Neurological disorders included those of surface
perception, handwriting difficulty, tremors, and of hearing. Ophthalmologi-
cally, a moderate 30 - 50° of centripetal constriction of the field of vision
was noted. It is to be noted that no minute examinations of the eyeball
movement or pupil reflex were made.
The specimens were cross sections of the forehead, obtained by slicing
at three places, approximately 6, 10, and 21 mm from the occipital pole of
the lobe. Staining was by the Kluver-Barrera, Haematoxylin-Eosin method.
Used as control was a brain specimen of a 69-year-old without any dis-
orders, which was close to the histological image described in previous
reports.
III. FINDINGS
In the falx cerebri of Minamata disease, there was fallout of nerve
cells, as well as contraction and hardening. Also noted were an increase of
glia and changes or loss of medullary sheath. Even in areas where the dis-
orders were relatively light, changes in the II-IV layers were conspicuous.
As for these layers, layer I evidenced a slight roughness, whereas layer II
evidenced great fallout of nerve cells and sometimes appeared to be spongy
when observed under an optical microscope. In layer III, there was patchy
205
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fallout of 50 - 80% of nerve cells as opposed to a comparable increase of
glia, with the remaining nerve cells contracting and hardening. Observed in
phagocytes were chromosome sedimentations, thought to be destructive by-
products of nerve cells. In layer IV, there was a great fallout of granular
cells, and it was difficult to distinguish IV a - c layers. Isolated cells
in the IV b layer were changed, and included within their bodies granules
stained red by He. Ccnical cells also evidenced regressive changes. In layer
V, 80 - 100% fallout was observed in concial cells, which were being replaced
by glia cells. Layer VI also had fallout of nerve cells, resulting in in-
distinct layer structure. When observed under a medullary sheath stain,
nerve fibers generally appeared rough and undergoing degeneration. This was
believed due to disorders of the cortical nerve cells. On the other hand,
a comparison with the specimen which had been slided at the forehead about 6,
10, and 21 mm from the occipital pole showed that changes in the 21 mm section
were greater than in the other two sections. Also, the ridge was affected
more than the apical area, and fallout of nerve cells was noted.
Next, in Area 18, changes were evident from layer I, there being rough-
ness as well as corpora amylacea. In layer II, there were, as in the case
of Area 17, fallout of granular cells and multiplication of glia, which ac-
counted for an indistinct layer structure. Conical cells in layer III had under-
gone a fallout, with the remaining cells in disarray or change. The indis-
tinct structural layer of layer IV had induced abnormal positions of large
conical cells. In layer V, the original nerve cells were few and in disarray
or change, with some presenting the appearance of Betz macro cells seen in
the precentral area. Layer VI and the medullary sheath were virtually
identical to that of Area 17.
In Area 19, the layer structure was in relatively good shape, but changes
were noted in all remaining nerve cells. Fallout of cells was slight as com-
pared to Areas 17 and 18, with almost no difference between the ridge and the
apex. Layer I was also in fairly good shape, with little fallout of cells.
Layer II had a 50% fallout of nerve cells. Layer III showed a fallout of
206
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conical cells, as in Area 17, but the remaining nerve cells showed only slight
change. Layers IV — VI were almost identical to that of Area 18.
IV. COMMENTS
Many points remain unclear with respect to the relationship of cell
structure and functions in the occipital lobe. This area is said to hold the
answers to many questions, ranging from simple vision to such complex visual
functions as mental reflex, eye movement reflex, and preservation of sight
functions in both eyes. According to notes of Duke-Elder, Walsh, Crosby, et
al., the centripetal impulse above the pathway of vision commences with optic
radiation and ends in the vicinity of layer IV b of Area 17, with the end
cell branches forming a synapse with granular cells of layer IV a, c, where-
upon amplification of impulses and production of transmissible substances to
Meynert cells begin. The impulse is also transmitted to identical cells,
identical layers, to conical cells in layer III, and to Martinotti cells in
layer V. It is further transmitted to layers I and II through the dentrite
from conical cells of layer III, with fibers in layer I transmitting the im-
pulse in all directions. On downward movement, Golgi type I cells of layer
III are said to be related with the corticofugal fiber, and Golgi type II
cells — with the association fiber. Upon moving further downward to layer V,
the impulse proceeds from the Meynert cells downward. In the meantime, there
are messages from Areas 18 and 19. The impulse from Area 18 is thought to be
transmitted to Areas 18 and 19 on the opposite side via the corpus callosum.
However, there is no direct transmission path from Area 17 to Area 19. The
downward pathway from the Meynert cells of layers V of Areas 18 and 19 passes
through the Internal Sagittal Layer, rising in the Pulvinar vicinity, and
running lengthwise in the inner side. The pathway of optic motion is thought
to exist along this route.
The pathological studies of the brain by Takeuchi and his associates,
relative to Minamata disease, can be summed up as follows: Brain damages
from Minamata disease are due to circulatory disorders brought about by the
initial cranial vascular disorders and regressive changes of the cortex of
207
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the cerebrum and cerebellum. As the chronic condition progresses, fallout
of nerve cells and related changes occurs, affecting nerve fibers. Of the
brain cortex, those areas especially affected are falx cerebri of the occi-
pital lobe, front center, rear center, and parietal lobe. Localization is
hardly seen in cases of juvenile or fetal Minamata disease, and shows a trend
of extensive cortical disorders. Also, in the same cortex, there are great
changes in the pit of the cerebral fissure. In the cerebellum, disorders of
the granular cells are prominent, but changes of Purkinje cells are slight.
However, relatively weak changes were noted in neurons in the diencephalon,
with little damage on the base of the brain and spinal cord. In the spinal
cord, secondary changes were noted in the lateral and posterior fibers when
degenerative changes were great in the front center. In the peripheral
nerves, the sensory nerve was relatively susceptible to injury, with changes
in posterior fibers being noted around this time. No prominent degenerative
changes were noted in the apical region, optic nerve and the retina. In
considering the correlation of the histological image of Minamata disease
in Areas 17, 18, and 19 in the occipital lobe with functions, it can be ob-
served that there is a fallout of nerve cells in all cases and a complete
severance of neurons, except for a few. Thus, we believe that in Minamata
disease, the primary cause of abnormalities of occipital lobe-type eye move-
ment, myopic reflex of pupils, centripetal constriction of field of vision,
and patchy dark scotomas in the central, residual field of vision can
all be traced to cerebral changes in the occipital lobe. Generally, dis-
orders of eye movement and pupil reflex are considered to be due to disorders
of the brain stem, but in the case of Minamata disease involving the brain
stem, eye abnormalities of this type develop only in relatively serious
cases. Thus, we believe that our position is correct.
208
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V. CONCLUSION
Neuroophthalmological symptoms observed in the case of Minamata disease
are patchy dark scotomas, constriction of the visual field and of the
residual region, inability to perform coordinated movement, myopic reflex
disorders of the pupil. Microscopic studies of the visual association area
were conducted to compare such clinical findings with cerebral, pathological
findings. Patchy fallout of nerve cells was prominent in layers II, III,
and IV of Area 17. A comparison of Areas 18 and 19 with Area 17 showed that
both 18 and 19 also had great, patchy fallout of nerve cells throughout the
whole layers, with many neurons being severed. Thus, the reason for dis-
orders in the relay of messages from the optic sense to the motor fiber and
in the myopic reflex of the pupil is believe to lie extensively in the
occipital lobe.
Report to the Tenth Neuroophthalmological Society
(September 7, 1972). Proposed for publication in
Volume 67, No. 6, of Ophthalmological, Clinical
Medicine Bulletin
209
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6. 4) Development of Visual Field. Eyeball Movement Meter for Use in Mass
Examination
Opthalmological Seminar, Department of Medicine,
Kumamoto University
Team member: Jun Tsutsui
Research Assistants: Hiroyoshi Ogata, Fumio Miyamoto,
Sakuko Fukai, Kimiko Mayuzumi
I. PREFACE
In neuroophthalmological disorders, examinations of the visual field and
eyeball movements are particularly vital. Speedy examinations are required
in these days of such pollution diseases as organic mercury poisoning and
pesticide poisoning. Therefore, a new device enabling the examination of
both the field of vision and eyeball movements was developed.
II. METHOD
This device is basically a muscle trainer, on which an arm and a light
were attached to serve as a visual field meter. The index comes in two types
for use with outer or inner isopters, and can measure the visual field in all
directions. With respect to eyeball movement, the device permits observation
with the naked eye or can record EOG simultaneously. The speed of the visual
chart is 0.25 - 0.5 c.p.s.
III. RESULTS
1. On normal persons; A comparison was made with the visual field
registered by the Goldmann perimeter. The outer isopter corresponded to 4/v
of the Goldmann perimeter, whereas the inner isopter showed almost 3/1. In
the case of EOG, normal, coordinated movement of the sinusoidal wave-type
210
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, r
i
tj ;_•
- ,^./.i <_
Figure 1 Figure 2
was measurable.
2. For mass examinations: In the screening x
test, abnormalities of the visual field and of /\\
eyeball movement were detected in about 6-8 min- i . / ' *
• ••' t
utes per case. When the device was actually used ! . I
for Mlnamata disease examination, the results ; /
relative to constriction and gravitation in the
visual field were identical to those observed with ' -^"
I ' i
the Goldman perimeter. Examination of eyeball
movement with the naked eye achieve the same
results as the EOG. Figure 3
IV. CONCLUSION
Reliable screening was possible with our visual field, eyeball movement
meter for use in mass examinations from the standpoint of tests of visual
field constriction, gravitation, and coordinated reaction movement. It per-
mits examinations of about 8-10 cases per hour. Visual field readings were
almost commensurate with 4/V, 3/1 registered by the Goldmann perimeter. The
rate of detection of abnormality of coordinated reaction movement by the naked
eye was identical with the EOG. It was also an outstanding screening device
for use in everyday examinations. It was tentatively named Kumamoto Univer-
sity type neuroophthalmometer.
Report to the general meeting of Japan Ophthalmological Society on May 26,
1973
211
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7. OTOLARYNGOLOGICAL STUDIES RELATIVE TO MINAMATA DISEASE (Part 2)
Otolaryngological Seminar, Department of Medicine,
Kumamoto University
Team member: Yasuji Nozaka
Research Assistants: Takezo Kiyofuji, Yoshimi Mioki,
Kosei Shimoyama, Yoichiro Ochiai,
Kenjiro Tuschio, Shinya Araki,
Hidetoshi Iwasaki
Since 1957, we have periodically announced the results of our Otolaryngo-
logical studies relative to hearing, equilibrium, taste, smell, and speed im-
pairments attributed to Minamata disease. Also, in 1959, we reported finding
an improvement in the hearing power and vestibular, equilibrium functions in
Minamata patients 10 years later.
Our principal interest in Minamata disease is in the area of hearing
difficulty, which is one of the major symptoms. We touched on this matter in
our previous report, but now wish to discuss this more in detail. We also
wish to discuss the results of examinations of patients visiting our hospital
on suspicion of having contracted Minamata disease.
The chief aim of our research was as follows.
1. Experimental study on the sequence of development
of hearing difficulty
In the study of hearing difficulty, it was not only necessary to conduct
clinical hearing tests but also biochemical and electrophysiological obser-
vations of the inner ear fluid, including general and histological observa-
tions of the auditory nerve pathways and the inner ear. In our latest report,
we have covered pathological and histological studies on the mercury content
212
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in the inner ear, cochlear reaction, hearing nerve movement potential, and
the inner ear.
2. Test results of patients suspected of having
Minamata disease
1) Hearing impairment
The object of this study was 96 individuals (52 males, 44 females) on
whom hearing tests were conducted from among those requiring such tests on the
basis of the second questionnaire survey conducted by the Minamata disease re-
search team of Kumamoto University. A breakdown by locality showed 40 from
Minamata, 34 from Goshonoura, and 22 from Ariake, ranging in age from 12 to
80, but mostly in the 40 - 60 age group. Tests consisted mainly of pure
sounds, word sounds, recruitment, T.T.D. and T.T.S. Results of the test are
as indicated in Table 1.
TABLE 1. LIST OF HEARING IMPAIRMENTS
I Normal range (includes psyio-
logical degeneration)
II Suspected
rear labyrinth type
III Inner ear type,
-------
2) On impairment of vestibular functions
Of the 72 individuals examined, 11 had eye tremors (+), and 3 (+) ,
mostly of the horizontal type. Three were of the perpendicular type, suggest-
ing impairment of the central nervous system. A careful study is under way,
since even in these cases one cannot say that there is a link with organic
mercury.
3) On olfactory impairment
A new method applied in our latest study was the use of an Arinamin
solution (50%, 20%) of a close density to determine the relationship, if any,
with the central nervous system. Determination could not be made in 12 out
of 72 cases, and some were in error. We wish to conduct a further study on
this matter.
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7. 1) The Amount of Mercury in the Inner Ear Fluid in Experimental Organic
Mercury Poisoning
Otolaryngological Seminar, Department of Medicine,
Kumamoto University
Team member: Yasuji Nozaka
Research assistants: Yoshimi Mioki, Kazuki Umeda
Since the 1940 report of Hunter-Russell on organic mercury poisoning,
the latter has been identified as a strange malady affecting the masses of
Minamata district in 1953, followed by another similar outbreak in Niigata
in 1964. As a result, remarkable progress has been and is being made in its
study. Yet, there still remain many unknown matters, research on which is
currently under way. In the area of ear and nose, impairment of hearing,
equilibrium, speech, and taste functions are recognized, but the real nature
of these impairments has not yet been established. With respect to hearing
impairment, rear labyrinth type disorders are held primarily responsible, but
inner ear type disorders also cannot be dismissed [2, 3, 4]. Thus, we meas-
ured the total volume of mercury in the inner ear fluid as a means to deter-
mine whether or not inner ear cells are directly impaired because of the
contamination of the inner ear by organic mercury.
II. EXPERIMENTAL METHOD
1. Experimental animal
Mature cats, 2.0 - 4.0 kg in weight.
2. Materials administered
Into 1 ml of a puropyrene compound TH3Htjl was dissolved methyl mercury
iodide 'OI,CH'OWCH..Oir } so that its proportion would be Hg 2.0 mg.
215
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3. Method and period of administration
The foregoing solution was injected daily into the abdominal cavity of
the animal at a dosage of 0-1 mg - 2.0 mg per kg of weight until symptoms of
poisoning appeared. Before any loss of control of movement occurred, animals
Nos. 8, 10, 12, 17 suffered immensely from diarrhea, frothing, and runny nose,
and were in weak condition. Then, the injections were suspended and the ani-
mals were killed (Table 1).
TABLE 1
Cat
Daily
dose/
kg
Period
admin.
Total
amount
admin .
Inner
ear
'
Spinal Blood
fluid
1
Brain
Remarks
•2 i ,nif 13 days lOl.Omg 0.54ppm i
20 72 0 0. II
ppm
1
0
12
]('
17
.)
9
13
s
1"
1 !
i"
15
If)
20
l.(!
1.0
1.0
1.0
! 0
Average
0.5
0.5
0.5
Average1
0.1
0 1
Control;
'/
'/
's
'/
23
19
16
22
15
19
30
32
39
34
143
137
5 7 . 5
4,~. 5
32.0
4-1.0
; 30 0
42 5
51.0
-10.0
, 48.8
47.6
35.75
34.25
'*..»"
0 !-J9
0 32
0.31
0.53
0.46
0.63
1 0.57
\ 0.52
: 0.57
0.37
0 33
0.39
0.49
1 0.37
0.49
0.49
i 12.22
20.2"
: 10.2-1
1 6.25
2.44
i 5.90
4. SO
0.03 ' f..i!7
0.17 0.97
0 . • •?
: O.nr,
; 0.35 ii <»•
. O.lu u 02
2 ! 1 "•
17.7)
1-i li
JO . Sc
7 i>
17 32
! 22. 02
• 12.80
j 15.23
16. 6^
5.96
(i 39
u . i , i
1 1 . t r '
0.07
O.i.)
O.o'i
Debilitative death
Debilitative death
Slaughtered because
of debilitation
Debilitative death
Average 0.45 i
4. Collection of material examined.
o ni-i
After anesthetization through abdominal injection of ketimine, bone
cells past the rear part of the pinna were removed, and a 1/4 ml hypodermic
syringe with a 26G 1/2 needle was inserted into the labyrinth through the
round window, drawing the inner ear fluid, while carefully avoiding a mixture
of blood. Since the amount'of fluid from one ear was too small for examina-
tion, the fluid from both ears was combined.
216
-------
For reference and comparison purposes, segments of other organs were
also examined as follows.
(1) Brain: after incision on the head, the brain was severed at the
mid-sagittal surface, and half of the portion was examined.
(2) Arterial blood: the carotid was severed, and the arterial blood
drawn and examined.
(3) Spinal fluid: extended from the nape of the neck to the vertebrae
in animals no. 8, 10, 19, 20; spinal fluid was drawn after opening the area
between the vertebrae.
5. Quantitative determination of total
amount of mercury
The procedure employed was the method devised by Winkler [5] and Sandell
[6], as well as by Kai [8], which is patterned after Snell's [7] method.
(1) Conversion of objects of study into ashes: objects of study were
converted into ashes by adding strong acids (nitric acid, sulfuric acid) and
permanganate, and applying heat.
(2) Extraction of mercury: hydrochloric acid and hydroxylamine were
added to nullify surplus permanganate; urea solution was then added to inac-
tivate nitrous acid formed during ashing, after which dithizone was added.
Mercury was then extracted for examination.
(3) Quantitative determination of total amount of mercury.
(i) In solutions with a large mercury content, a QB50 type spec-
trophotometer was employed to conduct colorimetry at a wave-
length of 500 my.
217
-------
(ii) In the case of low mercury content, the solution was dried
in a test tube, and the mercury therein was subjected to high
temperature and vaporized. A Beckman mercury vapor meter
(Model K24) was then used to determine the volume according to
the ultraviolet, atomic absorption method [9].
III. RESULTS OF THE EXPERIMENT
1. Inner ear fluid (Tables 1 and 2)
(1) With respect to the group of 5 mice each administered 1 mg/kg per
day, injection was continued for a 15 - 23 day period, for a total dosage
of 30 mg - 57 mg. Of these, Nos. 12 and 17 died of disease during the same
period. The total volume of mercury in the inner ear fluid was from 0.32
ppm to 0.53 ppm, or an average of 0.46 ppm, which was close to the 0.45 ppm
average for tuc control group.
(2) With respect to the group of 3 mice administered 0.5 mg/kg daily,
injection was continued from 30 - 39 days, for a total dosage of 40 - 54 mg.
The total amount of mercury in the inner ear was 0.52 ppm - 0.63 ppm, with
an average of 0.57 ppm, which was slightly higher than in the control group.
The difference was not considered significant.
(3) In the case of the group of 2 mice administered a daily dose of
1 mg/kg for a prolonged period of approximately 140days, the total volume
was 34 - 36 mg, with an average 0.38 ppm in the inner ear fluid, and somewhat
lower than in the control group. The difference was also considered insig-
nificant.
(4) In the case of two mice administered a daily dose of 2.0 mg/kg
and 1.5 mg/kg, respectively, the aggregate dosage for each was greater,
with 104 mg and 72 mg. Yet, the total volume in the inner ear fluid was
0.54 and 0.44 ppm, with no significant differences from the control group.
213
-------
Thus, no significant differences could be found between the entire
groups and the control group with respect to the inner ear fluid.
2. Spinal fluid (Table 1)
Test specimens were obtained only from two cats administered mercury
(Nos. 8 and 10) and an equal number of control cats (Nos. 19 and 20), Of
those cats administered mercury, the average amount was 0.13 ppm, which was
slightly lower than the 0.23 ppm registered by the control group. The differ-
ence was insignificant. Strictly speaking, while that value is lower than
the value for the inner ear fluid, it would be safer to state that there was
no significant difference between them.
3. Brain (Tables 1 and 3)
Cats affected by organic mercury poisoning registered over 16 ppm,
while even that group administered 0.1 mg — although they did not develop
mercury poisoning — showed 6 ppm, or more than a hundred-fold of the control
group's 0.06 ppm. These values are almost identical to the amount of mercury
in the brain of experimental Minamata diseased cats and those of the control
groups as reported by Ujioka [19].
TABLE 2. COMPARISON OF TOTAL VOLUME OF MERCURY IN
INNER EAR FLUID
Administered groups
(amount per day/kg)
2.0 mg Group (1)
1.5 mg " (1)
1.0 mg " (5)
0.5 mg " (3)
0.1 mg " (2)
Control group (5)
Average value
volume of
0.54 ppm
0.44
0.46
0.57
0.38
of total
mercury
0.45
219
-------
TABLE 3. COMPARISON OF TOTAL MERCURY CONTENT
IN BRAIN
Administered group
(daily dose/kg)
2.0 mg Group (1)
1.5 rag " (1)
1.0 mg " (4)
0.5 mg " (3)
0.1 mg " (2)
Control group (5)
jt
Spontaneously afflicted cat
ti ii ii
Experimentally afflicted cat
ii it ii
*
Control area cat
Average value of
total mercury content
i7. \J ppm
In 06
17 32
i'JjN
ti.i;
0.06
8. OS
10. -4
18 6
I*. I
10.0
0 05
0.04
0.02
Findings by Ujioka [19](1960)
4. Blood (Tables 1 and 4)
The total amount of mercury in the blood of the group administered 1.0
mg mercury was especially high, with more than 12 ppm. In the case of groups
administered 0.5 mg and 0.1 mg, the lowest was 2.5 ppm, or an average of
5-6 ppm. This was approximately more than 40 times that of the control
group average 0.06 ppm.
220
-------
TABLE 4. COMPARISON OF TOTAL VOLUME OF MERCURY
IN BLOOD
Administered group
(daily dose/kg)
1.0 rag Group (2)
0.5 mg " (3)
0.1 mg " (2)
Control groups (4)
*
Spontaneously afflicted cat
M ii ii
Control area cat
11 ii n
Average value of total
amount of mercury
lti.ll! DO.n
I.SC)
0.52
i) '•',:•
10. Ii
!5.,c
0.13
0 . 118
O.Of)
Findings by Ujioka (1960) [19].
IV. SUMMARY AND COMMENTS
It was reported in 1940 by Hunter [1] that hearing impairment was a
serious clinical symptom of acute organic poisoning. In 1958, Nestrugina [4],
after having conducted a hearing test of 60 patients with chronic organic pois-
oning, reported that the impairment could be of both peripheral and central
nervous system types. Nozaka and his associates [2, 3] held that the disorder
could be of the rear labyrinth, but stated that inner ear disorder could not
be dismissed because of positive cases of recruitment. The reason for his
assertion was that, under the present hearing test method relying on subjec-
tive examinations, there were limits in attempts to determine the impaired
region. According to Matsumoto [10], changes occurred in the cerebrum frontal
and parietal lobes, as a result of which mental and intellectual disorders
and voluntary movement impairment developed. Prominent changes also occurred
in the cerebellum, resulting in an advanced degree of loss of movement.
Thus, reactions against tests have decreased in many cases. Even if there
221
-------
were 100% changes and fallout of the cortical cells in the lateral, temporal
side of the cerebrum — which is the hearing center as claimed by Matsumoto
[10] and Takeuchi [11], it would still be necessary to be especially careful
in the determination of results of the hearing test. As Matsuzaki [12] says,
there are occasions where determination cannot be made.
Miyakawa [24] and his associates used rats to study changes in the peri-
pheral nervous system. Based on their findings, they claimed that even before
changes appear in the cerebellum due to organic mercury poisoning, the peri-
pheral sensory nerve has already been affected, along with trifurcated and
vestibular nerves. However, when the results of hearing tests are considered,
along with the fact that there are almost no disorders of the retina or optic
nerve, even in cases of prominent constriction of the visual field, the
belief is that hearing impairment is due to rear labyrinth type disorders
[10, 11]. In the hearing tests, there were cases of advanced degree of hear-
ing difficulty or even deafness, although biopsy showed relatively slight
changes in the central nervous system, making one suspect that inner ear dis-
orders [10,2,11] were also involved. Histological studies of the inner ear are
being attempted, but no reports have yet appeared because of various dif-
ficulties.
We measured the total amount of mercury in the inner ear fluid for the
purpose of determining whether the contamination of the inner ear by organic
mercury caused direct destruction of cells therein.
In a study on fetal Minamata disease, Fujita [13] reported that through
use of radioactive materials, he had discovered that mercury in the mother's
body was transferred to the fetus via the placenta, and that mercury was
transferred to the child by the mother's milk. However, the blood of both
the infant and the mother do not combine, and metabolism takes place through
osmic action of the placenta and the peculiar permeatic nature of epithelium
cells [14]. Thus, it was very interesting that organic mercury migrates from
the mother's body under such circumstances. It also suggests the possibility
222
-------
of organic mercury being transferred to the inner ear fluid or spinal fluid
because of the peculiar permeability of epithelium cells or through blood
vessels.
With respect to impairment of nerve cells by organic mercury, Kuwahara
[15], Yoshino [16], Miyagawa [17], and Brown[18] contend that the reason may
be due to obstruction of cell metabolism owing to interference of mercury
alkylide with enzymes involved in protein formation by cells. Thus, if mer-
cury contamination and histologic sedimentation in the inner ear can be
established, there exists a possibility that a similar metabolic obstruction
could develop in inner ear cells.
However, according to our findings relative to the total amount of mer-
cury in the inner ear fluid, there were not significant differences as indi-
cated in Tables 1 and 2. There also was almost no difference even in the case
of spinal fluid (Table 1) . Nevertheless, a remarkable difference of mercury
level was noted in other internal organs (brain, blood) as compared to the
control group (Tables 3 and 4). What is the reason that accumulation and
transfer of mercury occurs in mother's milk and fetus, when there is vir<-
tually no such transfer in the inner ear fluid or spinal fluid?
It is said that endothelium cells of the vascular system engage in the
production of endolymph fluid, whereas endothelium cells of cerebral capil-
lary vessels take part in the production of spinal fluid, and that they —
by means of differences of osmic pressure or ion density and unusual per-
meability — screen out the materials that pass through [20, 21]. Thus, it
could be that in these endothelium cells, placenta, and mammary gland,
physical and basic differences exist with respect to permeability.
It is further stated that mercury alkylide in the blood is found in very
small quantity in blood serum, being found mostly in red blood corpuscles
[19, 23]; that it circulates in the body by a weak combination with globin,
a protein [13], enabling it to travel freely among proteins in internal
223
-------
organs [8]. Thus, it is able to move easily from the mother's red blood
corpuscles to those of the fetus, as well as to milk containing such proteins.
However, it is believed difficult for it to travel from the blood serum to
the inner ear fluid or spinal fluid which contain only a small number of
proteins.
Thus, it is apparent that there was no such thing as mercury contamina-
tion of the inner ear fluid, and the possibility of organic mercury — a type
of mercury — damaging inner ear cells was ruled out. However, it cannot be
denied that there are other causes of hearing difficulty in the inner ear.
According to Takeuchi [22] and Matsumoto [10], vitreous, uniform changes
of micro blood vessel walls were noted in the brain of patients suffering
from organic mercury poisoning, as well as slight, unusual enlargement of
wall endothelium cells and edema of the surrounding area of blood vessels.
It is therefort conceivable that similar changes have occurred also in the
vascular system in the inner ear. Deficiencies in the production of the
inner ear fluid due to changes in the vascular system or in its formation
could possibly lead to disorder of inner ear cells, It is also possible that
because of changes in the vascular system, inner ear cells may be confronted
with a chronic lack of oxygen and become irreversible.
According to results obtained by Ochiai, who made a histological study
of the inner ear of poisoned cats used in our experiment, there were no
differences in Corti's organ, spiral ganglion cells, and the vascular system
when compared to those of the control cats. Thus, it can be stated on the
basis of histological studies of the inner ear fluid and the inner ear that,
in our method of experiment, we found no evidence of impairment of the inner
ear brought on by organic mercury poisoning.
V. CONCLUSIONS
We conducted a study to determine whether or not mercury contamination
developed in the inner ear fluid of cats suffering from organic mercury
224
-------
poisoning. We injected methyl mercury iodide into the abdominal cavity of
fully grown cats to develop poisoning symptoms. We then extracted all the
mercury and measured its amount through colorimetry and the ultraviolet, atomic
absorption method. For comparison with other internal organs, the total mer-
cury content in the spinal fluid, brain, and blood was also measured according
to the same method. As a result, it was found that the total amount of mer-
cury in the inner ear fluid was not linked to the dosage or period of ad-
ministration of mercury, for there were no differences from the control group.
No differences were noted in the spinal fluid, but prominent differences were
noted in the brain and blood between poisoned and control groups. Thus, we
assumed that there was no contamination of inner fluid by organic mercury,
or impairment of inner ear cells.
REFERENCES
1. H Hunter, D. , et al. Poisoning b,y Methylmercury Compounds. Quart. J.
Med., Vol. 9, 1940, p. 193.
2. Nozaka, Yasuji. Minamata Disease — Research on Organic Mercury Poison-
ing. Minamata Disease Research Team, Department of Medicine, Kuma-
moto University, 1966, p. 193.
3. Nozaka, Yasuji, et al. Effect of Impairment of Hearing, Vestibular
Functions, Taste and Speech in Minamata Disease, Otorhinolarngy,
Vol. 73, 1970, p. 1006.
4. Nestrugina, Z. F. Disturbance of Auditory and Vestibular Functions in
Chronic Intoxication with Mercury. Vestn. Otorhinolarygn., Vol. 20,
1958, pp. 4, 32.
5. Winkler, W. 0. Report on Mercury. Association of Official Agricultural
Chemist., Vol. 21 (2), 1955, p. 220.
6. Sandell, E. B. Colorimetric Determination of Traces of Metals. Third
Edition, 1959, p. 621.
7. Snell, F. D. and C. T. Snell. Colorimetric Methods of Analysis. Third
Edition, 1958, p. 63.
225
-------
8. Kai, Fumio. Trend in Animal Bodies of Organic Compounds and Methyl
Mercury Compounds Found in Minamata Bay Fishes and Shellfishes,
Kumamoto Medical Association Journal, Vol. 37 (12), 1963, p. 673.
9. Yamaguchi, S. Ultra Microdetermination of Mercury in Biological Mate-
rials by Atomic Absorption Photometry. Industrial Medicine, Vol. 10
(3), 1968, p. 125.
10. Matsumoto, Hiedyo. Neuropathological Study of Minamata Disease in
Humans (Third Edition). Kumamoto Medical Association Journal,
Vol. 35 (11), 1961, p. 1133.
11. Takeuchi, Tadao. Minamata Disease: Research on Organic Mercury Poison-
ing. Minamata Disease Research Team, Department of Medicine,
Kumamoto University, 1966, p. 264.
12. Matsuzaki, Chikara. Literary Reminiscences Concerning Hearing Sense
Cortical Center and Cortical Hearing Difficulty. Autiology Japan,
Vol. 12 (1), 1969, p. 43.
13. Fujita, Eisuke. Experimental Research on Organic Mercury Poisoning
— Movement of Substances Producing Minamata Disease from the Body
of Mother Rats to Their Offspring via the Placenta or Mother's Milk,
and Trend of Movement in the Mother's Body. Kumamoto Medical
Association Journal, Vol. 43 (1), 1969, p. 47.
14. Kaki, Michitaka. Obstetrics. Regular Edition. Nanzando, 1962, p. 34.
15. Kuwahara, Shunsuke. Effects of Mercury Compounds on Cerebral Functions
— Especially Inhibitive Effect of Methyl Mercury Compounds on
Transaminase, Aromatic Araino Acid Found in Brain of Rats. Kumamoto
Medical Association Journal, Vol. 44 (3), 1970, p. 214.
16. Yoshino, Y., et al. Biochemical Changes in the Brain in Rats Poisoned
with an Alkyl Mercury Compound, with Special Reference to the
Inhibition of Protein Synthesis in Brain Cortex Slices. J. Neuro-
chem., Vol. 13, 1966, p. 1223.
17. Miyagawa, Tahei, et al. Electron-Microscopic Study of Experimental
Minamata Disease — Chronology of Development of Pathological Changes,
Mental Nerve Journal, Vol. 69 (12), 1967, p. 1352.
18. Brown, W. J., et al. Organic Mercurial Encephalopathy — An Experi-
mental Electron Microscope Study. Mental Progress, Vol. 9 (1),
1965, p. 34.
19. Ujioka, Irei. Chemical And Analytical Study of Mercury Found in Food-
stuffs and Animal Organs. Kumamoto Medical Association Journal,
Vol. 34 (Supplement 2), 1960, p. 383.
226
-------
20. Nakamura, Fumio. Outline of Physiology — Physiology of Sensation.
Igakushoin, 1967, p. 757,
21. Broman, T., et al. An Experimental Study of Disorders in the Permeabil-
ity of the Cerebral Vessels (the Blood-Brain Barrier) Produced by
Chemical and Physiological Agents. Acta Physiol. Scandinav., Vol. 10,
1945, p. 102.
22. Takeuchi, Tadao. Pathology of Central Nervous Disorders (First Report).
Kumamoto Medical Association, Vol. 31 (Supplement), 1957, p. 37.
23. Katsunuma, Harue, et al. Study on Distribution of Various Mercury
Compounds in the Body. Nisshin Medicine, Vol. 48 (6), 1961, p. 373.
24. Miyakawa, T., et al. Experimental Organic Mercury Poisoning — Patho-
logical Changes in Peripheral Nerves. Acta Neuropath. (Berl.), Vol.
15, 1970, p. 45.
227
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7, 2) Cochlear Reaction in Organic Mercury Poisoning and Changes in Hearing
Hearing Nerve Activity Potential
Otolaryngology Seminar, Department of Medicine, Kumamoto
University
Team member: Yasuji Nozaka
Research assistants: Kosei Shimoyama
Second Seminar, Pathology, Department of Medicine
Kumamoto Univeristy
I. PREFACE
In Minamata disease, hearing difficult is one of the major symptoms,
along with centripetal constriction of the visual field, loss of movement,
and articulation difficulty. As to the area affected in the case of hearing
difficulty, Nozaka [I, 2], as the result of hearing tests on Minamata disease
patients, concluded that the rear labyrinth was mostly affected, but also
suspected afflictions of the inner ear, based on the DL test and other findings,
On the other hand, Cho [3, 4] and his associates claimed, based on hearing
tests of pure tones on 50 ears in 25 cases and subsequent use of Bekesy
audiometry, that hearing disorders in organic mercury poisoning begin with
cortical hearing difficulty, and that the rear labyrinth disorders which ex-
tend, as the condition worsens, to the base of No. 8 cranial nerve were the
chief area of concern. From the pathological viewpoint, Takeuchi [5] stated,
based on biopsy of Minamata patients, that the side region of the head, which
is the cortical center of the hearing sense, the falx cerebri, and the central
area of the occipital lobe were susceptible to damage with fallout of cortical
nerves being noted. As noted above, the nature of hearing impairment was
gradually being discovered. In order to study whether disorders occurred
in the inner ear and auditory nerve ends, using chronic electrodes we
228
-------
administered Mlnamata disease-producing organic mercury to cats, and observed
changes in the cochlear reaction [6, 7] (hereinafter referred to as CM) and
auditory nerve activity potential [8] (hereinafter referred to as AP). Chronic
electrode methods have been used on cats by Galambos [9] and Simmons [10, 11],
and on domestic rabbits by Ouchi [12], Shiraiwa [13], Ogawa [14], and Otani [15]
[15] to detect potential changes from poisons of the ear organ, such as di-
hydrostreptomycin and kanamycin.
II. EXPERIMENTAL METHOD
1) Experimental animal
Cats used were those which had been established as having Minamata
disease, naturally or experimentally, and on which pathological studies had
been conducted [16, 17]. Of four fully grown mice weighing between 2.7 - 3.0
kg, two were tested on both ears, and the other two on one ear.
2) Electrodes
A silver ball tip 500 y in diameter affixed to the end of a 200 y-
diameter steel wire was insulated with polyethylene tube and used.
3) Insertion of electrode
Insertion of terminal on top of head: Following anesthetization by
muscular injection of about 40 mg/kg of hydrochloric ketimine, a skin incision
was made on the top of the head under sterile conditions, the periosteum re-
moved, four small holes made in the skull, and the terminal affixed with the
300 y-diameter steel wire and dental cement (Repairsin F),
Electrode insertion surgery: After incision of the rear part of the
ear, the bone cell of the inner ear was exposed, a hole approximately 4 mm
was opened, using a bar, in the upper rear part of the bone cell. Using a
229
-------
surgical binocular microscope, the silver ball tip of the electrode was
affixed, so that it would touch the membrane above the round window. The
electrode was affixed to the hole with dental cement, and the hole was closed.
Next, the other end of the electrode was guided to the area of the top of the
head through the periosteum, and affixed to the terminal on the top of the
head. For a fukan [sic] electrode, a portion of the steel wire used to affix
the terminal to the skull was utilized. Following the operation, penicillin
and tetracycline were administered for about a week to prevent infections
or tympanitis.
4) Experimental devices
Pure tones were applied for measurement (Audiometer Rion A-1002k).
Sounds were directed to the cats' ears by the closed method from the 20 cm
receiver, using a 4 mm-diameter vinyl tube. The vinyl tube was affixed with
an ear-mold made of plaster to fit the cats' ears. In the AP measurement,
a constant 0.05 msec impulse from an electronic stimulator (Nihon KodenMSE-3)
was converted into a click sound by a specially-manufactured crystal receiver
and guided to the cats' ears by the closed method. The level of click sounds
was measured with a precise noise meter, NA-51, manufactured by Rion. CM and
AP directed from the round window electrode was carried to the Braun tube
oscilloscope (Nihon Koden VC-7) through the preamplifier, and then photo-
graphed.
:M
Photo 1
Figure 1. Experimental devices
230
-------
5) Measurement
As a rule, measurements were taken every other day, when the animals
were anesthetized with hydrochloric ketimine. In CM, the potential hearing
level (hereinafter abbreviated as HL) of 90 dB stimulating sounds and the
visual detection level (hereinafter abbreviated as VDL) or the minimum sound
required to recognize CM we re measured. In AP, the potential for 50 dB (SPL)
of stimulating sounds, as well as the latent period, were determined. There
were two negative peaks in AP, at N.. and N_. The potential (amplitude) ex-
tended from the base line to the peaks of NI and NL, and the latent period
was from the commencement of sound stimulation until the peaks of NI and N .
A soundproof room was not used. The noise level at the time of measurement
was 35 phons.
6) Method of administration of methyl mercury
Allowing for a three-week recovery time after positioning of the elec-
trodes, 0.5 - 1.0 mg/kg mercury was injected daily into the abdominal cavity
of the animals until poisoning symptoms appeared. For this purpose, methyl
mercury iodide 'OUW, was dissolved in > UIjCIl.Ol^CHjUH to reach a mercury
content of 2 mg/ml (see Table 1).
7) Observation of entire body conditions
In addition to such three major characteristics as some loss of control
in walking, spasmodic convulsions, and torpidity, as noted in cats afflicted
with Minamata disease, there were other disorders such as loss of appetite,
vomiting, diarrhea, a general weakening, loss of weight, eye lipid, and flow
of saliva. These disorders were divided into four phases [18], and observed
(see Table 1).
231
-------
TABLE 1. AMOUNT OF MERCURY ADMINISTERED AND
ITS EFFECTS
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8) Pathological studies
The brain and auditory nerve of cats which had died, including those
slaughtered because of imminent death, were fixed in formalin, and patho-
logical studies were conducted thereof.
III. FINDINGS
1) Appearance of symptoms of organic mercury poisoning
Twenty-five to 41 days after commencement of administration of methyl
mercury, initial symptoms of loss of movement in hind legs were noted. The
aggregate amount of mercury administered was 58.8 - 74,8 mg. Until the ini-
tial symptoms appeared, the cats were generally in good condition; however,
with the onset of the symptoms, they suddenly began to stagger to one side
or collapse and were unable to walk. Spasmodic convulsions were observed in
three cats. Toward the end, their condition deteriorated due to loss of
appetite, vomiting and diarrhea. They appeared to be in a state of lethargy
232
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and died 5-8 days following the outbreak of initial symptoms. Their weight
loss ranged from 200 - 600 g.
2) Changes in CM and AP
Figure 2 reflects the changes in the average values of CM and AP in the
case of 6 ears, following commencement of administration of methyl mercury.
In CM, the pure tone stimulation of 90 dB (HL) did not cause any distinct
lowering of either 1 KHz or 4 KHz, but in both ears of one cat, there was a
loss of control of movement and a simultaneous decrease of the potential.
Figure 3 shows this CM decline as a change of reaction intensity curve. The
decrease of potential was slight, but was accompanied by a movement to the
right. VDL was somewhat high at an average value of 60 - 70 dB (HL), but the
effects of administration of methyl mercury were virtually unseen. A rise
in the level was observed in only one ear.
mV
1.0
0 r
0 6
0 4
dB
•fiO
'70
mV
0 3
0 1
m«er
2 8
2 4
2 0
1.6
CM'90ciB-HL
o—olKFJz
*—*4 KHz
- 20
- 15
Figure 2. Changes in CM and AP following
administration of methyl mercury (aver-
age values of 6 ears)
mV
2.0
1.0
r.3
0.2
0 J
50 60 70 80
Figure 3. CM reaction inten-
sity curve:
1 — Appearance of loss of con-
trol of movement; 2 — after 2
days; 3 — after 6 days
J_
233
-------
The average value of AP amplitude reflected a slight decrease as time
progressed. Of the 5 ears which induced AP, 2 showed a decline of AP, but
these were considered to be secondary changes because they were accompanied
by a CM decline. The average value of AP latency was 1.6 msec for N.. , and 2.4
msec for N~, but began to extend as loss of control of movement became notice-
able. At the time of final determination, it was 1.9 msec for N , and 2.8
msec for N~, or an extension of 0.3 msec for N.. and 0.4 msec for N~ . This
variation was common in all cases.
IV. COMMENTS
The plan was to determine the potential without putting the cat under
anesthesia to avoid any changes in muscular reflex suppression in the inner
ear. however., we were forced to resort to anesthesia because of the difficulty
of securing the cat. The effects of anesthesia cannot be dismissed in light
of Simmon's [20] experiment. He found that in a chronic experiment [11] using
Nembutal as an anesthetic, the degree of potential variation did not differ
from that when no anesthetic was used. Thus, it was believed that a variation
of the potential could be avoided by controlling the strength of the anes-
thetics.
The lowering of CM in the two ears began as disease symptoms appeared,
giving rise to the suspicion of inner ear disorders. However, since the
other four ears were unaffected, it was necessary to examine more cases. In
the case of two ears, variations of the reaction intensity curve were accom-
panied from the outset by a decline of the potential as the curve moved to
the right. Ogawa considered that such a change in DHSM was due to variations
of endocochlear potential as a result of changes in the endolymph structure.
The extension of AP latency was slight, but an important finding that
was noted in all cases from the time of outbreak of symptoms. It is gener-
ally stated that AP latency [21, 22] is prolonged by diminished sound pressure,
234
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masking, cooling, and anoxia. Otani, who has reported on KM with respect to
drugs, contends that this may be due to the keen sensitivity of nerve endings
of capillary cells, as in the case of synapses, to various attacks, when con-
sidering that variations in AP latency occurred prior to changes in the CM
and AP amplitudes. Because of such an occurrence, even in cases without a
lowering of CM and AP, it could mean the beginning of disorders of capillary
cell nerve endings or of auditory nerve endings. Thus, a long term study
would be required.
Pathological and histological studies
Pathological studies were conducted to verify the onset of symptoms,
their extent, and auditory nerve afflictions of 4 cats used in this experiment.
1) Method of study
Visceral organs of the nervous system of 4 cases of slaughtered or dead
animals were fixed in formalin and stained under the haematoxylin-eosin,
KlUver and Barrera method. Studies were made chiefly of the posterior slice of
the central area of the cerebrum, the posterior slice of the occipital lobe,
the appendage of the cerebellum, lobe area, cervical spine, spinal nerve,
and auditory nerve.
2) Findings
CD Cerebrum: In all cases, an acute enlargement of small nerve cells
was seen, not only in the optic region, but also in the cortex. Acute changes
such as chromatolysis were observed, with numerous cells becoming large or
being obliterated. An increase of glia was also noted in the area of cell
obliteration. Some conical cells were also noted to have undergone some acute
growth, with some showing a slight degree of hardening and atrophy. These
pathological changes were observed most keenly in No. 3, and only to a slight
degree in the other 3 cases (see Photo 2 and 3).
235
-------
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on
Photo 2. Acute enlargement of conical cells in the cerebral occipital
lobe cortex of No. 1, along with an acute enlargement of small nerve cells.
Obliteration of cells can be observed.
Photo 3. Nuclear enlargement of small nerve cells in the cerebral
temporal lobe cortex of No. 4; obliteration of cells can also be seen.
Photo 4. In the appendage of the cerebellum of No. 1, fallout of Pur-
kinje cells is notable; an increase of Bergmann's glia is seen in the area
of the fallout. Granular cells are falling off to some extent directly below
the Purkinje cell layer.
Photo 5. Around and deep in the cerebellum of No. 4, there is a fallout
of Purkinje ceils and an increase of Bergmann's glia. A very few granular
cells have decreased at the apical area.
Photo 6. Auditory nerve of No. 2, with the upper half being the center
and the lower half being the peripheral nerve fibers. From the border area
of the brain to the peripheral region can be seen a slight damage (upper side
of photo) , becoming more conspicuous in the peripheral region (lower
side of photo) .
Photo 7. Enlarged view of peripheral side of auditory nerve of No.l,
showing ganglionic degeneration.
Photo 8. In the lateral cross section of the posterior root of the
spine of No. 3, the disintegration of the medullary sheath and enlargement
and/or contraction of the axons can be seen on a segment of the nerve fiber.
A trend toward increase of Schwann cells is also noted.
Photo 9. In the anterior root nerve of the spine of No. 3, the nerve
fibers are in normal position; disintegration of the medullary sheath is
238
-------
seen only in a part of the nerve fibers. There is no increase of
Schwann cells (see Photos 2 and 3).
© Cerebellum; Acute enlargement or fallout of Purkinje cells in the
appendage was prominent in all cases, with some showing poor stainability and
disintegration or obliteration. A multiplication of Bergmann's glia was found
in the area of fallout. In Nos. 1 and 3, granular cells were also noted
undergoing fallout from directly below the Purkinje cell layer (see Photo 4).
In No. 4. a minute quantity of granular cells has decreased in the apical
region deep in the cerebellum (see Photo 5), but almost no fallout of granular
cells can be seen in No. 2. Thus, the fallout of granular cells was slight
in either case. Although there were some differences, it constituted only
a patchy fallout.
@> Nucleus: Even in nuclei in the brain stem, no prominent change was
noted in their nerve cells, there being only a slight growth of nuclei in a
part of the nerve cells.
© Auditory nerve: Localized or glandular changes were seen in various
areas of the medullated nerve in all cases, and achromatism in the medullary
sheath, which showed an enlargement. Changes were more prominent towards the
periphery. Schwann cells showed a slight reaction, some reflecting a trend
toward increase. These changes were relatively great in the order of Nos. 3
and 1, but relatively slight in Nos. 2 and 4. As seen in No. 2, these
changes were slight in the region having nerve fibers in the center, but
suddenly became greater toward the periphery (see Photos 6 and 7),
© Cervical spinal cord: In No. 3, changes were seen in the lateral
fiber, achromatism and irregular shapes in the medullary sheath, as well as
changes in the axons, accompanied by an increase of glia. In the cerebellum
of this case, localized, inflammatory cell infiltration was. noted in one
region, but this was not believed to be due to poisoning.
239
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f) Posterior root of spine: Here, changes have appeared in a part
(1/4 - 1/5) of nerve fibers, with disintegration of the medullary sheath and
enlargement of axons being noted. An increase of Schwann cells is also noted
(see Photo 8). The anterior root nerve is systematic; a slight destruction
of the medullary sheath due to changes in the nerve fiber was noted, but there
was no increase of Schwann cells (see Photo 9). This change was common in
all cases.
3) Comment
The pathological changes in the nervous system in our experimental
cases, such as disorders of the cerebral cortical cells, partial fallout of
granular cells in the cerebellum, Purkinje cell disorders, and peripheral
nerve changes, are all in accord with the findings of Takeuchi [5] and Takaya
[6], and attest to their causing methyl mercury poisoning.
Nerve cell disorders of the cerebral cortex have extended to the entire
cerebral cortex, and to the auditory center cortex. However, no noticeable
pathological changes were noted in the nerve fibers of the cerebrum and the
brain stem. Furthermore, almost no changes were noted in auditory nerve cells
in the central nervous system. However, in the peripheral nerve, there were
ganglionic or localized changes extending to nerve endings, accompanied by an
enlargement of the area. This change distinctly became greater toward the
periphery.
In our experiment, ganglion spirale cochleae and Corti's organ in the
inner ear were not studied. In a separate study, however, Ochiai studied
acute period pathological changes in methyl mercury poisoning cases, and dis-
covered that during the acute period, no great changes were induced as re-
gards ganglion cells of the ganglion spirale, and that no great changes were
equally induced in such Corti's organs as Zona pectinata, Zona arcuata,
Deiter cells, capillary cells, and Membrana tectoria. Thus, he found that
they maintained their own mutual structure and did not accept changes within
the cells. He claims, however, that chronic cases will require further study.
240
-------
Thus, from the foregoing it can be seen that, in methyl mercury poison-
ing, cerebral, cortical cells sustain relatively greater damage than the
nucleus or nerve cells, with respect to the central nervous system, and that
changes in the nerve fibers tend to become greater toward the periphery, and
that no pathological changes occur in the inner ear at the time of acute
affliction. It may be more appropriate to consider electro-physical findings
from the standpoint of changes in the peripheral region of the auditory nerve,
rather than primary obstructions of nerve endings of capillary cells. No
definite conclusion is possible, however, because of the small number of
cases studied in our experiment and inadequacy of study of the inner ear.
Further studies are required.
Conclusion
. 1) Changes of CM and AP were observed, using 6 ears of four cats on
which chronic electrodes were attached and methyl mercury administered.
2) Under 90 dB (HL) of pure tone stimulation, the lowering of CM
potential, suspected to be due to the effects of methyl mercury, was seen in
two ears of one cat.
3) Elevation of VDL was seen in only one ear.
4) AP amplitude was not noted in cases with no CM decline.
5) The prolongation of AP latency was observed in all cases. It was
assumed to be the beginning of disorders in the capillary cell nerve endings
or in the periphery of the auditory nerve.
6) Pathologically speaking, unusual changes brought about by Minamata
disease in the cerebrum, cerebellum, and peripheral nerve were confirmed.
In the field of otorhinology, acute changes and patchy fallout were seen in
cerebral, cortical nerve cells, and, in the auditory nerve, partial or
ganglionic changes were seen in nerve fibers.
241
-------
Finally, we wish to express our gratitude to Professors
Yasuji Nozaka and Tadao Takeuchi for their assistance in preparing
this manuscript; also, to Assistant Professor Etsuji Ogawa and Lec-
turer Heiichi Uchiyama of Fukushima Prefectural Medical College and
Hearing Difficulty Research Facility, Tokyo Medical and Dental
College, respectively, for their kind guidance to us in our experi-
ment; to Assistant Professor Joji Eiki of Central Examination
Department, Kumamoto University for this frequent assistance in
measurement, and to Miss Yachiyo Shigemura for her services as an
assistant.
242
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7 . 3) Pathological and Histological Changes in the Hearing Organ of Experi-
mental Cats Poisoned by Organic Mercury
Otolaryngology Seminar, Department of Medicine,
Kumamoto University
Team member: Yasuji Nozaka
Research assistant: Yoichiro Ochiai
In Minamata disease-related ear impairments, disorders are considered to
be primarily of the rear labyrinth type, but on the basis of hearing tests,
inner ear obstructions cannot be completely ruled out. Therefore, methyl
mercury was injected into the abdominal cavity of fully grown cats to produce
experimental organic mercury poisoning. Biological fixation was then per-
formed and studies conducted on histological changes in the hearing organ.
The results of the experiment are discussed below.
Experimental Method
Fully grown cats were used for the experiment. Methyl mercury iodide
CH-Hg I was added to 1 ml of CH CH(OH)CH OH so as to attain a mercury content
Hg 2.0 mg. The solution was administered daily into the abdominal cavity of
the animal until there was a great loss of control of movement, at which time
it was biologically fixed. The Hg administration rate in this experiment
aggregated 30 - 72 mg. The period from the time of administration to the out-
break of the disease was from about 20 to 40 days, with apparent symptoms of
acute poisoning. Tests were conducted on 12 ears of 6 cats. For control,
4 ears of 2 cats were utilized to effect comparison.
method
An incision was made on the cervical region of the cat, secured on its
back, and its cervical veins and the carotid on either side exposed. Two
243
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hypodermic needles attached to the end of a branched, rubber washing tube
connected to an irrigator filled with biological saline solution were stuck
into each side of the carotid, and the artery and the hypodermic needles were
ligated firmly. Cervical veins on either side were severed to make an open-
ing for the flow of the washing solution. Washing was continued until the
washing solution flowing from the cervical vein was completely clear, without
any reddish color (about 1000 ml of biological saline solution). Next, the
fixing solution was administered. Initially, the fixing solution was added
over the remaining biological saline solution, in an amount equal to the
latter, and gradually replenished. The Wittmaack fixing solution was used.
Wittmack fixing solution:
5% heavy chromic acid, potash solution 83 ml
Japan Pharmaceutical Standard formalin 10 ml
Japan Pharmaceutical Standard glacial acetic acid 3 ml.
Following fixation, the auditory organ was removed, taking care to obtain
a small specimen to include the auditory organ. Then, the middle ear cavity
was opened, followed by post-fixation, ash removal, washing and drying. Soft
tissues and unneeded bone fragments were removed as much as possible to ob-
tain a small specimen. Tsueroijin [sic] covering was performed. The frag-
ment was stained with haematoxylin-eosin, and pathological, histological
studies were conducted with an optical microscope.
Findings
The Corti's organ, vascular system, and spiral nerve ganglia cells were
studied and compared with those of normal cats.
1. Corti's organ
Both outer and inner capillary cells retained their shapes fairly well,
with no signs of obliteration of the nucleus, or enlargement, swelling, or
244
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fusion of cytoplasm. Almost no changes were noted in supporting cells, such
as Deiter's cells or Claudius' cells (Photos 2 and 2').
2. Vascular system
Cell alignment in the surface layer was almost normal, with no indication
of attrition of cytoplasm, obliteration of nucleus, or change (Photos 3 and 3')
3. Spiral nerve ganglia cells
Spiral nerve ganglia cells assisted in maintaining the normal pattern
of the cells' internal structure, and virtually no changes, such as
nucleus contraction, enlargement, or disintegration, were seen (Photos 4, 4').
Conclusion and comments
In this experiment, we produced experimental organic mercury poisoning
in fully grown cats, or so-called acute poisoning, by administering 30 - 70
mg mercury for a period of from 20 - 40 days. We then performed biological
fixation and observed changes in Corti's organs, vascular system, and spiral
nerve ganglia cells. As anticipated, our examination under the optical micro-
scope did not reveal any great change, and did not differ from those of con-
trol cats. Such drugs as quinine, salicylic acid, alcohol, nicotine, arsenic
agents, lead, carbon monoxide, and dihydrostreptomycin are known to cause
toxic inner ear disorders. These, which all have an affinity with the audi-
tory organ, caused changes of various degrees in Corti's organ, especially in
the outer and inner capillary cells, spiral nerve ganglia, and the vascular
system. However, Mioki of our classroom claimed that in the case of organic
mercury, he found virtually no transfer of the aggregate mercury to the
inner ear. Even though mercury may not directly impair the inner ear as in
Minamata disease attributed to chronic organic mercury poisoning, it can be
assumed that some secondary changes occur in the inner ear. Based on our
experiment, we can say that in the case of acute poisoning from organic
245
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Normal cat
«#?""'.*"'
Cat administered organic mercury
r
t;
.'•2'
it
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*»
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i '
246
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mercury, no pathological or histological changes (under an optical microscope)
were noted in the inner ear as a result of organic mercury.
REFERENCES
1. Nozaka, Yasuji. Minamata Disease — Study on Organic Mercury Poisoning.
Kumamoto, 1966, pp. 139-148.
2. Nozaka, Yasuji, et al. Effects of Auditory Power, Vestibular Functions,
Sense of Taste and Speech Impairments in Minamata Disease. Japan
Otorhinology, Vol. 73, 1970, pp. 1006-1007.
3. Cho, Hatsuo. Hearing Power and Vestibular Equilibrium Function Impair-
ment in Organic Mercury Poisoning. Otolaryngology, Vol. 42, 1970,
pp. 165-170.
4. Fujisaki, Ryuzo, et al. Auditory Impairment in Organic Mercury Poison-
nig. Audiology, Vol. 14, 1971, p. 484.
5. Takeuchi, Tadao. Pathology of Minamata Disease — Study on Organic
Mercury Poisoning. Kumamoto, 1966, pp. 264-265.
6. Sakurai, Tokio. Study of Auditory Nerve Activity Potential Induced by
Round Window and Summating Potential. Japan Otorhinology, Vol. 64,
1959, pp. 1766-1784.
7. Wever, E. G., et al. Physiological Acoustics. 1954, p. 305.
8. Murai, Kazuo. Study of Auditory Nerve Activity Potential of Domestic
Rabbits. Japan Otorhinology, Vol. 72, 1969, pp. 1129-1139.
9. Galambos, R. and A. Rupert. Action of the Middle Ear Muscles in Normal
Cats. J. Acoust. Soc. Amer, Vol. 31, 1959, pp. 349-355.
10. Simmons, F. B. and D. L. Beatty. The Significance of Roundwindow-
Recorded Cochlear Potentials in Hearing. Ann. Otol., Vol. 71, 1962,
pp. 767-800.
11. Simmons, F. B., R. Galambos, et al. Serial Studies of the Onset and
Progressions of Drug-Induced Cochlear Damage in Cats. Archives of
Otolaryngology, Vol. 72, 1969, pp. 233-239.
12. Ouchi, Hitoshi, et al. Study of Permanent Electrode Method in Cochlear
Reaction. Japan Otorhinology, Vol. 67, 1964, pp. 426-427.
247
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13. Shiraiwa, Hosei. Study of Permanent Electrode Method in Domestic
Rabbits. Japan Otorhinology, Vol, 69, 1966, pp. 631-660.
14. Ogawa, Etsuji. Experimental Study of Attack of Dihydrostreptomyocin on
Auditory Organ. Japan Otorhinology, Vol, 71, 1968, pp. 217-232.
15. Otani, Iwao. Acute Experimental Study on Auditory Organ Toxicity of
Kanamycin. Japan Otorhinology, Vol. 71, 1968, pp. 688-707.
16. Takaya, Gochu. Experimental, Pathological Study on Genkai [sic] in
Minamata Disease, Especially the Effect of Methyl Mercury Compounds
on Cats. Kumamoto Medical Association Journal, Vol. 38, 1964,
pp. 100-139.
17. Ushikusa, Sadao. Experimental Supplement on Oral Administration of
Methyl Mercury Iodide to Cats. Kumamoto Medical Association Journal,
Vol. 39, 1965, pp.33-39.
18. Grizzle, C. and W. C. Cutting. Vestibular Apparatus Intoxication of
Experimental Animals with Streptomycin and Dihydrostreptomycin and
Mixtures. Acta Oto-Laryng., Vol. 43, 1953, pp. 421-427.
19. Henriksson, N. G. et al. The Caloric Test in the Cat. Acta Otolaryng.,
Vol. 53, 1960, pp. 21-32.
20. Simmons, F. B. Middle Ear Muscle Activity at Moderate Sound Levels.
Annals of Otology, Rhinology and Laryngology, Vol. 68, 1959, pp.
1126-1143.
21. Coats, A. S. Depression of the Click Action Potential by Attenuation,
Cooling and Masking. Acta Otolaryng, Suppl. 284,
22. Deatherage, B. G. and D. H. Eldredge. Latency of Action Potentials
in the Cochlea of the Guinea Pig. J. Acoust. Soc, Amer,, Vol. 31,
1959, pp. 479-486.
248
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8. STUDY ON PREVENTION AND TREATMENT OF MINAMATA DISEASE AND METHYL MERCURY
POISONING
Biochemistry Faculty, Toxic Research Facility,
Department of Medicine, Kumamoto University
Team member: Hitoshi Takahashi
Research assistants: Kimiko Hirayama, Etsuko Hirata
Kenichi Enami
Purpose of Study
The purpose of this study, which will have a great effect on human
health, is to seek biochemical and pharmacological supplemental methods of
examination of socially-feared organic mercury, especially methyl mercury,
with respect to its presence in the body, as well as its level; also, to
discover safe and effective methods of treatment in the event of possible
deposit in or sudden internal contamination of the body. Another purpose
is to further the knowledge concerning metabolism of methyl mercury in the
body, necessary to formulate treatment guidelines.
Summary of This Year's Report
As several items were clarified following publication of last year's
report, we shall first follow up on our observations of metabolism of methyl
mercury in the body, and on drugs for treatment. We shall then report on
the results of experiment as an approach to clinical applications, utilizing
drugs in examination and treatment.
249
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Results of study and findings
1. Subsequent findings on metabolism of methyl
mercury in the body
Many kinds of methyl mercury derivatives have been used in experiments,
and there exist equally various forms of methyl mercury in industrial
wastes. There are few or no research reports dealing with the possibility
of their being taken into the bodies of mammals, including humans. Speci-
fically, how and in what chemical form do they exist in blood, other body
fluids, tissue cells, bile, and urine, in a biological environment consisting
of a pool of numerous substances with pH of about 6-8? Reports are avail-
able concerning changes in distribution in animal bodies, based on utiliza-
tion of radioactive methyl mercury iodide (CPJj-";Hg-Cl;, and many quantitative
experiments in which methyl mercury adhering to tissue protein is dissolved
and removed with such acids as hydrochloric acid are being performed. In
time, a change occurs in the distribution of this methyl mercury in the body,
with mercury undergoing a gradual decrease in the liver and kidney after
concentration in those areas. Conversely, methyl mercury content in the
central nervous system begins to rise to a peak several days later. Con-
sidering that the discovery of the form of methyl mercury moving in blood
plasma during this period would be necessary for prevention of its movement
in the brain, we studied the form of low molecular methyl mercury found in
small quantities in the blood serum. Also, it was necessary to learn
whether such mercury compounds can pass into urine and bile, from the
standpoint of treatment.
9 On absorption
It was subsequently found that some methyl mercury contained in
fish flesh is dissolved by hydrochloric acid of stomach fluids and becomes
methyl mercury iodide, but, as in the case of ingestion of methyl mercury
iodide solution, it is not readily absorbed in that form, remaining for a
while on the epithelium of the digestive tract. But, as proteins are
digested and converted into amino acid, its cystine combines readily with
methyl mercury, and becomes methyl mercury cystine at a pH on the alkaline
250
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side in the intestines; also, methyl mercury which had been in stagnation
after merging with proteins in epithelial cells of the digestive tract is
freed by cystine in the process of absorption as methyl mercury cystine,
and by riding on the activity transport of amino acid is effectively and
rapidly absorbed. As in the case of amino acid, the principal path of ab-
sorption to the liver is past the portal vein. Since methyl mercury iodide
is rather insoluble in water, but soluble in fat, it was possible, when
administered with fat, to gain entry together with chyle into the lymphatic
stream and enter the entire blood stream by way of the thoracic duct. The
following experiment was, therefore, conducted.
An operation was performed on a rat about 300 g in weight, at which
time a small vinyl tube was attached to the thoracic duct. Following the
operation, the rat was placed on a fixed platform for one day. The next day,
at the moment when the chyle disappeared because of blood, an aqueous solu-
tion containing 1.25 mg (1.0 mg as Hg) of methyl mercury iodide — or the
same solution but with a small quantity of salad oil added — was orally
administered with a catheter. Subsequently, lymphs, up to a six-hour period,
were collected and measured for their mercury content. It was found that
the average content in the group of three mice administered an aqueous solu-
tion was about 1.1 yg, and in the group with an equal number of mice ad-
ministered with a salad oil mixture, 0.9 yg, or only 0.1% of the amount of
mercury administered, showing no difference between the two groups. At that
time, the average amount of mercury in the liver was 48 yg and 55 yg, re-
spectively, or an equivalent of 5%, a large amount of methyl mercury yet
remaining in the digestive tract.
The above established that methyl mercury was absorbed by way of the
portal vein system, and rejected the possibility of highly fat soluble methyl
mercury iodide entering the lymphatic stream along with absorption of fat.
Probably, when methyl mercury iodide was administered, it (methyl mercury
iodide) became stagnated in epithelial cells of the digestive tract, and
it was freed by low molecular SH compounds derived from subsequently absorbed
cystine or cystine from the blood stream, entering the portal vein as a
251
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component of such compounds. We previously reported about methyl mercury
cystine passing through the digestive duct walls and being absorbed at about
10 times the speed of methyl mercury iodide. This type is not only absorbed,
but can pass through the blood-brain barrier.
@ Migration in the brain
Our experiment was conducted on the belief that the principal factor in
cerebral migration of methyl mercury was in the form of methyl mercury
cystine; that methyl mercury iodide used in the experiment was also ingested
by some cell and combined with SH of its protein, and then freed later by
cystine, by combining with the latter to enter the blood plasma and pass
through the cerebral blood gateway, after which they were drawn into cerebral,
parenchymal cells. It was necessary for us to repeat various indirect experi-
ments because of the difficulty of establishing the foregoing, although it
would have been simple if a perfusion test of the brain in the absence of
blood corpuscles could have been performed.
We administered 2.5 mg (2.0 mg in Hg) of methyl mercury iodide dissolved
in 1 ml of biological saline solution, or an equal amount of the former mixed
with surplus cystine fluid and modified completely into a compound, at a
specific speed into the tail vein of male Wistar strain rats weighing about
200 g. A comparison was then made of mercury compounds by studying the
amount of methyl mercury in the brain over a given time (Figure 1) and in
the liver (Figure 2). It was found that there was almost no rise in the
mercury level in the brain after a lapse of 30 - 60 minutes following injec-
tion in the group administered methyl mercury iodide, but that a distinct
rise occurred in the group administered cystine compounds. This was true
also for the liver. Subsequently, however, both groups showed a similar
rising trend of the methyl mercury level in the brain and a lowering trend
in the liver. This was believed due to the fact that methyl mercury iodide
which had infiltrated the liver and other organs was, because of the cystine
252
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pool in the body, being guided by methyl mercury cystine and later behaved
in a completely similar manner. When discussing the infiltration of these
compounds in the brain through such an injection method, it would be best to
rely on results obtained within 60 minutes after administration to preclude
any chance of compounds undergoing changes.
tfi 2
^x.
to
0---MMC
• -- M M C Y
0 30 60
120
Time (min)
Figure 1. Changes over time of
mercury level in brain following
intravenous injection of methyl
mercury compounds:
MMC (methyl mercury iodide) and
MMCY (mixture of methyl mercury
cystine and 9 times mole cystine)
were intravenously
administered (2.0 mg mercury).
Subsequently, the cerebral mercury
level, 30, 60, 120, and 240 min-
utes after injection was studied
for each group of 3 mice at the
respective time
10
•-MMC
-MMCY
0 30 GO
240
Time (min)
Figure 2. Changes over time in the
mercury level in the liver after
intravenous injection of methyl
mercury compounds:
MMC (methyl mercury iodide) and
MMCY (mixture of methyl mercury
cystine and 9 times mole cystine)
were intravenously injected (2.0 mg
mercury). The mercury level in the
liver at various times following
administration is indicated. Three
mice were examined at any one time
Figure 3 reflects the result of a similar experiment, the mercury level
being studied after a 60-minute period following administration. In the
brain, the methyl mercury iodide-administered group reflected a value close
253
-------
O
§
MMC
o
0
0
MMCY
X4CY
8
MMCY
XQ^Y
8
MMCY
X19CY
40
30
20
10
0
' o
8
MMC
o
O
o
MMCY
V4CY
0
8
MMT, V
X9CY
O
0
MMC Y
X19CY
Figure 3. Mercury level in brain and liver at
time of density change of cystine:
MMC (methyl mercury iodide), MMCY (methyl mer-
cury cystine) and cystine of various density
(2.0 mg Hg) were administered intravenously
to rats. Mercury level in the brain and liver
one hour after injection is indicated
to that of the untreated brain; the cystine compound-administered group
showed a high intake level, irrespective of the amount of surplus cystine
administered. The cystine compound intake was also notable in the liver.
It was once considered that, because of solubility in fat, methyl mer-
cury iodide would more readily infiltrate into a brain which has fatty mate-
rial. However, water soluble methyl mercury cystine was able to infiltrate
more easily. This could not be explained in terms of fat solubility.
Figure 4 reflects the results of an experiment wherein three compounds
— i.e., synthesized, unadulterated methyl mercury iodide, methyl mercury
cystine, and methyl mercury acetylcystine —were added to blood, and their
distribution into blood corpuscles and blood plasma was determined over a
254
-------
After
6 min
After
30 man
After
60 min
After
90 min
0.004.
0.003
0.002
0.001
n
-
r-i-'t-i j
C1.C.VAC CLCVAC CLCYAC CLCYAC CLCVAC CULIAC CLC1AC CLOAC
Bp Be Bp Be Bp Be Bp Be
Figure 4. Distribution of methyl mercury deriva-
tives in blood:
0.5 M mole each of methyl mercury chloride, methyl
mercury cystine, and methyl mercury acetylcystine
was added to 3 ml human blood and mixed well. Its
distribution in blood corpuscles and blood plasma
at the end of 6, 30, 60, and 90 minutes is shown
(6N HC1 was added to 200 ]il of sample, extracted
with 1 ml of benzene and 4 yZ subjected to gas
chromatography)
Bp — in blood plasma; Be — in blood corpuscles
given time. The latter two compounds reflected almost the same distribution
rate, whereas methyl mercury iodide immediately entered into the blood cor-
puscles. In order to enter the brain, it would be necessary for it to assume
another shape and be released from inside the corpuscles to blood plasma.
The cystine pool in the body is believed to become involved here.
As an experiment in support of our belief, 10 male mice of the Wistar
strain, weighing about 200 g, were divided into two groups. One group was
fed synthetic feed containing relatively little cystine, and the other group -
the same feed but containing 0.5% cystine. From the sixth, day onward for a
period of five days, 1 mg methyl mercury iodide was dissolved in biological
255
-------
saline solution and administered daily by muscular injection to each group,
for a total of 5 rag. On the twelfth day of the experiemnt, they were de-
capitated, blood drained, and the mercury level in the brain and liver was
measured. It was determined that in the group which did not ingest cystine
there was little migration of methyl mercury from the liver and, consequently,
a low mercury level in the brain (Figure 5).
Brain
Liver
10
•
o
&
o
synthetic
feed
o
8
0
Synthetic
feed 4-
cystine
50
40
30
20
10
0
6
o
o
Synthetic
feed
o
o
o
o
Synthetic
feed +
cystine
Figure 5. Effects of low cystine feed and cystine-
supplemented feed on mercury level in visceral organs:
Mercury level in brain and liver of rats. Rats were
administered synthetic feed containing a small amount
of cystine and also synthetic feed containing a
greater amount for a period of 10 days. During the
last 5 days, they were also administered 1 mg methyl
mercury iodide, or a total or 5 mg, by muscular injec-
tion, and decapitated and drained of blood 48 hours
after the last injection
The intake difference will probably become larger if the animal can be
made to survive even under the most severe conditions lacking cystine. The
use of halogenized benzene to cause dissipation and deficiency of cystine as
mercaptan acid weakens the animal excessively, and for that reason has not
yet been successful.
256
-------
® Discharge into the bile
When methyl mercury was administered by muscular injection to animals,
a considerable amount of methyl mercury appeared in the bile for a while
thereafter. Figure 6 reflects the methyl mercury level in the bile of a rat
during a two-hour period of time. The rat involved, about 250 g in weight,
was administered through muscular injection 1 mg of methyl mercury iodide
daily in biological saline solution, or a total of 5 mg in a five-day period,
with methyl mercury being drawn from the rat on the 12th ? 24th} 36th? and 48th
days. Even at the end of 48 days, discharge continued. A considerable amount
was discharged in the bile daily. Our calculations may appear to be off, due
to such a constant discharge. However, as described in our next experiment,
this is because this form of methyl mercury is mostly in the form of readily
re-absorbable methyl mercury cystine, which circulates in the liver and
intestines.
Figure 8 reveals the results of an analysis of a portion of bile derived
on the 12th day under the improved analytical method (Figure 7) for methyl
mercury compounds, integrating isolation by negative ion exchange, as ex-
plained in our previous report, and quantitative determination method by gas-
chroma to graphy. As can be seen, much of the methyl mercury is in the form of
methyl mercury cystine, with some methyl mercury acetylcystine present. Under
this improved method, it is possible to concentrate mercury compounds in the
fluids without destruction. Therefore, thin layer chromatography was con-
ducted on a specimen, and we were able to establish by comparison with syn-
thetic products that they were the actual compounds. We were unable to dis-
cover at this point any trace of methyl mercury iodide used in injection in
the bile. It is possible to conclude that this effective circulation in the
liver and intestines of methyl mercury cystine is a key factor in continued
mercury residues in the animal body. This knowledge should help when examin-
ing methyl mercury found in the bile, or in treatment by preventing circula-
tion in the liver and intestines in a manner to be described later, and
effecting elimination through excrement by connection to that part of the or-
gan which does not absorb mercury.
257
-------
30«
JO-/,
12 24 jG 48
(Day no.)
Figure 6. Quantitative
changes over time of
methyl mercury compounds
in bile of rats adminis-
tered methyl mercury:
Methyl mercury level ex-
creted within 2 hours
after collection of bile
on 12
,th
th
24th,
36
th
and
0.05-
0.04'
0.03
0.02-
0.01
DOWEX-1-CL-
IfcctCL
F 1 2 3 4 5 6
CHjHgCL
12345678 9101112131415161718 19202122232423
CHjHgCY CHjHgAC
Figure 7. Chromatography showing separation of
pure methyl mercury compounds:
Extraction using Dowex-1-Cl-resin (1.2 x 18 cm)
and gradual increase of NaCl (0.05M phosphoric
acid buffer solution pH 7.6) of methyl mercury
iodide, methyl mercury cystine, and methyl
mercury acetylcystine (50 y moles each); hydro-
chloric acid added to each extracted solution
with extraction by 2 ml benzene; 1 yl subjected
to gas-chromatography
Discharge into urine
481"" days from rats ad-
ministered, by muscular
injection, 1 mg/day of
methyl mercury iodide
over a 5-day period (as
methyl mercury iodide)
It was previously reported, and many
people are aware, that excretion of methyl mer-
cury in urine is extremely serious. It is pos-
sible that at the time of its excretion there
are, aside from the importance of low molecular
substances in blood plasma, a minute amount of
methyl mercury in blood plasma, which probably is in the form of methyl mer-
cury cystine carried to the brain. Methyl mercury on this amino acid is
apparently highly re-absorbable, for intravenous injection of synthetic methyl
mercury swiftly into a rat did not result in its elimination in the urine.
258
-------
0.005
0.004
0.003
0.002 '
0.001
F 1 2 3 4 5 6
12345678 910 1112 13 14 35 16 17 18 1<) 2021 2223 24
Figure 8. Chromatography of isolation of bile:
Bile of rat administered 1 mg methyl mercury idodide
for 5 days was isolated according to the method
outline in Figure 7
Figure 9 reflects the findings obtained as a result of surgical placement
of a catheter in the peripheral ureter of a male rat about 400 g in weight
for taking urine specimens at a specified time. Five \i moles methyl mercury
iodide, methyl mercury cystine, or methyl mercury acetylcystine, together
with phenolsulfophthalein (PSP), were injected into tail veins to observe
the secretion of chromosomes and methyl mercury. No excretion was observed
in the form of the first two, but a considerable amount of methyl mercury
acetylcystine was excreted during a short 20-minute period. In methyl mercury
adhered to amino acid, the amino group clogged with acetyl group showed poor
re-absorption capability in the kidney, accounting for the good "clearance"
into urine.
Compounds mixed with this acetylcystine are generally known as mercaptan
acid. It is a well known fact that when animals are administered halogenized
benzene, the mercaptan acid-containing body purified in the liver is secreted
259
-------
O.D
0.3'
0.2
0.1
PSP
O.D
0.3
Hg (/-'g) J0 20 30 40 50 60min- us
2 A 2H
BSP
O.D
0.3
0.2
o.:
10 20 30 40 50 60 min.
^
PSP
10 20 30 40 50 60 min.
A — ft—ft — ^ — *•— *•
10 20 30 40 50 60miu 10 20 30 40 50 ftOmin. 20 20 03 40 5U 60-nin.
CHsHgAC. CHsHgCL CHsHgCV
Figure 9. Excretion from kidney:
Amount of methyl mercury compounds excreted from peri-
pheral ureter of a rat about 400 g in weight was ob-
served when intravenously administered with 5 u moles
methyl mercury iodide, methyl mercury cystine, or methyl
acetylcystine. PSP had been added to methyl mercury
compounds
in the urine. On the belief that such a purification function may occur even
with respect to methyl mercury, we tested for methyl mercury acetylcystine as
a metabolic product, and finally succeeded in discovering it, even though in
a small quantity, in the urine of methyl mercury poisoned rats. Figure 10
shows the results of an experiment in which rats which had been administered
by muscular injection 1 mg per day of methyl mercury iodide solution for
five days were also administered, every other day, 12.1 mg (100 y moles)/2 ml
biological saline solution, 16.3 g (100 y moles)/2 ml acetylcystine. Urine
excreted during the subsequent 24-hour period was then examined according to
the method outlined in Figure 7. In all cases, peaks denoting methyl mercury
acetylcystine (can also be termed methyl mercury mercaptan acid) were observed,
which was not unusual in the case of acetylcystine-administered animals. As
such peaks were found also in other animals, we prepared other similarly
260
-------
0.003
0 002
0.001
.rfflTh-, „
Fl 2 3 4 5 6
12345678 9:011I2!3U1516:7!S19:02122232425
0.001
F1 2 34 5 6
1234567C 91011!21314151617!81920212Z232425
n
poisoned rats and collected
and condensed their urine
by chromatogic separation,
and established the pre-
sence of methyl mercury ace-
tyleystine when it matched
with the synthetic sample
under the secondary devel-
opment process of thin layer
chromatography. It was
possible to find such meta-
bolic products, although in
a small quantity because of
their characteristics
readily appearing in urine.
In the results of the
experiment reflected in
Figure 11, the aim was to
cause, through administra-
tion of acetylcystine, ex-
cretion of methyl mercury
in the form of mercaptan
acid, which is readily dis-
charged by urine. We ad-
ministered 16.3 mg/2 ml
acetylcystine mixed with PSP
intravenously to two groups of rats: one group — 10 days after muscular in-
jection of a total of 5 mg of methyl mercury iodide, and the other group —
one hour after having been injected 2.5 mg/2 ml of methyl mercury iodide. A
rise in the excretion of chromosomes and methyl mercury was noted. Additional
efforts are thus being exerted, so that the characteristics of this substance
can benefit diagnosis and treatment.
0.004
0.003
0.002
0.001
rr
F 1 2 3 4 5 6
_n
12345678 910111213141516171819202122232425
Figure 10. Analysis of urine following
the administration of table salt (top) ,
cystine (middle) and acetylcystine
(bottom) to methyl mercury poisoned
rats rats
261
-------
O.D
0.4,
0.3
O.Z
0.1
PSP
O.D
0.3
0.2
0 inj 10 20 30 40 50 60
PSP
10 20 M 40 SO 60 In; 10 20 30 « SO (0 70 c n
10 20 30 40 50 60 Ini m 20 30 40 50 SO 70 din.
A.C
Figure 11. Clearance from the kidney:
Left chart is an analysis of urine extracted
from the bladder of a 250 g rat on the tenth
day following muscular injection of 1 mg methyl
mercury iodide for 5 days
Right chart reflects the results of intravenous
injection of 16.3 mg acetyl cystine with PSP,
an hour after injection of 10 \i moles of methyl
mercury + PSP
2. Therapeutic agents
Excluding therapeutic agents now under experimentation, we turn our
attention to Pyridoxine-4-thiol and Pyridoxine-5-thiol, which we believe are
the closest to practical application. These two substances have a structure
resembling vitamin B,, and a SH radical easily bondable with methyl mercury.
We previously reported on their effect in lowering the mercury level in
visceral organs (brain and liver) of methyl mercury poisoned rats through sub-
cutaneous injection.
Figure 12 shows the results of oral administration of these two sub-
stances, and also the oxidized form of Pyridoxine-4-thiol, on a specific day
262
-------
60
50
— 40
s:
~a 30
20
10
PIN-4SH
BO
„
~"
50
1 -~ 40
| S
V. 30
20
10
n ,
P I X - 4 S S
B
;
ny^/
n— —i- . .- ... _._i- J «r
63
-=30
P1N-5SH
123456789
t *tt
12345B7S91U
Do-tr 12
uay t
123456789 10
Day
Figure 12. Level of methyl mercury excreted in
urine after oral administration of various drugs:
Methyl mercury excreted in urine after oral ad-
ministration of 22 mg Pyridoxine-4-thiol, oxi-
dized form of Pyridoxine-4-thiol, or Pyridoxine-
5-thiol on the 2nd, 6th, 7th, and 8th day follow-
ing intravenous injection of 2.5 mg methyl mer-
cury iodide (shown as mercury level)
during a 9-day period, when about 200 g rats were intravenously injected with
2.5 mg methyl mercury iodide and 22 mg Pyridoxine-4-thiol. The methyl mercury
level in the urine was determined by gas-chromatography. Even in oral adminis-
tration, there was sufficient inducement of methyl mercury toward urine, the
greatest effectiveness being observed in the order of Pyridoxine-4-thiol >
oxidized form of Pyridoxine-4-thiol > Pyridoxine-5-thiol. The effectiveness
of this oxidized form suggests that it becomes a monomer, upon reduction in
the body.
Figure 13 reflects the mercury induced in urine and excrement when, as in
the case above, equal moles (22 mg) of Pyridoxine-4-thiol and -5-thiol were
orally administered continuously for a period of 7 days to approximately 200 g
rats which had been intravenously injected with 2.5 mg of methyl mercury
iodide. Both caused inducement of mercury toward urine and excrement, with
Pyridoxine-4-thiol showing the greatest effectiveness. As Pyridoxine-5-thiol
becomes an energizer of cerebral metabolism known as Pyrithioxine (Figure 14)
when oxidized in the body, its ability to remove mercury may be somewhat
weaker, but may be highly effective from the symptomatic and functional aspects.
We wish to utilize this if we can correctly determine the type of treatment
required for poisoned animals , as explained later.
263
-------
100
90
SO
70
„ 60
> 50
40
30
20
10
0
P IN-4 SH
P IN-
p Urine Excrement Urine
^— i
1 *
^ S*
LTj <»
L 3a
20
-1 10
. ^. n
"^
<
^
3
"$!>•
40'
20.
10
k
-5SH
Excrement
I?
3? 50
40
n^ju "'
^ H 23
J
1234567' Qav 1234567 Qav" 1234557
10
,-,
LJ
pay 1 2 3 4 5 6 7 Day
Figure 13. Mercury level in urine and excrement
after continuous administration of drugs for 7
days :
Aggregate mercury level in urine and excrement
upon continuous oral administration for 7 days
of 22 mg Pyridoxine-4-thiol and Pyridoxine-5-thiol
subsequent to intravenous injection of 2.5 mg
methyl mercury iodide
Agents to capture methyl
mercury of the type dis-
charged by bile
CH2OH
HO N^^-r CI!2 ~ S - S - CH2
Figure 14. Structure of Pyri-
thioxine
It was previously stated that the
reason for prolonged excretion of methyl
mercury into the bile was circulation
between the intestines and the liver. As a means to prevent re-absorption,
Substances with a capability to bond with methyl mercury and not prone to
digestion and absorption are effective. With this in mind, the use of reduced
pulverized human hair was beneficial. We were able to utilize SH synthetic
resin, developed by Kokoku Jinken Co. Of the polyacrylic acid type substance,
1 gram of the product indicated an absorption capability of 277 mg methyl
mercury iodide at pH 7.4.
Eleven male Wistar strain rats weighing about 220 g were intravenously
injected in the tail veins with 2.5 mg methyl mercury iodide dissolved in 1
ml of biological saline solution, and put into cages. Four rats of the
264
-------
control group were fed commer-
cially available pulverized
feed, and another group of 7
rats were given the same feed,
but with 1% of SH resin added,
for a period of 12 days. Dur-
ing this period, excrement and
urine were separately collected
daily, and their mercury level
determined. On the thirteenth
day, they were decapitated and
drained of blood, and the mer-
cury levels in the brain,
liver, and kidney measured.
Figure 15 is a graph of the mer-
cury levtl in the excrement of
the animals. The value of the
group administered SH resin
was 2-3 times more than in
the control animals. Figure 16
is a comparison of the mercury
level in visceral organs. In
the treated group, mercury in
the liver was significantly low
''PxO.O'ij) 5 no significant dif-
ference was noted between the
brain and the kidney.
1COO
750
500
250
o—
Resin administered
Control
6 7
9 10 11
Figure 15. Effect of SH resin in causing
excretion of mercury in excrement:
Level of mercury excreted in excrement of
group of rats administered feed contain-
ing 1% SH resin and by control group, sub-
sequent to intravenous injection of 2.5
mg methyl mercury iodide
In addition, 0.2 ml biologi-
cal saline solution in which methyl mercury iodide had been dissolved to make
a density of 1 rag/ml was administered in both thighs (total amount, 400 ug)
of each of 48 DD-strain mice weighing about 17 grams. Divided into two groups
of 24 mice each, one group was fed commercially available pulverized feed,
265
-------
Liver
Kidney
Brain
10
u
Me«n± Sd
M
11.08+0.61
Treat .
•
<,
s
7.24il.65
3ontr.
40
20
-
^
25.53+1.34
Treat.
1
*
•*
24 30 A 5 I
3ontr .
" "
*
i
2 03- 0.23
Treat.
•
•
r
l.SliO 3!
Contr.
Figure 16. Changes in mercury level in visceral organs
due to oral administration of SH resin:
Level of mercury in visceral organs of group of rats
provided with feed containing 1% SH resin for a period
of 12 days, and of the group supplied with ordinary
feed, subsequent to intravenous injection of 2.5 mg
methyl mercury iodide
and the other group was fed the same but containing 1% SH resin, for 20 days.
On the 2lst day, they were decapitated and their blood drained. Aggregate
mercury level in the body was then determined. The average value and the
plus or minus difference was 94 +_ 25 pg for the experimental group, and 108. ±
27 yg for the control group. The significant difference was 0.1 > P > 0.05.
Prolonged administration of SH resin inhibits weight increase. Since a
greater effect can be anticipated by use of reduced, pulverized hair, we are
currently considering the use of another animal protein for the therapeutic
method.
3. Experimental administration of drug inducing
methyl mercury in urine, as a supplemental
examination
As Pyridoxine-4-thiol can strongly induce methyl mercury in the body
toward urine and also lower mercury level in visceral organs, we conducted
266
-------
an experiment to determine whether it can be utilized as a supplemental
examination method for detecting residual methyl mercury in the body.
We administered 2.5 mg methyl mercury dissolved in biological saline
solution intravenously to rats weighing about 200 g, and two days later,
varying amounts of Pyridoxine-4-thiol were administered orally or through
abdominal cavity injection. When the mercury level induced toward urine was
measured at the time of the above-described administration, the increase of
mercury excretion was commensurate with the amount administered; also, a con-
siderable amount of mercury was found even where only 2 mg/200 g had been
administered. Where a large dosage was involved, oral administration was
more beneficial in inducing mercury toward the urine, probably due to high
blood density over a longer period. After one month, when the mercury level
in the body greatly decreased (half-life is said to be 7 days), the animals
were once again treated in the same way as before. It was found that a small
amount cf mercury , commensurate with the dosage administered, was being
excreted (Figure 17). Because of extreme sensitivity to methyl mercury in
1
10'
su
.so
;.
"""'
rt
40
.id
10
Arcer j. aay
40
„ "3"
— ''^T =20
^"^ ' 10
Aitei
- ; - — " — '
/„,-'' 0 li. JH
40
-/ ^3°
•
r"''"'
0 l.l 20 50 100 0 10 20 30
PIN 4SH
mg kg
month
1"°
1'IN fall
p,.!02
PU JV
mg lg
Figure 17. Relationship of amount of PIN-4-SH ad-
ministered to amount of mercury excreted in urine:
Aggregate level of mercury excreted in urine upon
oral administration and abdominal cavity
administration O of various Pyridoxine-4-
thiol, one day after and one month after intravenous
injection of 2.5 mg methyl mercury iodide
267
-------
gas-chromatography, 1 pg of methyl mercury chloride was added to 100 ml urine;
the benzene was extracted and transferred to glutathione solution. Finally,
when extraction was achieved with 2 ml benzene, an approximately 70% recovery
rate upon injection of 5 yZ was sufficient to conduct measurement.
Hoping that this method might disclose any residual methyl mercury, if
any, in cats inhabiting the Minamata district, we administered Pyridoxine-4-
thiol (20 mg/kg) to three cats, and attempted to measure the mercury level
in their urine, but not enough was excreted to permit a measurement. We are
studying the toxicity of this drug in the hope that the drug can be used to
treat those with possible methyl mercury contamination, such as tuna fisher-
men and others with Minamata disease symptoms. No strong toxicity, however,
has been noted so far.
4. Effectiveness of therapeutic agents on methyl
mercury poisoned animals
In order to determine the effectiveness of therapeutic agents in the
elimination of mercury, animals having a specific amount of mercury in their
bodies are required. We administered drugs to them, measured the amount of
mercury excreted or in their visceral organs to determine the effectiveness.
When an increased amount of mercury was administered, the animals exhibited
loss of control of movement, particularly of their hind legs, loss of appetite,
loss of weight, and went into a stationary state, with extreme irregularity
in the mercury level in visceral organs. Determination of effectiveness of
any therapeutic agent was thus made difficult. Yet there was great interest
in whether any improvement could actually be effected in their ill conditions.
Treatment was rendered to diseased rats, but most died during the early
stages of treatment, without any indication of the effectiveness of treatment.
As a new method of treatment, we recently acquired an electronic scale
to monitor and record the animals' actions. Thus, before the animals' condi-
tions could deteriorate to the point where further treatment would be futile,
unusual symptoms were detected and therapeutic drugs were administered.
268
-------
2 3 4 5 6 7 8 S 10 11 12 13 14 15 16 !7 IS 19 :o :'l 72 2J
Figure 18. Changes in body weight of stricken mice
and day of death:
Methyl mercury iodide was administered for 10 days;
of the 7 mice which showed an abnormal condition when
observed with the electron scale, one group of 3
mice was treated with Pyridoxine-4-thiol, and the
other group of 3, with 0.9% saline solution, all
from the 12th jay an(j ±n the abdominal cavity.
PIN-4-SH treated group — no great change in weight,
one death; 0.9% saline solution treated group —
great change in weight; all died
Each of the 10 male (DD strain) mice weighing about 20 g was supplied
with feed consisting of a mixture of methyl murcury and fish protein, remov-
ing any bitter taste. Pulverized feed was then added and solidified, and
300 ug methyl mercury iodide was put into 5 g feed, the daily portion for a
mouse. Body weight was taken every two or three days, and the animals'
actions monitored and recorded every 10 minutes during the morning with the
electronic scale. About seven mice lost some weight, and their actions slowed
down during the 10-day period. Thus, three mice each were selected from the
two groups of mice formed. One group was administered biological saline
solution, and the other group — the same, but with 3 mg of Pyridoxine-4-
thiol added. Injections were made into the animals' abdominal cavities for
a period of 10 days. Regular solid feed was supplied. Figure 18 shows the
impact of treatment on body weight and their lives; Figures 19 and 20 give a
record of findings using the electronic scale of mice which recovered after
treatment, and of mice which died without receiving any treatment. We
269
-------
~>
r ,\>-;v-ȣva
Figure 19. Activity of stricken mice
as determined by electronic scale
(PIN-4-SH treated cases):
1st day — normal movement (before
administration of Hg) 6th day —
normal movement (during administra-
tion of HG); 10th day — statical
movement (Hg administration suspended
the following day); 12th day —
statical movement (administration of
PIN-4-SH commenced); 2ist day — re-
covery of movement (during PIN-4-SH
administration); 23rt* day — normal
movement (P1N-4-SH administration
suspended)
}
™~».jj
Figure 20. Activity of stricken mice
as determined by electronic scale
(0.9% saline solution administered
cases):
1st day — normal movement (before Hg
administration); 6th day (some stati-
cal movement (during administration
of Hg); 10th day — statical movement
(Hg administration suspended the fol-
lowing day); 12th day — statical
movement (0.9% saline solution ad-
ministration commenced) 16th day —
some recovery of movement (during ad-
ministration of saline solution);
2lst day — statical movement (death
on following day
realize the need for repeated experiments hereafter in order to come up with
an effective method of treatment for methyl mercury poisoning.
Conclusion
As a result of this study, we were able to enhance our knowledge of
biological metabolism of methyl mercury and apply it in formulating guide-
lines for treatment. We wish to continue our study on effective treatment,
examination and preventive medicine to arrive at a general method of treat-
ment. We wish lastly to acknowledge the receipt of scientific research
assistance funds from Kumamoto Prefecture for this study.
270
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APPENDIX
TRIAL APPLICATION OF COMPUTER CARDS FOR USE IN
EXAMINATIONS FOR MINAMATA DISEASE
Minamata Disease Research Team, Department of
Medicine, Kumamoto University
In order to promote efficiency in examination of Minamata disease, a trial
card was completed after study by all departments concerned to provide selec-
tion of patients through the Tanac-type computer. By means of this card, it
will be possible to automatically categorize cases into confirmed Minamata
disease, possible Minamata disease, suspected Minamata disease, or doubtful
Minamata disease. The card shown in Figure 1 was prepared on the basis of
important elements of information furnished by various departments.
The upper six columns are for neuro-internal medicine affairs. Main ele-
ments of information are printed in a block, with space on its right being
blank. This space is to be darkened in the event that positive findings are
indicated. The Tanac-type computer will automatically read the shaded area
and make a selection of cards containing the appropriate data. The lower col-
umns are reserved for ophthalmological, otorhinological, and neurological
matters.
About 2/5 of the space on the right is not linked to the computer selec-
tion, being used to enter such information as name, sex, date of birth,
findings, etc.
Figure 2 is a sample card with entries on Minamata disease
(Tsutsui, Ophthalmology)
The assistance of Professors Araki of Kawasaki Medical College and Igata
of Kagoshima University and Assistant Professor Okashima of Kumamoto Univer-
sity in programming this card is gratefully acknowledged.
271
-------
*" "2 -
3 to
0) o ' •'. x •'- * "i i
co ; !- T
•H g ;-••..;
T3 0 S
n> ti i • '
4J (0 'i - •
to C . j " i ."'!•".
id $ r j M- !- ._. .'
: K? -:r..-L
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l ' -~! .' ' i ' "
i: r! Ti .'
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t vr
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C W
o cu
•H >
'O *H
o -w
. i
4J tfl
P. S
d'e'f^'g^ ^ **M 1 ii j k: '
Figure 1. Minamata disease examination card:
a — visual constriction; b — visual sedimenta-
tion; c — eye movement; d — hearing difficulty;
(left); e — hearing difficulty (right); f — eye
disease; g — strabismus; h — bone; i — sense
of smell; j — intellect; k — mercury
translator's note. Column headings at the top
of the card are all illegible in the original
foreign text.
Translator's note. Illegible in the original
foreign text.
*
I
cu *o
CO M
cd to
CD CJ
CO
ri c
*l3 O '
-H
rt jj
4J cO
fll r4
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,
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ra*
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tl-:.
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t
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. • i ,' r\
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Minamata Disease si to
1 4J
: u-i o
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i • f.-r yv« i :T'! ) ; ' j'i, i T
Figure 2. Minamata disease examination card
translators note. Illegible in the original
foreign text.
272
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IV. GENERAL FINDINGS AS RESULT OF EXAMINATION
All members of Minamata Disease Research Team
Department of Medicine, Kumamoto University
Our first year's report covered the results of the epidemiological sur-
vey of all residents of our research area, particularly on how we collected
information on disorders through questionnaire surveys or general examina-
tions and selected those individuals with neurological disorders who may pos-
sibly have contracted Minamata disease. Specifically, out of 304 households
or 1119 individuals (520 male, 599 female) of Minamata district (Yudo, Dezuki,
Tsukiura), 459 households or 1871 individuals (902 male, 969 female) of Go-
shonoura district (Ariashiguchi), and 278 households or 1180 individuals
(570 male, 610 female) of Ariake district (Akazaki, Zushi, Oura), the latter
as control arta (although this was inappropriate), those with possible neuro-
logical disorders numbered 315 (33.7%), 135 (8.5%), and 29 (3.1%) in Minamata,
Goshonoura, and Ariake districts, respectively.
This year, we classified and examined the foregoing individuals into
those with Minamata disease, possible Minamata disease, undetermined and re-
quiring further observation, other disorders, miscellaneous. We wish at this
time to report on the results of general studies, based on detailed examina-
tions by the Neuropsychiatric Departments and epidemiological and clinical
observations (ophthalmological, otorhinological, pediatrics, and minute
examinations).
Findings
1. The following cases were diagnosed this fiscal year (until the end
of March, 1963) by the Neuropsychiatric Department:
273
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A total of 245 patients (113 male, 132 female) were examined from Mina-
mata district. Of these, those confirmed as probable cases of Minamata
disease numbered 191 (91 male, 100 female) or 78.0%; those with possible or
doubtful affliction — 20 individuals (9 male, 11 female) or 8.2%; undeter-
mined — 24 (9 male, 15 female) or 9.8%; other ailments, 12 (5 male, 7 female)
or 4.8%; and healthy individuals and unknown cases — 1 each.
From the Goshonoura district, a total of 134 individuals (61 male, 73
female) were examined. Of these, probable cases numbered 25 individuals
(13 male, 12 female) or 19.4%; possible or doubtful cases — 34 individuals
(21 male, 13 female) or 25.4%; undetermined — 30 individuals (12 male, 18
female or 22.4%; other ailments, 34 individuals (11 male, 23 female) or 25.4%;
unknown — 1, and virtually no disorder in 10 individuals.
From Ariake district, a total of 23 patients (12 male, 11 female) were
examined. Of these, those having all of the major symptoms and confirmed as
Minamata cases numbered 5 individuals (4 male, 1 female) of 21.7%; those with
all of the Minamata disease symptoms except for articulation difficulty or
other ailments— 3 (0 male 3 female) or 13.0%; those with symptoms similar to
those of Minamata disease — 2 (2 male, 0 female) or 8.7%; undetermined — 9
(5 male, 4 female) or 39.2%; other ailments — 2 (1 male, 1 female), and
others — 2.
2. With the participation of members of the Epidemiological and Clini-
cal Departments, there was sufficient basis for the findings.
During the examination, all clinical symptoms related to Minamata
disease were probed. Major symptoms included unique sensory disorders (such
as those on the area of the mouth, extremities of limbs, or throughout the
body; senses of touch, pain, warmth, coldness, position, motion, etc.), loss
of coordination (impairment in walking straight, turning right), standing on
one leg, bending backwards, squatting, difficulty in following instructions,
foot ailment, difficulty in getting up or lying down, resilience, penmanship,
line stretching, imitating, etc.), articulation difficulty, field of vision
274
-------
constriction, abnormality of eyeball movement, and hearing difficulty —
especially involving the rear labyrinth. Others included such motor disorders
as difficulty in walking, tremor, loss of energy, increase or decrease of
muscular tension, reflex disorder, limping in one leg, muscular atrophy, etc.
In the psychiatric field, intellectual and emotional disorders were observed,
as well as mental diseases in special cases. Observations were conducted from
all aspects, including senses of taste and smell and dysphagia.
The utmost efforts were made to avoid any erroneous findings, taking
into consideration proprioceptive symptoms and various other test results.
When there was a probability of mercury contamination as indicated by
epidemiological tests accompanied by the outbreak of complete major symptoms,
the case was diagnosed as a probable Minamata disease case. If the symptoms
were considered to be unique, encompassing the vast field of cerebral cortex
and cerebellum and peripheral nerves (sensory and articulation difficulty,
loss of coordination, constriction of visual field, hearing difficulty, and
intellectual-emotional obstructions), the case was treated as involving Mina-
mata disease even in the absence of major symptoms. An example of this would
be abnormality of eyeball movement, rather than constriction of the visual
field. In the case of other symptoms where they could not be distinguished
from other ailments, such matters as positive findings of mercury tests,
serious contamination of family members, and uniqueness of sensory disorders
were taken into consideration before the case was judged to be Minamata
disease related. Cases having all the required symptoms but without the
presence of mercury or absence of any seriously contaminated family member
were treated as possible or doubtful cases. This means that while many Mina-
mata disease patients come under this category, a definitive medical decision
was difficult. By undetermined is meant cases in which further monitoring is
required, such as where individuals reside in a contaminated district and
consume fish and shellfish, but display few symptoms of the disease. This
category is likely to include those with a slight degree of disease.
275
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Based on overall observations, medical determinations were made as
follows (see table).
TABLE 1
District Minamata
Determinat ion j
Minamata
disease' 1
Probable
Minamata
disease
Undetermined
Other
ailments '
Unknown
Sound
health '
Aggregate
total
N.D.
191 [ ° 11
20 ;« ,;
*>{$ 13
12 ( 5 5
12 i 9 7
j f S 1
1 1 9 0
1 1 9 1
„.- < 5 113
•"J \ 9 132
,G.d.
i-n f s 71
Jou i 9 79
20 1 9 13
( ± Q
r) t ' O J
~4 1 9 15
0
0
, (3 0
1 IP 1
inz / <5 88
190 1 9 107
Goshonoura
N.D.
' ,- f S 13
~° I? 12
,, f 8 21
34 (. 9 13
i ,,n f S 12
I 3° I ? IS
i o, f 5 11
: 34 1 9 23
1 , C9 0
1 l Is i
f 4 4
I 9 6
ru f o 61
i Jv34 19 73
G.d.
16 • *
8 19
q f 5
I
5 f 5
' 0
i I 9
OQ ' 0
39 i v
S
8
i
1
4 !
5
3 '
2 !
i
i
0
1
17
A.riake
.N.D:
- f :• i
^ 1 c •*
2 1 ? o
q f 5 5
" (. ? 4
9 fo 1
- 1? 1
0
„ f .1 0
- I 9 2
23 f 3 12
2ci (. 9 11
G.d.
< 3 4
° i 9 4
1 f 3 °
2 1 9 U
i Q f 6 5
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1
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rt " O i
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0
., i a ')
"192
.-., f o 12
-J 1? 11
Recognized by: rs 3f,(Death - 1)
March 30, 1973 M\9 45 ,. _
Remarks: Figures for the Neuropsychiatric Department shown in III - 4
are as of May,1950, while those in this table are as of the
end of March.
N.D. — Neuropsychiatric Department; G.d, — general deter-
minat ion
Individuals from Minamata district who were subject to general examina-
tions totalled 195 (88 male, 107 female). Of these, 150 (71 male, 79 female)
or 77.0% were determined to have Minamata disease; 20 (7 male, 13 female)
or 10.2% were diagnosed as probable cases; 24 (9 male, 15 female) or 12.3%
were undetermined, £nd others — 1.
From the Goshonoura district, a total of 39 persons (22 male, 17 female)
were given general examinations. Of these, 16 (8 male, 8 female) or 41.0%
were diagnosed as having Minamata disease; 8 (7 male, 1 female) or 20.5%
276
-------
were probable cases; 9 (4 male, 5 female) or 23.1% were undetermined; 5 had
other ailments, and others — 1.
From the Ariake district, 23 were examined. Of these 8 (4 male, 4 fe-
male) had symptoms considered likely to be Minamata disease, of which 5 dis-
played all major symptoms of the disease, while the other 3 evidenced symp-
toms of visual field constriction, sensory disorder, loss of coordination,
and hearing difficulty. Two (male) were diagnosed as probable cases, having such
symptoms (3) as sensory disorder, loss of coordination and constriction of
visual field. Nine cases (5 male, 4 female) were undetermined; 2 had other
ailments, and another 2 were in fairly good health.
Incidentally, 81 (36 male, 45 female) out of 195 from Minamata district
had previously been designated as having Minamata disease.
Note: Figures cited in III - 4 for the Neuopsychiatric Department
are not in agreement with those cited in this section. This
was because the department continued to collect data even
after the end of March of this year, and then readjusted its
system, resulting in a delay of submission of data. Hence,
the general determinations reported herein cover the period
up to the end of March. The differences must be reviewed in
the future.
(Takeuchi)
277
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V. PATHOLOGICAL STUDY OF MINAMATA DISEASE (Part 2)
9. PATHOLOGICAL RESEARCH OF MINAMATA DISEASE TEN YEARS LATER (Part 3)
1) Especially, Cases of Autopsy in Chronic Symptoms and Chronic Mina-
mata Disease
Second Seminar, Pathology, Department of Medicine, Kumamoto
University
Team member: Tadao Takeuchi
Research assistants: Mitsuaki Eto, Hidetoshi Kojima,Ken Sakai,
Tohiko Miyayama, Shuji Suko; Nobuyoshi
Sakurama, Kazuko Sato, Koji Shigenaga,
Shinichi Tokumitsu, Teruo Iwamasa
I. PREFACE
In last year's report [1] dealing with results of autopsy in Minamata
disease cases over a lengthy period of time, we pointed out that there were
acute as well as chronic symptoms of Minamata disease, among which were those
difficult to examine clinically, such as partial Minamata disease, masked
Minamata disease, abnormal Minamata disease, diffusive cerebral disorder and
non-manifest type Minamata disease. Occasionally, therefore, Minamata disease
could not be diagnosed.
Subsequently, based upon 5 cases of autopsy and 10 cases mentioned in our
previous report, we found there were certain developments until the outbreak
of acute symptoms of Minamata disease and possible appearance of new symptoms
because of an accumulation of attritional changes. These are reported herein.
278
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II. STUDY MATERIALS AND METHOD
Autopsy was focused around 5 recent, unreported chronic cases, reference
being made to cases discussed in last year's report. Of the 5 cases, one
(No. 5946) had been diagnosed prior to death as having Minamata disease, and
four (Nos. 5987, 5972, 6013, and 5952) had died from possible Minamata disease
while they were petitioning for designation as Minamata disease carrier. The
disease was confirmed as a result of biopsy in these cases.
The method of study is not described herein as it was mentioned in last
year's report.
III. FINDINGS
General items are noted in Tables 1 and 2 (see Tables 1 and 2). Other
matters will be described in detail with respect to each case.
TABLE 1. LIST OF AUTOPSY CASES INVOLVING CHRONIC SYMPTOMS OF MINAMATA
DISEASE
i
Biopsy| Name
no. ,
1
5987 Miya, Mu
5972 Yoshi, Go
6013 Hayashi, Fumi
5946 !Funa, Iwa
5952 Taki, Ta
—
Sex
M
F
F
F
M
Age
64
81
75
79
85
Years
trans-
pired
(3)
10
12
14
17.5
Cerebral
weight,
g
1050
1375
1100
1020
1150
Remarks
Infarction of myocardium*
Cerebral hemorrhage*
Bronchopneumonia*
Minamata disease
Infarction of myocardium
Determined to be Minamata disease as result of biopsy.
279
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TABLE 2. LIST OF PSYCHIATRIC AND NEUROLOGICAL SYMPTOMS IN CHRONIC
CASES OF MINAMATA DISEASE
\, Symptom
Miya, Mu
Yoshi, Go
Hay ash i , Fumi
Funa , Iwa
Taki, Ta
i
p4
O
O
13
rH C
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<4H 4J
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rH -H
(tf ^1
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/
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co
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S
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00 X
O
-------
TABLE 3. LIST OF MERCURY LEVELS IN VISCERAL ORGANS OF HUMANS
AFFECTED WITH CHRONIC MINAMATA DISEASE
Biopsy
- -:
•' "-
.'• U
r. -16
ac.2
Sex
:
.3.
-
Age
i>i
51
7.>
79
S>3
Years transpired
(3)
10
12
14
17.5
Liver
ppm
n.3J«
(0.024)
n./4ft
1 0. !00
1.2ol
'(0.03V)
0.2^0
Kidney
ppm
2.479
(O.ull)
1.3?5
0.225
10.045
(0.016)
0.263
Brain ppm
Cerebellum
0.0:1;:
(0.010)
0.06-:
0.17S
1.515
(o.irti)
0.033
Cerebrum
0.0,33
(0.013)
0.020
0.010
1.3.K
(0.017)
O.L'll
( ) — Numbers in parentheses indicate the amount of mercury (measured by
Hygiene Facility).
History of employment. Engaged in agriculture, and resided in Tsukinoura
since around 1947; consumed fish, shellfish, oysters and shrimp in great quan-
tity; caught and consumed shellfish and oysters, in particular.
Current medical history. Paralysis in both hands, swelling sensation in
limbs since 1969, subsequently unable to move fingers, drops things, unable
to button up, hands quiver when carrying heavy objects, footgear comes off,
eyes hurt, hearing difficulty, stutters, headache, irritable, forgetful,
unable to think clearly, dislikes to do anything, depressive, and unable to
sleep. She was unaware that she had contracted Minamata disease all this
time. In September, 1971, she was examined at the Psychiatric Department,
with the following diagnosis. Unable to walk upright. Romberg ( - ). Unable
to stand on either foot with eyes closed; finger test: clumsiness on either
side, slow on the right, as well as on the left; foot test: clumsiness on
either side; Barre symptoms on the right (-1-) and left (+) ; motor coordination
disorder (-H-); articulation disorder (+); eyeball movement restricted in
either direction; pupils small on either side; auditory disorder (+); olfac-
tory and taste senses almost normal; muscular tension generally progressive,
281
-------
spasmic contraction (++), solidus contraction (+); local reflex intensified
in upper leg and knee on either side; Hoffmann, Wartenberg positivity on
either side; sensory disorder on both hands, but none on lips; no centric
field of vision constriction; no excessive perspiration or muscular atrophy as
symptom of autonomous nerve affliction; deformity of left hand; adduction of
I and V fingers, and bayonet-attached-gun type I, III, and IV fingers; mental
disorders as sensory affliction (+), temperament (+), lack of aggressiveness
and emotional insensitivity. Blood pressure, 118/86 mm Hg.
Because of the foregoing observations, the individual was treated as a
probable case of Minamata disease. From May 27, 1969 to June 30 of the same
year, she was hospitalized at Minamata Municipal Hospital for congestive heart
disorder and a clot in the right leg. On May 8, 1970, she suffered edema of
the whole body, and was readmitted; while in the hospital, she developed
jaundice, but was released on June 23. In 1956, she had undergone chole-
cystectomy.
From mid-February, 1971, she felt fatigue throughout her body, had dis-
order of mood and emotion and lost her appetite, and was hospitalized on
April 20. She was administered a liver protecting agent and a drug for urine
condition, and was released on May 14. Subsequently, she was examined as an
out patient, but on December 1, she complained of chest pain and respiratory
difficulty, and was readmitted after she was found to be suffering from liver
enlargement. An electrocardiogram indicated a clot in the right leg, and
after failing to respond to treatment, she died on March 30, 1972.
The patient applied for designation as a Minamata disease patient on
September 20, 1971, and died while her application was still pending. An
autopsy established that she had Minamata disease.
282
-------
Pathological Considerations
j[ajutoj>sy_no. _598T)
1. Arteriosclerosis type changes
1) Hardening of arteries: i) Degeneration and hardening of middle
membrane of arteries in the brain; softening of the brain: right diencephalon,
right occipital lobe (macro), right lobe (macro), cerebellum (macro).
ii) Hardening of coronary artery and scar of heart muscle, a growth on heart
muscle and swelling, enlargement of the lumen, iii) Arteriosclerosis type
atrophorous kidney. iv) Hardening of brachiocephalic trunk artery.
v) Spleen, etc.
2) Atherosclerosis
2. Minamata disease: cerebral atrophy (1050 g)
1) Patchy fallout of cerebral cortical nerve cells; optic center, front
center area, parietal lobe, temporal lobe, frontal lobe, etc.
2) Degeneration of cerebral medulla (especially, occipital lobe).
3) Fallout (moderate) and thinning of centric granular cells of
cerebellum.
4) Degeneration of long fibers in medulla and atrophy and fallout of
anterior horn, cells (moderate) .
5) Pathological changes of peripheral nerves (posterior root, lumbar
ischium, gastrocnemius) :
i) loss, regeneration of posterior root and sensory nerve fibers;
ii) increase of Schwann's cells.
283
-------
3. Condition following cholecystectomy
1) Adhesion of portal area of liver with duodenum and transverse colon,
and enlargement of chorion.
2) Liver: chronic inflammation of the bile duct and centric, fat
accumulation in small lobe.
4. Congestion in various visceral organs
1) Congestion, dropsy of lungs as well as brownish coloration and
hardening.
2) Congestion in other visceral organs.
5. Edema: water in lungs (left, 200 ml; right, 50 ml)
6. Chronic cystitis
7. Atrophy, scar formation in pancreas islets of Langerhans. Cause
of death: heart disorder.
General External Appearance and Visual Observations
of the Nervous System
Nutrition and skeletal growth were of moderate degree. Muscles of thenar
eminence, thenar prominence on either side had a slight degree of atrophy,
and some bending and contraction from the No. II joint of either hand to
gliding joint. No muscular atrophy was observed in the femoral and gastrocne-
mius muscles. The heart was 460 g in weight, with enlargement of the cavity
of the left atrium and left ventricle markedly visible. No clot was seen,
but some crookedness and hardening of the coronary artery was found. Conges-
tion of various visceral organs throughout the body was noted.
284
-------
The weight of the brain was 1050 g, its size was generally smaller, and
the fissure was wider. Atrophy was especially noted in the occipital lobes
on either side. In one section, atrophy was found in the cortex, as well as
atrophy in some portion of the optic center. A moderate degree of softening
of the brain was noted in the right diencephalon, and a trace of softening in
the right frontal lobe, right lobe, and cerebellum. No marked changes were
found in pons, medulla oblongata, or spine. Some atheroma was noted in the
brachiocephalic trunk artery.
Histological Observations on Cerebrospinal,
Peripheral Nerves
Cerebrum: A moderate degree of cortical atrophy was noted in the occi-
pital lobe, but was particularly deep in the cleft of falx cerebri. The
layer structure was relatively preserved, but there were a disarray of nerve
cells, patchy fallout, and an increase of glia. Atrophy and hardening was
also noted in some nerve cells. A partial loss of the marrow line was seen,
as well as diffusive spottiness deep in the medulla. In the forefront of
the occipital lobe, there was a moderate degree of atrophy in the cortex, and
the layer structure was relatively intact.
Spottiness is seen in Layer I; a moderate degree of fallout and decrease
of conical cells deep in Layers II and IV, with localized glia multiplication
in some areas, are also visible. Some spottiness is seen in the medulla,
and a thickening of the walls of small veins. Infiltration of glia cells is
also observed. At the optic chiasma, thickening and hardening of the inner
membrane of small blood vessels is seen in the area of the aorta, including
some softening over a relatively wide area. Softening is also visible in the
right diencephalon. The softening involved the blood vessels, and this con-
dition was similarly noted in the temporal lobe and parietal lobe. Generally,
in the cerebral cortex, all layers showed patchy fallout of nerve cells
(Photo 1) and some spottiness (Photo 2). Some increase of glia cells was
found in the fallout area of nerve cells. Many of the remaining nerve cells
were undergoing consumption, in addition to hardening and atrophy.
285
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Photo 3. Noted near the center of Photo 4. Atrophy of cerebellum
Cerebellum (HE-stained) of Case No. and spottiness of medulla in above
5987 was atrophy, extensive fallout case (NO. 5987)
of granular cells and apical scar
formation; also partial fallout of
Purkinje cells and Bermann's glia
-.cells increase
Cerebellum: Slight atrophy was seen around the brain, but was rather
distinct near the wall of No. 4 cavity. Partial fallout of Purkinje cells
and an increase of Bergmann's glia cells was noted, with fallout of granular
cells from directly beneath Purkinje cells (Photo 3). Spottiness was noted
in the medullary sheath (Photo 4). Apical scar formation was also noted in
some areas. A calcified cell bundle which developed subsequent to the soften-
ing was seen in a molecular layer of the lobe.
Mesencephalon: No marked changes were found.
287
-------
I'V,1—^-'•'' '• '"'•'•!!
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The case discussed here is that primarily of cerebrovascular disease,
accompanied by Minamata disease. Three years had passed since the patient
was stricken in 1969, but the mercury level in her visceral organs was normal.
It is possible that she had been exposed to mercury contamination for a long
time prior to that period. The nerve cells in the cerebral cortex showed
regressive diffusive changes, in addition to fallout, indicating a phenomenon
which occurred over many years.
Case No. II. Yoshi, Go; male; Idemizu-shi, Kagoshima-ken.
Date of birth: August 15, 1890.
Date afflicted: 1962.
Date of death: February 19, 1972 (81 years old).
Years transpired: 10 years.
Family history: Second son (47 years old) was treated at a mental hos-
pital in Idemizu-shi about 7-8 years ago; received
head injury (hospitalized 2 days) in a traffic accident
in May, 1970; even now complains of headache and
numbness in limbs. Third son (41 years old) also com-
plains of numbness of hands.
Life history: Engaged in fishery since childhood; loves to eat fish;
ate fish even during the days when fishing was prohibited. Unable to work
for 14 years because of physical deterioration.
Current medical history: Hands tremble, numbness of fingers and partial
blindness from about 10 years ago. Is unaware even when his footgear comes
off; staggers, and from about 5-6 years ago, felt twitching sensation in
feet; unable to speak clearly, and forgetful. Believed at first to be
senile problems.
Symptoms at time of examination on December 12, 1971 (by Dr. Hirata):
Senses of touch and pain impaired in both forearms and lower thighs, hearing
difficulty, articulation difficulty, positive Lonberg's phenomenon, etc.
289
-------
The field of vision in the right eye was: external 55°, internal 45°, top,
40°, bottom, 50°; the left eye could not be examined because of pterygoid
fragment.
Noted were trembling of hand, involuntary movement, and changes in nails;
also poor memory and difficulty in mental calculations.
Patient was diagnosed as a probable case of Minamata disease, and having
high blood pressure.
He was treated by a certain doctor for respiratory condition in April,
1969 (allegedly, bronchitis since 1945); suffered paralysis on the right side
of body on February 4, 1972, and temporarily lost consciousness; bed-ridden
ever since; on liquid diet; again became unconscious on February 17, 1972,
and died on February 19.
Patient died while his application for designation as Minamata disease,
filed on January 18, 1972, was still pending. An autopsy confirmed that he had
Minamata disease.
Pathological Matters
AUJL°!ES.Z jxaminat^on _(Case _No_^ _597_2)_
1. Cerebral hemorrhage (left diencephalon); weight of brain: 1375 g
(to include swollen area on left side).
2. Arteriosclerosis, especially sclerosis of arterioles
1) Atrophy of the kidney, of the arteriole-sclerotic type (accompanied
by partial arteriosclerotic cicatrice); 2) papilloma of the heart muscle and
hardening of the coronary artery; 3) hardening of cranial vessels and
mortification of the middle membrane of arterioles.
290
-------
3. Minamata disease
1) Extensive fallout of nerve cells of cerebral cortex (including
optic center); 2) spottiness of cerebral medulla; 3) fallout of centric
granular cells of cerebellum (including apical scar formation); 4) moderate
spottiness of axons of spine; 5) relatively marked pathological changes in
peripheral nerves (including sensory organ): i) loss of fibers, regeneration
and scar formation in posterior root greater than in anterior root; ii) mul-
tiplication of Schwann's cells.
4. Moderate degree of bronchopneumonia and chronic bronchitis, and
emphysema.
5. Scarred, pathological changes in upper lobe of the lung and tubercu-
losis of the lymph glands (moderate).
6. Atrophy of various visceral organs (spleen, liver, etc.).
Cause of death: cerebral hemorrhage.
General External Appearance and Visual Observation
of Nervous System
A small skeletal framework, malnutrition, muscular atrophy throughout
body, and loss of weight in the liver, 715 g, spleen, 25 g, and kidney, 75 g.
Brain weight, 1375 g, with moderate dispersion of soft membrane. Atrophy on
right side of brain, being edematic in the opposite hemisphere, extending
from the apex to the occipital lobe. As for the divided side, there was a
sign of serious hemorrhage on the left diencephalon, which proved fatal.
Relatively serious atrophy on right occipital lobe, with edematic condition
on left occipital lobe and a wider medulla; narrower cortex, expecially in
falx cerebri; moderate atheroma formation in cephalic trunk artery.
291
-------
Histological Observations of the Nervous System
Cerebral hemisphere: Bleeding in left diencephalon region, extending
from the capsula interna to putamen, with surrounding tissues of the edematic
type; red blood corpuscles still present, with hemolysis in the central area;
infiltration of undernourished cells and multiplication of star-shaped glia,
with a trace of hemosiderin cells; slight hemorrhage in right diencephalon,
with some thickening of vessel walls; no marked changes or loss of basal
nucleus of cells.
In the occipital lobe, the region transforming into a cleft manifested a
thinning of the cortex and indistinct layers, each layer showing a marked
fallout of nerve cells even around the surface layer (Photos 7, 8). Great
fallout of nerve cells was also seen in Layers II - IV, microscopically in a
spongy condition (Photo 8), as well as in Layers IV - VI (Photo 7). Spotti-
ness of the medullary sheath and partial loss of the marrow line was visible.
In the right lobe (non-hemorrhage region), some fallout was noted; also,
a slight sign of bleeding in the medulla, and a slight spottiness. Even now,
there were consumptive changes in the nerve cells, undergoing atrophy and
obliteration. Hardening of cells and degeneration were also seen in the
gyrus. In the left gyrus (hemorrhaged area) where there was a swelling caused
by hemorrhage of putamen, cranial edema was noted, with bleeding in the vici-
nity of small vessels, extending to the medulla. A reactory multiplication
of glia and spottiness of tissue were also observed.
Cerebellum: At the center of the appendage, fallout of granular cells
from directly beneath the Purkinje cells was noted (Photo 12). A slight
fallout of even Purkinje cells was noted, with an increase of glia in the
molecular layer. The medulla was narrowed, with slight fallout. No vascular
disease was seen in this area. Slight changes were seen in the hemisphere
as well as a trace of apical scar formation near the ventricle. Signs of new
bleeding were observed in the medulla opposite the No. 4 ventricle.
292
-------
,• ::'••' '- v
293
-------
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Photo 9. Spinal cord (cervical) of
No. 5972; non-stainablity of posterior
Goll fibers following degeneration can
be observed
Photo 10. Ganglion of spinal cord in
No. 5972; ganglion cells are generally
intact, but some fallout are seen,
with an increase of satellite cells;
also marked increase of consumptive
pigments in ganglion cells
Pons: A slight retrogressive degeneration was seen in olive nucleus,
and a slight fallout and swelling of nerve cells. Degeneration and fallout
of nerve cells of trigeminal nerve was noted; also spheriod bodies in the
vicinity of medulla oblongata and the soft membrane. A trace of hemorrhage
was seen in a part of nucleus dorsalis; also, localized, achromatic medullary
sheath in the left conical groove region.
Spine: Achromatic medullary sheath due to slight changes in posterior
fibers in the cervical spine; these changes lessened in the lower area, being
found in the thoracic but not in the lumbar regions. Slight achromatism
294
-------
" f I f 1 If1!") I
r I '> i v 71'tow i
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Photo 11. Posterior root of spinal
cord of No. 9572; marked irregularity
of axons and an irregular increase of
micro-fibers; regenerative image is
visible
Photo 12. Cerebellum of No. 5972;
thinning and fallout from .directly
below the Purkinje cell layer
of medullary sheath was found in the anterior fibers in the lumbar region.
Anterior horn cells were few, due to fallout, and were hardening, especially
in the surrounding area; spheriod bodies were also detected.
Posterior root ganglion: Ganglion cells were relatively intact, but an
increase of consumptive pigment in nerve cells was found. A slight increase
of Schwann's cells was found in fibers (Photo 10).
Root nerves and cranial nerves: In the anterior root, there was a slight
increase of Schwann's cells, loss of medullary sheath, increase of microfibers
and restructure (Photo 11). The trigeminal nerve also showed changes as in
the posterior root, though to a lesser extent.
295
-------
Although this case focused primarily on senile changes, in discussing
vascular, pathological changes, typical symptoms of Minatnata disease were
also found. It appeared that the senile changes have been compounded by symp-
toms of Minamata disease — representing one type of acute case among the
elderly.
Case No. III. Funa, Iwa; male; Tsunaki-mura, Ashikita-gun.
Date of birth: June 1, 1892.
Date afflicted: 1957.
Date of death: December 17, 1971 (79 years old).
No. of years transpired: 14.
Family history: Son succumbed December, 1957, from Minamata disease.
Current medical history. Initially became aware of tremor of hands
about 1957; neglectad treatment on belief that he was an alcoholic, since
tremor ceased when he drank; more violent tremor; unable to converse; paraly-
sis of limbs; hearing and walking difficulty since late September, 1959.
Admitted to Minamata Municipal Hospital on October 14, 1959; unable to
walk since November of same year; speech and hearing ability restored somewhat
in mid-December; able to take five or six steps before collapsing; diagnosed
as Minamata disease at time of admission; had been found to be a Minamata
disease patient on October 14, 1959.
Began to complain about pain in limb joints in January, 1960; confined
to bed and unable to walk since; muscular atrophy of hands since around April
of the same year; stiffness of wrist and finger joints.
Transferred to Yunoji Hospital on March 10, 1965, for purpose of re-
habilitation; tremor of both hands, difficulty in speaking, constriction of
visual field, loss of coordination, hearing difficulty, drooling, limb de-
formity; somewhat undernourished; difficulty in changing body position in bed,
296
-------
but able to sit up on own power with aid of device; unable to stand without
help; wholly unable to walk; barely able to brush teeth; unable to wash face
or comb hair; required toilet assistance and in changing clothes.
Partial results of tests were: PSP, 18.5% at 15 minutes, 61.4% at two
hours; cholesterol, 248 mg/dl, CRP (-H-H-) , RA (+).
Treatment was administered on the basis of diagnosis of Minamata disease,
acute articular rheumatism, and intestinal disorders.
Was able to walk using parallel bars from around September, 1965, until
June of the following year.
Confined to bed because of difficulty in urinating since June 22, 1966;
increasing stiffness of limbs; gradually started to mumble and drool due to
glossitis and inflammation of inner mouth.
Fever developed in April 1969; urine volume decreased; blood precipita-
tion increased in June of same year; coughed at night, with greater expec-
toration; blood pressure tended to increase from around July of the same year
(180/86 mm Hg).
Strong sense of fatigue in entire body since around February, 1971;
vomiting, fever, intensive expectoration, irregular- heartbeat and edema of
lower limbs since early November of same year.
Succumbed on December 16, 1971, due to heart disorder attributed to
general deterioration (according to records of Doctor Misumi of Yunoji Hos-
pital Annex).
297
-------
Pathological Considerations
Auto£s;£ examjuia.ti.ori ^autoj>sy_jio.=_5946)
1. Minamata disease: cerebral atrophy (1020 g)
1) Extensive thinning and fallout of nerve cells in cerebral cortex
(extensive in optic center and others).
2) Spottiness in cerebral medulla.
3) Centric atrophy of cerebellum: i) fallout of granular cells;
ii) fallout and part of Purkinje cells; iii) apical scar formation.
4) Medullary oblongata: changes in conical groove section.
5) Spine: changes in posterior fibers (cervical, thoracic), and in
side fibers (cervical, thoracic, lumbar).
6) Peripheral nerves: i) obliteration, regeneration of posterior root
and sensory nerve cells; scar formation; ii) slight similar changes also in
anterior root; iii) increase of Schwann's cells.
2. Bronchopneumonia (primarily pneumonia of the infectious, effusive
and bleeding type on the right side).
3. Condyloma-type pericarditis.
4. Arteriosclerosis: 1) sclerosis of arterioles (kidney, spleen);
2) sclerosis of the aorta; 3) papilloma on the heart muscle.
5. Tuberculosis (slight): 1) tuberculosis of right lung, of the small
lobe, nodulous type; 2) empyemic pleura adhesion on the right side, calci-
fication, scar formation.
298
-------
6. Atrophy of various visceral organs: liver (580 g), spleen (40 g),
and others.
7. Tumor in the prostrate and edema of scrotum.
8. Fibrous/round stomach tumor.
9. Atrophy of islets of Langerhans in pancreas, scar formation.
10. Marked deformation of fingers and of other joints.
Cause of death: bronchopneumonia.
General External Appearance and Visual Observation
of Nervous System
The skeleton was of moderate growth, and there was considerable mal-
nutrition. Muscular atrophy was noted in the arm, forearm, and fingers, with
contraction in fingers. In both hands, the III and IV fingers were crooked
in the direction of the palm, leaving only II and V fingers for grasping
(Photo 13). No swelling of PIP, MIP, GIP joints was noted; diffusive atrophy
of all fingers and deformed nails were seen. Muscular atrophy was also noted
in lower extremities, especially in gastrocnemius of the shank. Moderate
contraction was also seen in joints of both elbow and legs; the right elbow
joint was swollen, had luster and was slightly crooked; and a slight con-
traction at the pointed end of the foot. Moderate edema was noted in the
instep of the left foot and in the frontal tibia. In the small of the back
was a bedsore 10 x 10 cm in size.
The weight of the heart was 230 g, and rather small. A wart about the
size of a bean was found in the area of the semi lunar valve of the aorta.
The weight of the right lung had increased to 890 g; it was tinged with red-
dish color, and had an increase of fluid and blood. Clumps of bood were
dispersed; also, hyperplasia of the plura and adhesion was noted on either
299
-------
». to-
V.
Photo 13. Deformed fingers of No.
5946, due to Mlnamata disease and
articular rheumatism
Photo 14. Atrophy of cerebellum of
No. 5946; slight spottiness in medul-
lary sheath
side. Atrophy of the liver (580 g),
spleen (40 g), and kidney (60 g)
was seen.
The brain weighed 1020 g, and
the pia mater was generally turbid;
atrophy was noted around the brain,
especially on the occipital lobe.
A slight atheroma was noted in the
brachiocephalic trunk artery. No
visual indication of softening was
seen in the cerebral parenchyma.
Histological Observations
of Nervous System
Photo 15. Atrophy of cerebellum of
No. 5946; diffusive fallout of granu-
lar cells and also great, localized
fallout of many Purkinje cells (due
to Minamata disease and pathological
changes involving lack of oxygen)
Cerebral hemisphere: Atrophy of the cortex was notable, expecially in
the occipital lobe and falx cerebri groove, where even the layer structure
was indistinct and thin (Photo 17). Fallout of nerve cells was great (Photo
300
-------
18), and appeared to be microscopi-
cally spongy (Photos 19 - 20). Fall-
out was also noted in the cortical
area, but there glia increase was
moderate (Photos 19 - 20). An in-
crease of brown pigment was seen in
remaining nerve cells, as well as loss
of the medullary line. Diffusive
spottiness was also seen deep in the
cortex.
In the temporal lobe, Layers II -
IV appeared to be spongy, and fallout
of nerve cells was notable. Atrophy
and hardening was seen in remaining
nerve cells, some on the verge of
disintegration.
In the central fissure in the
parietal lobe, the layer structure was
intact, but fallout was seen, with a
notable decrease of Betz cells.
Similar changes were found in
other cerebral cortex.
Cerebellum: In general, there
was atrophy with a thinning of the
molecular layer. Relatively heavy
fallout of Purkinje cells; granular
cells were not clustered together in a
normal pattern, and heavy fallout had
caused their number to decrease, but
no large scale fallout was seen
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Photo 16. Anterior (upper) and
posterior (lower half) root of
No. 5946; axons highly irregular
in both; unusual multiplication
of microfibers seen in anterior
root; greater changes noted in
posterior root; increase of
Schwann's nucleus
301
-------
f
U
Figure 17. Cerebral cortex (optic center) of No. 5946; marked
atrophy in cortex (KB-stained)
(Photos 14 - 15). Apical scar formation was noted. Increase of both glia
and Bergmann cells in the mocecular layer was observed; also, slight thicken-
ing of the middle and outer membranes of the meninges.
Pons: Various nuclei are intact, but achromatism of the medullary
sheath of Tr. mesencephalicus n. trigemini (V) was noted.
Medullary oblongata: Achromatism of the medullary sheath of Fasciculus
gracilis, Fibrae pyramidales was seen.
Spine: Achromatic medullary sheath, with general changes in posterior
fibers; secondary changes in the conical groove section, with some atrophy
and fallout of anterior horn cells of certical vertebrae and thoracic verte-
brae. Some anterior horn cells in the lumbar vertibrae are in an atro-
phorous condition, but most are intact.
302
-------
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• * • «t • - .•
'i'l ••"•"'-.' " ••"•*,''•''" •*-'>••*- • T "••""./ * : * ^ "r ',"
Figure 18. Enlarged view of of outlined area in Figure 17
(Case No. 5946); much thinning and fallout of nerve cells;
some increase of glia; modified form of remaining conical
cells is visible
Peripheral nerves: Increase of Schwann's cell nucleus in both anterior
and posterior roots; irregularity of an achromatic medullary sheath; irre-
gularity in color of axons; appearance of microfibers. A greater part of
the gastrocnemius nerve bore scars.
This case was of a fairly chronic type which became aggravated with the
lapse of time and was recognized as a typical Minamata disease. During the
ten years that have elapsed, the patient also developed articular rheumatism
Abnormalities of the limbs and deformed fingers subsequently developed, due
to additional conical groove symptoms induced by motor nerve disorder as a
result of extensive cortical impairment of the cerebrum.
303
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Case No. IV. Hayashi, Fumi; male; Tsunaki-tnachi; Ashikita-gun.
Date of Birth: January 20, 1897.
Date afflicted: 1960.
Date of death: June 22, 1972 (75 years old).
Years transpired: 12 years.
Family history: Sensory disorders and lack of coordination noted in
wife (61 years old) (Tachizu).
Life history. Former marine carpenter; loved to eat fish; consumed fish
three times a day; ate fish until about March or April of 1971.
Current medical history. Unable to work well because of impairment of
feet, hands, and eye from around 1960 (63 years old); a large flow of sputum;
paralysis of hands and legs since 1962; difficulty in speaking from 1964;
difficulty in walking since 1965; unable to express himself due to indistinct
words; bedridden since 1969; since symptoms progressed slowly did not know
whether diesease was due to old age or Minamata disease.
Examined at the Psychiatric Department of this University on June 3,
1972. 1) Was unable to change body position on his own power when lying down;
both legs crooked at knee joint, with right leg extending outward, and left
leg upright. Peculiar deformity also noted in fingers: left fingers were
crooked at first and third joints; extended at second joint; in the right
hand, the first finger was crooked at the first joint and rested atop the
second finger.
2) In the upper extremities, muscular atrophy was particularly marked
around the middle finger, small finger, thumb, mid-palm, near the elbow of
the forearm, and from the thigh to the shank. 3) Constantly hollered
and occasionally motioned, as if brushing thing aside with hands. 4) Rigid-
ity: slight degree on head (+), moderate to advanced degree in upper extremi-
ties on either side; rigidity in lower extremities on either side, unable to
stretch beyond 30 degrees. 5) Slight paralysis on either side, moderate
305
-------
loss of coordination in right hand; slight degree of voluntary tremor (+).
6) Evasive reaction against painful stimulation noted in upper arm and shoul-
ders, even though absent in back of hands and sole of foot. 7) Great deteri-
oration of hearing capacity and vision; no blinking reaction even when eye
was poked; slight cataract in left eye. 8) Talks nonsense. 9) Furrows on
tongue. 10) Grasping reflex on both hands, and partial resistance in upper
right extremities. 11) High degree of intellectual and personality disorder
lacking inhibition, lack of emotion. 12) Blood pressure: 185/100 mm Hg.
13) Constantly complains of headache and demands massage of legs by spouse.
14) Requires nursing care. The patient was diagnosed as having Minamata
disease because of the foregoing symptoms.
The patient developed fever on May 30, 1972, lost appetite, and also
developed bronchial pneumonia; succumbed on June 22, 1972.
The patient was subjected to autopsy examination, while his application
of October 16, 1971, for designation as a Minamata disease patient was still
pending.
Pathological Considerations
Autop_sy_ examination jCajitopj^__np_. 6_013)
1. Minamata disease: cerebral atrophy (1100 g)
1) Extensive fallout of nerve cells in cerebral cortex (optic center
and other areas).
2) Spottiness in cerebral cortex.
3) Centric atrophy of cerebellum (slight): i) deciduation of granular
cells; ii) apical scar formation; iii) spottiness in medulla of cerebellum.
306
-------
4) Peripheral nerve changes: i) obliteration, especially of posterior
root and sensory nerves, regeneration, and scar formation; ii) increase of
Schwann's cells.
2. Senile changes
1) Arteriosclerosis: i) hardening of arterioles and atrophy of the
kidney; ii) hardening of the coronary artery and a slight growth on heart
muscle, changes in heart muscle; iii) changes in other arterioles, including
arteriosclerosis.
2) Softening of the brain: left diencephalon — microsoftening of
cerebrum, cerebellum and pons.
3) Atrophy of various visceral organs (liver, spleen).
3. Bronchopneumonia
4. Stones in kidney, bladder, and hydronephorsis
5. Rigidity of limbs
Cause of death: bronchopneumonia
General External Appearance and Visual Observation
of the Nervous System
The skeleton was of moderate development; general loss of weight, mus-
cular atrophy throughout body, especially in the limbs; deformity and rigidity
of small fingers on left and right hands in upper extremities; knee joint
crooked and rigid to about 120 degrees, and rigid foot joints in lower ex-
tremities, bedsores under first toe of left foot, another 3 x 3 cm in size
on heel, and another 8 x 8 cm in size on the small of the back; the heart
weighed 210 g; coronary artery was hard, and followed a curved course;
307
-------
diffusion of focus associated with bronchopneumonia and bleeding spots seen
in divided side of the lungs, which was the cause of death; the kidney weighed
90 g, with a countless number of stones, ranging in size from pebbles to that
of a soy bean, in the renal pelvis cavity on either side; as a result of the
stones, the ureter was enlarged and hydronephrosis was present; also, many
stones were evident in the bladder.
The brain weighed 1100 g, with indications of general atrophy, slight
hemorrhage under the arachnoid membrane at the tip of the frontal lobe, and
turbidity of the cerebral membrane in the same area; relatively large soft
spots on left diencephalon on the divided side, also micro-soft spots in
the cerebrum, cerebellum, and pons; relatively stronger atrophy in the cortex
of the occipital lobe on either side, compared to the other areas; slight
atheroma in brachiocephalic trunk artery.
Histological observations of Cerebrospinal
Peripheral Nerves
Cerebral hemisphere: Relatively strong atrophy of the cortex in the
optic area of the occipital lobe; greater cleavage in falx cerebri groove;
thinning of layer structure, with reduction of conical cells (Photo 21);
microscopically, spongy condition noted (Photo 22); diffusive multiplication
of glia cells (Photo 22); diffusive spottiness in medulla, and reduction of
medullary line.
Similar changes, although to a different degree, in other areas of the
cerebrum, with fallout in front center and reduction of Betz cells (Photo 23);
considerable fallout of nerve cells from Layer IV to Layer V; increase of
pigment, and consumptive changes in remaining nerve cells (Photo 24); also,
similar changes in the frontal lobe (Photos 25 - 26).
Diencephalon: Slightly soft spot in the white matter on the left side,
and many spheroid bodies in the surrounding area; spottiness following soft-
ness visible by staining the medullary sheath.
308
-------
•t .
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Photo 21. Falx cerebri on cerebrum of
No. 6013 (KB-stained); thinning of the
cortex, accompanied by marked atrophy;
coarseness of meninges; marked fallout
of nerve cells.
Photo 22. Enlarged view of cortical
III-IV layers.in optic center of No.
6013; spongy condition accompanied by
strong fallout of nerve cells and
sporadic increase of glia cells;
remaining nerve cells vanishing as
consumptive changes occur.
309
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Photo 27. Cerebellum of No. 6013.
Diffusive fallout of granular cells
due to Minamata disease, accompanied
by localized, vascular scars
Pons: Micro-soft spot in the middle neurons intact.
Medulla oblongata: Spheriod bodies in the surrounding area; spottiness
in the surrounding area of 4tn ventricle; increase of glia; olive nucleus
intact.
Cerebellum: Atrophy around the middle; partial fallout of Purkinje
cells; slight fallout of granular cells; apical scar formation; scars follow-
ing development of vascular micro-spots in some areas (Photo 27).
Spine: Slight spottiness in posterior fibers of cervical vertebrae;
many spheroid cells; reduction of anterior horn cells; absence of spottiness
in thoracic vertibrae, but spheroid bodies present in the medulla; slight
312
-------
spottiness in posterior fibers of lumbar vertibrae and spheriod boides in
the medulla; anterior horn cells intact.
Peripheral nerves: Increase of Schwann's cells and scar formation in
posterior root nerves; countless microfibers found by staining of axons and
regeneration in process; medullary sheath intact and of normal size in an-
terior root nerves, partial increase of Schwann's cells and few micro-
fibers seen.
This case involved diffusive, cerebral pathological changes associated
with chronic Minamata disease, and localized vascular and senile, consumptive
changes.
Case No. V. Taki, Ta; female; Taimodo, Minamata-shi,
Date of Birth: December 24, 1886.
Date afflicted: Summer of 1954.
Date of death: January 4, 1972 (85 years old).
Years transpired: 17.5 years.
Family history: Grandson had fetal Minamata disease; mercury level in
his mother's hair was 72.9 ppm in December, 1968.
Life history. Fished with fishing pole or net until 1954; ate all the
fish and shellfish caught.
Current medical history. Numbness below the hip, sore foot, tremor of
hands and inability to hold plates or food since summer of 1954; inability to
walk without collapsing or hurting herself; such conditions temporarily
alleviated around 1965; then stupefaction and inability to do anything by
herself. As of July, 1971, suffered from numbness of hands, tremor, hearing
difficulty, acataphasia, flow of sputum, and virtual inability to walk.
Was examined by Dr. Mishima of the Internal Medicine Department, Mina-
mata Municipal Hospital on July 6, 1971; found to have poor judgment, loss of
313
-------
memory; occasional emotional incontinence, uncooperative during examination;
lacks facial expression; virtually deaf; slow tongue movement; some muscular
strength in upper extremities; absence of tremor or speech disorders; coor-
dination, sensory disorders and vision undetermined because of inability to
perform test, due to imbecility of patient.
On December 29, 1971, the patient appeared to have less strength than
usual and could not even hold an apple to her mouth, although there was no
change in the facial color. On the next day, on December 30, the patient was
able to pick pieces of fish with her own fingers, but often dropped them
around her. On January 1, 1972, the same conditions persisted; on the even-
ing of January 3, was unable to sit on her own power and could not talk;
could not swallow food, and eyeballs drooped and were still. She succumbed
the following day on January 4.
The patient was diagnosed as having softening of the brain; she had
applied for designation as a Minamata disease patient on June 16, 1971.
Pathological Considerations
Autopsy examination (autopsy no. 5952)
1. Minamata disease: cerebroatrophy (1,150 g)
1) Extensive fallout of nerve cells in the cerebral cortex (optic
center and other cortex).
2) Spottiness in medulla of the cerebrum.
3) Centric atrophy of cerebellum (slight): i) fallout of granular
cells; ii) apical scar formation.
4) Fallout of anterior horn cells in the spine; slight spottiness of
posterior fibers.
314
-------
5) Pathological changes of peripheral nerves: i) obliteration and
regeneration of posterior root, sensory nerve fibers and scar formation;
ii) increase of Schwann's cells.
2. Senile changes
1) Arteriosclerosis: i) hardening of arterioles and atrophy of the
kidney of the arteriosclerosis type; ii) papillotna on heart muscle; iii)
other pathological changes of the arteriole-arteriosclerosis type.
2) Softening of the brain (diencephalon; other small, localized
softening of the cerebrum and cerebellum).
3) Atrophy of various visceral organs (liver, spleen).
3- Chronic bronchitis.
Cause of death: softening of the brain and Minamata disease.
General External Appearance and Visual Observations
of the Nervous System
The skeleton was of normal development; slightly undernourished; no
muscular atrophy; heart weighed 450 g, with hypertrophy in left ventricle
(3 cm thick); no marked visual changes except atrophy of the liver and spleen;
general atrophy around the brain, especially in the occipital lobe; atrophy
of falx cerebri in the occipital lobe on the divided side, with deeper cere-
bral fissure; small softened area on left diencephalon.
Histological Observations of Cerebrospinal
Peripheral Nerves
Cerebral hemisphere: Layer stricture intact in the optic area of the
occipital lobe, but thinning and fallout in certain areas, yielding a micro-
scopically spongy appearance (Photo 28); increase of consumptive pigment
and consumptive atrophy and loss; reduction of conical cells; diffusive
315
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increase of glia cells; diffusive spheroid bodies, especially in the ridges,
as spottiness progressed in Layer I; diffusive spottiness deep in the medulla,
with spheroid bodies in the vascular area; coarse meninges, with thickening
of the outer membrane of blood vessels; signs of calcification, subsequent
to softening, in a part of the cortex of the occipital lobe (mid-position)
and scar formation, the boundary relatively clear, but with spottiness in the
medulla underneath; spottiness in Layer I in the occipital lobe, and diffused
spheroid bodies; slight fallout trend in Layer 5, but relatively intact in
Layer III, although hardening of nerve cells noted; few cells in Layer IV;
considerable Betz cells in Layer V, with precipitation of brownish pigment
and reduction of small cells; diffusive spottiness in the medulla; sign of
localized softening in the medulla of the gyrus, as well as vascular, patho-
logical changes.
Similar cortical, pathological changes in the frontal lobe and temporal
lobe, accompanied by diffusive fallout and cells undergoing consumptive
changes, atrophy and obliteration (Photos 28 - 29); glia cells localized and
increasing in the fallout area of nerve cells (Photo 29), but generally
limited in number, with star-shaped glia being notable (Photos 30 -31).
Signs of empyemic softening in the left diencephalon, extending from
the inner covering to lens neurons, with many fat cells and spottiness in the
surrounding area, together with numerous spheroid bodies; spottiness in part
of the thalamus; hyperplasia of the inner membrane of blood vessels, morti-
fication of middle membrane and partial calcium precipitation.
Cerebellum: Marked apical scar formation around cerebellum; slight
fallout of Purkinje cells; atrophy in mid-cerebellum notable, but changes
were not great (Photo 32); in the area of glia increase in the molecular
layer and fallout of granular cells, reduction of the medullary sheath noted
through KB-staining, but not extensive, diffusive spottiness; nerve cells
having odontoid nuclei were intact; as for the walls of blood vessels in the
meninges, hyperplasia of the outer membrane was noted, but not so much in
the inner membrane.
317
-------
".« -..
t* «
E--
** 1 > • *
__; •"__]"'-**
' *• .-. v *'; . ; a. **' ' ^ f
r/* •">•-•' :^;.^y/
Figure 30. Cerebral occipital lobe
of No. 5952. Diffusive increase of
star-shaped glia associated with
fallout of nerve cells
:,r../V
/" , rf«. - ' *
- «J«-s. ' ^ -
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Figure 31. Partial expanded view of
same case (No. 5952) . Increase of
star-shaped glia
Mesencephalon : Various nuclei
intact.
Medulla oblongata: Spheroid
bodies in the surrounding area; olive
nuclei intact; spottiness in part
of the 4th ventricle, and an increase
of star-shaped glia cells; calcium
precipitation directly below upper
covering of cerebral cavity; no
changes in various nuclei.
318
-------
V-C
Figure 33. Regeneration of posterior
root nerve fibers
Figure 32. Area near the
ventricle of cerebellum of No. 2592.
A peculiar apical scar formation is
seen in modest pathological changes
and partial fallout of cells
Spine: Few anterior horn cells
in spine; spottiness in posterior
fibers; loss of posterior horn nerve
cells and brownish pigment precipi-
tation; fallout of anterior horn
cells of the thoracic vertebrae, and
changes in transverse fibers; an-
terior horn cells intact in lumbar
vertebrae, but slight changes in
posterior fibers.
Peripheral nerves: Achromatism
of the medullary sheath, increase of
microfibers, and permeation of few
lymphocytes in the posterior root; some increase of Schwann's cells, partial
scar formation, and relatively uniform fibers in the anterior root.
This case involved pathological changes brought on by chronic Minamata
disease, accompanied by localized, vascular and senile changes.
IV. SUMMARY AND COMMENTS
The five cases of autopsy are unique in that the early symptoms of Mina-
mata disease, such as sensory, cerebellum and cerebrum cortex disorders,
gradually developed and with the passage of time induced the typical symptoms
of Minamata disease. As the symptoms accompanying the phenomenon of growing
old were diagnosed and clarified, the emergence of four cases of chronic
319
-------
Minamata disease among the elderly involving senile, pathological changes, and
one case (No. 5987) involving the emergence of symptoms as one grew older was
interesting.
1. Acute symptoms induced by advancement in age
and their pathological changes
No. 5987 is a typical case. This patient was afflicted with a sensory
disorder, beginning with numbness of limbs in 1969 (61 years old), followed
by a loss of coordination, articular and intellectual distrubances. As
symptoms were relative light, she neglected medical care and, finally, in
September, 1971 (63 years old), visited the Neuropsychiatric Department of
this University, when she was diagnosed as a probable case of Minamata disease.
The patient had previously been hospitalized for heart and liver ailments,
but Minamata disease could not be detected at the time. Biopsy revealed
localized, vascular changes in the brain, with pathological changes [2] of
Minamata disease apparent over an extensive area. A look at the behavior of
nerve cells revealed fallout of nerve cells, a manifestation of the peculiar
distribution existing at the time of methyl mercury poisoning, and also in-
crease of pigment precipitation in remaining nerve cells that occurs in ad-
vanced age, sclerosis, atrophy, and consumptive changes. The mercury level
in the visceral organs was already normal, even in the brain where mercury can
easily settle.
Judging from our previous examination [3] of the mercury level in vis-
ceral organs, it was our belief that such a level could not have developed
during the three-year period since the patient's exposure to methyl mercury
contamination. Rather than initially being afflicted in 1969, the patient
probably had hidden or incomplete symptoms from before; as the patient ad-
vanced in age beyond 60, fallout of nerve cells in Minamata disease became
aggravated by consumption associated with senile, consumptive changes, there-
by exposing Minamata disease symptoms. Symptoms such as these which appear
with advancing age take on a different meaning from that of late symptoms of
mercury level as expounded by Tsubaki and others [4], in that the latter
320
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even strikes the young, whereas the former strikes about the time when one
advances into the senile period. We would like to name such symptoms as
age-accumulative, late symptoms, a type of chronic Minamata disease.
Cases 5972, 6013, and 5952 can be considered as age-accumulative late
Minamata disease, symptoms of which appeared 10 to 17 years later. At the
onset, the symptoms were slight, and the patient believed it to be due to old
age, neglecting any medical care. As time progressed, sclerosis type vascular
changes took place, masking the typical Minamata disease symptoms until much
later. Diffusive, peculiar pathological changes of Minamata disease were
found to be linked with localized vascular changes and senile consumptive
changes.
2. Chronic symptoms of Minamata disease
The chroi.ic symptoms of Minamata disease consist of the aforementioned
age-accumulative, Tsubaki's, and others' late symptoms and the common chronic
symptoms. Clinically, it is sometimes possible to distinguish between them,
and at other times it is difficult to do so.
No. 5946 is a typical common case of chronic symptoms. This patient
was aware of hand tremors since 1957, but felt that it was due to drinking
sake. The tremors gradually became worse, and during the two years that
elapsed, sensory and articulation disorders developed, as well as walking and
hearing difficulties and malnutrition. After diagnosis as Minamata disease
on October 14, 1959, he developed abnormality of the joints, such as articu-
lar disease, finger deformity, and joint stiffness, and was hospitalized in
1965 for rehabilitation purposes. Gradually, he became incapacitated, with
all the symptoms of Minamata disease appearing. A biopsy revealed typical
Minamata disease changes, particularly fallout of nerve cells of the cerebral
cortex, a microscopically spongy optic center, fallout of nerve cells in the
front center), secondary changes in the spinal, conical groove section, and
atrophy and fallout of anterior horn cells, and changes in posterior fibers,
which usually occur after a lengthy period of Minamata disease. Since the
321
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patient definitely had articular rheumatism and condyloma-type endocarditis,
joint and finger demormity was not believed due to Minamata disease alone.
However, this case was interesting in that chronic symptoms of Minamata
disease were established and were gradually progressing. The fact that the
patient, despite his condition, lived until age 79, indicates that death from
Minamata disease is attributable only to acute symptoms, without directly
affecting vital organs. The same can be said of Cases No. 5972 and No. 5952,
both of whom lived until ages 81 and 85, respectively.
3. Progress of chronic conditions of Minamata disease
Even acute cases of Minamata disease, if not of the intensive type, can
survive for a long time, just as chronic cases do, but will die from added
complications or recurrent pathological changes. We shall not delve into long
term cases, since they were the subject of previous reports a few years ago.
The five cases of autopsy discussed herein fall under the chronic long-term
category.
4. Mercury level in autopsy cases
Changes in the mercury level in cases subjected to autopsy may be viewed
in the light of total Minamata disease-related autopsies conducted by our faculty.
Generally speaking, the mercury level in most visceral organs, in the case
of Minamata disease, returns to normal after 2 or 3 years, except in the
brain. In Cases Nos. 5987 and 6013, however, the level had already returned
to normal. In the former case, clinical records showed that three years had
elapsed, but pathologically it was believed to be considerably longer. Six-
teen years had elapsed in the case of No. 6013, so there is nothing mysterious
about the level being back to normal.
The problem concerns the typical, complete-type Minamata disease seen
in No. 5946, where the aggregate mercury level in the liver was 10 ppm wet
weight, and 1.5 ppm in the brain, or two digits higher than the normal rate,
322
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The methyl mercury value was, of course, near normal. Even though the mer-
cury found in the brain was in the form of inorganic mercury, it was possible
that at the outset, it was organic mercury exceeding the cerebral vascular
shelf. Therefore, despite the reduction, we feel that the effects of mercury
were felt not only at the onset, but for an extended period of time. Thus,
we believe it necessary to consider the chronic progress of symptoms and their
gradual aggravation (see Table 3).
V. CONCLUSION
Based on a study of 10 cases of autopsy covered in last year's report and
the current 5 chronic cases, the following conclusions were reached.
1. At the onset of Minamata disease, not only acute but also chronic
symptoms are involved.
2. In addition to the common chronic symptoms, a chronic symptom of
age-accumulative, late Minamata disease exists, evoked by hidden Minamata
disease striking about the time a person enters the senile period. This is
different from late Minamata disease symptoms occurring as a result of mer-
cury as claimed by Tsubaki.
3. In age-accumulative, late Minamata disease, senile consumptive
changes occur in nerve cells, as peculiar pathological changes develop in
the nervous system.
4. Neurological changes in chronic Minamata disease do not greatly
differ from those of the earlier long-term Minamata disease.
5. In chronic Minamata disease, neurological changes did not appear
to have a direct effect. However, neurological and mental symptoms were at
times aggravated by senile changes or vascular disorders.
323
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6. The mercury levels in long-term cases were back to normal, but in
some cases were high, probably due to residence in the Minamata district.
REFERENCES
1. Takeuchi, Tadao, et al. Pathological Study of Minamata Disease After
10 Years (Part 1), Particularly Autopsy Cases of Minamata Disease AFter
a Lapse of 10 Years, and Their Characteristics. Report of March,
1972. Kumamoto Medical Association Journal, Vol. 46 (11), 1972,
pp. 666-705.
2. Takeuchi, T. Pathology of Minamata Disease. (Kumamoto University)
Shuhan Co., 1968, pp. 141-228.
3. Takeuchi, Tadao, et al. Accumulation of Mercury in the Human Body and
Its Changes — Observations on the Basis of Minamata Disease Autopsy
Cases. Section on pathological study of this report.
4. Tsubaki, Tadao., et al. Personal notes.
5. Takeuchi, Tadao, et al. Two Cases of Autopsy of Minamata Disease
Involving Death from Semi-Acute Conditions. Kumamoto Medical Asso-
ciation Journal, Vol. 33 (Supplement), 1961, pp. 602-613.
324
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9. 2) Pathological Changes in Islets of Langerhans as Seen in Minamata
Disease Autopsy Cases
Second Seminar, Pathology, Department of Medicine,
Kumamoto University
Team member: Tadao Takeuchi
Research assistants: Takaji Shigenaka, Kazuko Sato
I. PREFACE
From the results of our autopsies and numerous research reports, it is
clear that in Minamata disease, the nervous system is affected the most by
methyl mercury. As for the effect of mercury on common visceral organs other
than the nervous system in humans and pathological changes thereof, almost no
studies have been conducted, except by Takeuchi and his associates [1].
Takeuchi and his associates reported that in acute and semi-acute
periods of Minamata disease, symptoms that developed were diffusive inflamma-
tion of the digestive tract, particularly, the duodenum; partial or scant
formation of bone marrow; atrophy of lymph glands; and fatty changes in the
liver and kidney. Shiraki [2] claimed that arteriosclerosis may be on the
increase in adults with Minamata disease, since pathological changes resem-
bling arteriosclerosis were present in fetal and infantile Minamata disease.
This problem requires further study, coupled with studies on artificial
nutrition and complex environmental livelihood factors.
We are currently in the stage of reviewing the effects of Minamata
disease on common visceral organs. In the course of such review, we happened
to observe relatively marked pathological changes in Langerhans islets of the
pancreas, as reported below.
II. STUDY MATERIALS AND METHOD
From the 37 cases of Minamata disease-related autopsy, those most suit-
325
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able for the tests following death were selected. Since chronic cases in-
volved mostly the aged with various changes in the spleen which make it
difficult to determine whether they were due to the effects of methyl mercury,
it was decided to focus our attention on six cases — three infantile and an
equal number of fetal cases. An additional 7 acute cases were probed, in an
attempt to observe relatively new changes. Six cases with chronic symptoms
were also observed. For control, infantile cases were primarily used, adult
cases being considered uneventful.
References were made to autopsy records, and then microscopic specimens.
From preserved visceral organs, tissue fragments were sliced and specimens
made of portions of the head, body, and tail of the pancreas. Poorly stained
ones were discarded. Thus, there were several instances wherein specimens
made at the time of autopsy had to be relied upon.
For staining, the usual pathological-histological method was combined,
primarily hematoxylin-eosin stain, Masson's trichrome stain, Azan's stain,
and van Gieson's stain. In the most recent case, the Gomori stain was
also used.
III. FINDINGS
1) Changes in the pancreas in fetal and
infantile Minamata disease
a) Reduction of the islets of Langerhans and islet cells
In the pancreas, the number of islets of Langerhans vary depending on
the area, but are generally more numerous in the tail section than in the
head. Thus, observation was concentrated in the tail tissue, but as the tail
tissue of each of the fetal and infantile Minamata disease cases could not be
obtained, the tissue from the body near the tail was observed. The findings
are shown in Figure 1.
326
-------
In this diagram, the
lateral column shows the great-
est number of islets found in a
10 x 10 x 1 visual field of a
single body, and the perpendicu-
lar column — the number of
islet cells within an islet.
From this diagram, it can be
seen that the number of islets
and islet cells is greatly re-
duced in the 6 Minamata-diseased
infants as compared to the 4
control cases. While there are
no distinct differences between
the infantile and fetal Minamata
cases, it can be generally stated
that changes in the fetal group
appear to be more conspicuous,
there being a marked reduction
in a 13-year-old.
2) Histological
cases
200
150
50
. I' *T*x***
:. " • * x
!?'
. „
« • =
* i
• 1 I x
: • • *
.£/5 6 7 8 9 10 11 12 13 14 IS 16 17 18
• - Minimata diseased infant
x - Control children
Figure 1. Observation of islets of
Langerhans in fetal and infantile Mina-
mata disease — a comparison of the
number of islets and islet cells
No acute changes were found in the pancreas. However, in an autopsy of an
individual who succumbed around 1959, new changes were found in a part of
islet cells, marked with variations and disintegration (see Photos 2-3).
Since there was a time lapse of from two and one-half to 13 years in most
cases, the changes were chiefly of a chronic nature, with reduction and
atrophy of islets being noticeable (Photos 3, 4, 5, 6). Compensatory hyper-
trophy (Photo 6) was seen in many cases, making for irregularity of sizes.
Relatively few scar formations were noted. Where present, it was an abnor-
mality considering the age of the individual (Photos 4, 5). However, none
327
-------
' * -
•-'J1
Photo 1*. Age, 6.3; fetal Minamata
disease (No. 3794); fairly normal
islets of Langerhans, with some 110
islet cells in cross section; such
islets have radically decreased
Photo 2*. Age, 6.3; fetal Minamata
disease (No. 3794) ; prominent islets
of Langerhans
p.
i.
.'* f.
« i
'V
-------
Photo 5*. Same case as above (No.
3794); atrophorous islets of Lan-
gerhans showing a fibrous trend
*Photos 1-5 — enlarged view of
equal magnification
;v- •
.-' •*
Photo 6. Weakly magnified view; age,
7; infantile Minamata disease (No.
3298); great atrophy and oblitera-
tion of islets of Langerhans in pan-
creas, accompanied by slight fibrous
trend; conpensatory hypertrophy in
the middle, and increased number of
islets of Langerhans
was vitreous. Because of the irre-
" " "I
gularity of size due to reduction and
regeneration of the islets, the glandular structure of the external secretory
gland became unsystematic in one case (see Table, 1, Photos 7 - 12).
2) Changes in the pancreas in acute
Minamata disease
From those who died of acute or semi-acute symptoms, 7 cases, all adults,
who succumbed on the 45th, 53rd, 60th, 90th, 96th, and 100th jay after onset,
were probed. There were marked irregularities in the size of the islets,
and indications of changes that had occurred in cases one and a half months
after the onset of the disease. Since these conditions were observed also in
younger adults aged 29 and 34, age was not found to make any difference.
Variations and atrophy were seen in the islets, with many reduced in size.
The number of decrease was not remarkable, except in one area; depending on
the islets, there was a large reduction of islet cells. Variation and disin-
tegration of islet cells (Photo 15) represented a new change. Although scar
329
-------
TABLE 1. PATHOLOGICAL AND HISTOLOGICAL CHANGES IN THE PANCREAS IN FETAL
MINAMATA DISEASE AND MINAMATA-DISEASED
INFANTS
Minamata
disease
biopsy
cases
(chil-
dren)
Stricken
child
Control
child
01
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7
8
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*
Fetal Minamata disease.
formation and compensatory hypertrophy denoted old changes, these could not
be necessarily viewed in the same light as the underlying cause of infantile
Minamata disease because of the age difference, but could be considered as
attributable to growing older. A vitreous character was noted in one case
(see Table 2, photos 14, 16, 17, 18).
330
-------
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Photos 7-12:
(Caption continued on following page)
331
• >••'.<
^•>;si
-------
Photos 7-12. (continued)
Photo 7 — slightly enlarged view of pancreas of infantile
Minamata disease case (No. 3298). Relatively numerous
islets of Langerhans, the islets being small and islet
cells being few
Photos 8-12 — identical pancreas of No. 3298, but
greatly enlarged view; atrophy and obliteration of islets
of Langerhans in the pancreas, with some forming scars; such
changes were marked even in a child (age 7) with Minamata
disease
Photos 8-9 — marked atrophy of islets of Langerhans
Photo 10 — Imperfect, unsystematic regeneration following
disintegration of islets of Langerhans; indistinct boundary
with external secretory gland
Photos 11 - 12 — various images of scar formation in islets
of Langerhans; not found in children, but marked in Minamata
disease infants and accompanied by fibrous tendency
Note: Photos 12 - 18 — magnified views of same
[!»•, .„••••;• .j? slV ;\v
Photo 13*. Islets of Langerhans of
infantile (age 6.3) Minimata disease
case (No. 3794); severe atrophy and
loss of two islets; no regeneration
Photo 14*. Semi-acute, adult Minamata
disease case (No. 3209); 90 days trans-
pired; two islets obliterated; one in
atroporous condition and in early
stages of fibrositis
Photos 12 - 18 — magnified view of same.
332
-------
r.
.*. •*
i V
-2
-• m» •, .iv.i. . .
Photo 15* Adult Minamata disease
patient (No. 3209) after 90 days;
mortification of islet cells and
fibril, vernal cells beginning to
increase
Photo 16*. Chronic adult Minamata
disease patient (No. 3497); atrophor-
ous and obliterated islet of Langer-
hans which became fibrous, and
fibrositis
I , 1 • - '•' ', ' . • .'*„" ~ 4
.
17
Photo 17*f. Fibrositis in above
case
J -'*" **•*'• i; ''<^>'r '•'; -i» •-,"I
•••**•
-->'
w <
' •* -' ^* 'C^
Photo 18*. Adult, semi-acute Minamata
disease patient (No. 3209); atropfeor-
ous and obliterated islets of Lan-
gerhans are indistinct; unsystematic
and undergoing regeneration of ex-
ternal secretory gland tissue
Photos 12-18 — magnified view of same.
333
-------
TABLE 2. PATHOLOGICAL AND HISTOLOGICAL CHANGES IN THE PANCREAS OF ADULT MINA-
MATA DISEASE AUTOPSY PATIENTS
General items
Pancreas
Islets of Langerhans
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1 Remarks
^
*
*
*
Note. 2.9 for lapse of time is defined as 2 years and 9 months.
* — examination of other than tail area.
3) Changes in pancreas in chronic Minamata disease
Six cases involving a time lapse of 1 year and 4 months, 2 years, 2.9
years, 4.3 years, 9.9 years, and 11.3 years' were studied, but since they were
all adults and mostly of advanced age, sufficient data were unobtainable. In
the chronic cases, there was no marked reduction in the number of islets, but
compensatory hypertrophy and irregularity in size of islets was seen. Atrophy
334
-------
and loss tended to be less than in infantile Minamata disease of acute or
semi-acute cases. Scar formation was noted, which can be explained by the
age difference.
IV. SUMMARY AND COMMENTS
As already indicated by some clinical practitioners, diabetes was some-
times found in Minamata disease patients. Whether this was due to the effects
of organic mercury, or somehow developed independently, was unknown. It is
known, however, that diabetes will induce diabetic neuropathy. Should peri-
pheral nerve disorders become the main symptoms in a light case of Minamata
disease, and diabetes is confirmed, it may become clinically difficult to
distinguish it from diabetic neuropathy and effect the diagnosis of Minamata
disease.
Okamoto and his associates [3] found in a detailed study that islet cells
biologically contain zinc, which plays an important part in insulin production.
Their diabetic zinc theory that obstruction of the functions of zinc will
readily lead to islet type diabetes is well known. Thus, substances reacting
with zinc will induce diabetic symptoms. Recently, it has been found that
kinohorumu [sic] will cause nerve disorders such as SMON, and also islet-type
diabetes (Miyoshi [4], Takeuchi [5], and others).
It may be possible for metals, which can be substituted for zinc to
produce a chemical reaction in lieu of zinc within biologically zinc-contain-
ing cells, to influence metabolism of cells. In fact, Kakiuchi, Takahashi and
Suikawa [6] reported last year (1972) before the Japan Pathological Associa-
tion that cobalt chloride (CoCl?) obstructs B cells of the islets of Langer-
hans. Thus, it is possible that mercury will affect zinc metabolism, but
Ammon horns containing much zinc in the nerve tissue generally remain unob-
structed by Minamata disease. Of course, obstruction by Ammon horns is some-
times seen in Minamata disease biopsy cases, but not as prevalent as in the
case of disorders of the optic center or cerebellum. For the above reasons,
335
-------
we did not then devote much attention to the disorders of the islets of Lan-
gerhans in the pancreas. However, when we realized from experimental obser-
vations that methyl mercury strongly impaired filaments of certain types of
cells and not of others, we calculated that a metal would produce a different
obstructive reaction, depending on the type of cell. As in the case of SMON,
even substances which will cerate with metals will obstruct zinc-containing
islet cells, but will not obstruct zinc-bearing Ammon horns of the nervous
system. Therefore, we feel it necessary to consider each phenomenon to study
the metabolism and consider the peculiarity of cells.
From the foregoing, it is highly conceivable that islet cells are ob-
structed during methyl mercury poisoning. In fact, the changes in the islets
of Langerhans found in the autopsy of Minamata disease cases represent a phe-
nomenon which we cannot ignore. It was interesting indeed to find that
marked changes had occurred in the Langerhans islets in the autopsy of adult,
fetal, and infantile Minamata disease cases.
In adult cases, the complications of diabetes can be expected because
of numerous old people among the autopsy cases. However, the fact that dis-
integration of islet cells was found to occur in chronic cases who succumbed
from adult chronic symptoms or in an environment of fish and shellfish con-
sumption is of concern. Moreover, the verification of adult-type diabetic,
pathological changes in infantile and fetal Minamata disease cases is a cause
for grave concern. Its prevalence in all cases, regeneration, hyperplasia,
irregularity of islet cells, and the marked reduction in the number of islets
and islet cells are enough to make one suspect the effects of methyl mercury.
It is to be regretted that a detailed study on the presence of diabetes
was not conducted while the patients were still alive. According to Tokuomi
[7], of 11 confined patients, 1 had diabetes and 2 had a slightly high blood
sugar value, but not much attention was paid to them. The existence of two
cases of diabetes out of 11 means that about 20% had a high blood sugar content.
Furthermore, according to last year's epidemiological report by Nomura and
336
-------
and Matsushita [8], 24 persons (3.3%) out of 725 residents of Minamata con-
taminated district showed a sugar reaction in a urine test, and in Goshonoura,
where there is less contamination, 21 (2.1%) out of 1009 residents showed a
positive reaction. However, these were simple tests in which blood sugar was
not determined. Whether the foregoing level of sugar in urine is high or
otherwise compared to other areas not contaminated by mercury is not known,
since there was no uncontaminated area for control purposes. We are inclined
to believe that the level is not so high, on the basis of observations of
islets of Langerhans in our biopsy cases, for even if the islets were destroyed,
regeneration and hypertrophy would follow and their functions would be main-
tained. However, it is true that, because of this, irregularities of size,
atrophy, and obliteration and reduction of the islets are induced. It is
believed that those islets unable to sufficiently regenerate sufficiently
induce an increase of blood sugar, leading to sugar in the urine. Thus, it
may be correct to state that pathological changes in the islets of Langerhans
take precedence, with only those severe changes inducing diabetes. This
theory, however, must be established experimentally in the future.
V. CONCLUSION
A study of pathological changes in the islets of Langerhans based on
Minamata disease-related autopsy produced the following results.
1) It was shown that in Minamata disease there were disturbances of
islet cells, commensurate changes being noted not only in adult acute cases,
but in chronic cases as well.
2) In fetal and infantile Minamata disease also, the effect of dis-
turbances of islets of Langerhans was noted, there being a reduction and ob-
literation of islets and decrease of islet cells.
3. The trend of pathological changes in islets of Langerhans was rela-
tively more marked in fetal rather than infantile Minamata disease; because
of the small number of cases, further study is required in this matter.
337
-------
4) In both fetal and infantile Minamata disease, there was shown to
be regeneration and hypertrophy accompanying the obstruction of the islets,
thereby resulting in a relatively marked irregularity of the size of islets.
There were scar formations in some cases.
5) In autopsy cases involving the aged or those over 50, differentiation
between changes caused by advanced age and those by diabetic conditions could
not be made.
6) Because of the regeneration pehnomena surrounding pathological
changes in the islets of Langerhans in Minamata disease, sugar in the urine
cannot always be established; however, any increase of blood sugar or com-
plications of diabetes brought on by severe pathological changes should be
taken into consideration.
7) Since mercury compounds could have an effect on zinc metabolism in
the islets of Langerhans, a future study is required.
REFERENCES
1. Takeuchi, Tadao. Pathology of Minamata Disease. Minamata Disease —
Study on Organic Mercury Poisoning. (Research team, Kutnamoto Univer-
sity) Shuhan, 1966, pp. 194-282.
2. Shiraki, H. Discussion for Neuropathology of Minamata Disease. Sym-
posium on Geographic Neurology with Special Reference to Geographic
Isolates. VII Intern. Congr. Neurology, Rome, 1961.
3. Okamoto, Kozo. Experimental Pathology of Diabetes. Japan Medical
Publication, 1951.
4. Miyoshi, Kazuo. SMON Symptoms and Chemical Substances. SMON Survey and
Research Council Report No. 2, 1970, pp. 198-206.
338
-------
5. Takeuchi, Tadao, Nobuyoshi Sakurama and Takaji Shigenaga. Pathological
Changes in Islets of Langerhans in the Pancreas as Seen in SMON
Biopsy Cases. Path, of Medicine, Vol. 83 (7), 1972, pp. 479-480.
6. Kakiuchi, Hiroshi, Kiyonobu Takahashi and Osamu Suikawa. Pathological
Observations of Islets of Langerhans of the Pancreas During Adminis-
tration of Cobalt Chloride. 61st General Assembly of Japan Patholo-
gical Association (Tokyo), 1972.
7. Tokuomi, Haruhiko. Clinical Minamata Disease; Minimata Disease —
Study on Organic Mercury Poisoning. (Research team, Kumamoto
University). Shuhan, 1966, pp. 48-76.
8. Nomura, Shigeru, Toshio Matsushita, et al. Transition and Epidemio-
logical Study of Minamata Disease: Results of Health survey of
Minamata, Goshonoura District Residents (Part 1). "Epidemiological
Clinical Medicine and Pathological Study of Minamata Disease After
10 Years." Team report (1), 1972, pp. 6-36.
339
-------
10. ACCUMULATION OF MERCURY IN THE HUMAN BODY AND ITS CHANGES AS VIEWED FROM
AN AUTOPSY OF MINAMATA DISEASE CASES
Second Pathological Seminar, Department of Medicine,
Kumamoto University
Team member: Tadao Takeuchi
Research assistants: Mitsuaki Eto, Ken Sakai,
Hidetoshi Kojima
I. PREFACE
Since an accumulation of mercury within an individual is required to
produce methyl mercury poisoning (Minamata disease), the level of mercury
needed to precipitate poisoning has been the subject of debate centered around
animal experiments and Minamata disease cases. Not long ago, Takeuchi and
associates [1, 2, 3] reported on the level of mercury needed to develop alkyl
mercury toxicity in cats and mice. At that time, they estimated the amount
of mercury in the human body required for affliction of Minamata disease, and
calculated that for an adult the amount (ingested) was 0.7 rag/kg (weight)
per day until a total volume of 20 mg/kg was reached, and for a fetus — 1/4
or 0.175 mg per day for a total of 5 mg/kg. They estimated that the dangerous
level would be one-tenth of the above, and added that a 2 mg/kg level would
require precaution.
On the other hand, Kitamura and his associates [4] came up with figures
relative to the intake and accumulation of methyl mercury. Based on findings in an
MeHg203 intake experiment in Sweden that its biological half-life was about
70 days, they calculated the lethal and toxic levels as 1000 mg and 100 mg,
respectively, for humans. They stated that a minimum of 100 mg was required
to produce a toxic level in the human body, but did not discuss body weight.
This meant that an individual weighing 50 kg would develop poisoning if 100 mg
of methyl mercury or 2 ppm (2 mg/kg) had been uniformly distributed throughout
340
-------
his body. This would agree with the dangerous level suggested earlier by
Takeuchi and others [3]. Nevertheless, no strict comparison was possible,
because Takeuchi and his associates concentrated on total mercury level, while
Kitamura directed his attention to the level of methyl mercury, and further
because their ratio would vary depending on visceral tissues or animal species.
Apart from such calculations, we felt the need to determine, in the case
of methyl mercury poisoning, how the mercury moved in human visceral organs,
in the light of related problems, such as affliction through minute ingestion,
probability of chronic affliction, and multiple affliction due to late symp-
toms or with age.
In this report, we reviewed the movement of the mercury in visceral
organs, on the basis of autopsies performed by this faculty.
II. RESEARCH MATERIALS AND METHOD
Thirty-seven cases of autopsy (30 adults, 4 juveniles, 3 fetal infants)
conducted at this faculty since 1956 were reviewed, of which 23 were previously
reported on and 11 more were covered in a supplemental report. Since no de-
tailed study was made on changes in the mercury level, we decided to present
an overall picture at this time.
Organs selected for review were the brain, liver, and kidney of biopsy
cases. Some organs, particularly the brain, were divided for observation
purposes into the cerebrum and the cerebellum, but we decided to study pri-
marily the cerebrum in keeping with the practice in early cases.
The measurement of mercury was by the Dithizone method. The Kitamura
method had been adopted in the earlier period, and then the Irukayama-Fujiki
method, subsequent to 1961. Both expressed the mercury present in visceral
organs by total level Hg ppm wet weight.
341
-------
III. FINDINGS
Table \ gives the level of mercury found in the liver, kidney, and brain
at the time of death of each of the 31 cases, out of 37, whose clinical pro-
gress was comparatively well known since the onset of the disease until death
(see Table 1). A graphical presenta-
tion of same is shown in Figures 1
and 2.
TABLE 1. CLINICAL PROGRESS AND LEVEL
OF MERCURY IN VISCERAL ORGANS
Observation of acute or semi-
acute periods from the nineteenth
to the one hundredth day from the
onset of symptoms indicated that
the mercury value was high in the
kidney and the liver, with the
former invariably showing a higher
value than the latter. On the
other hand, the mercury value in
the brain was very low, indicating
that the degree of disorder of
tissue cells and the level of mer-
cury did not always run parallel;
that, rather, some relationship
existed between the properties of
cell types or metabolism. However,
after one and a half years or more,
the mercury value gradually began
to decrease. In about two and a
half years, the mercury value in the liver and
but the level in the brain was still high (0.4
level (0 - 0.05 ppm).
No. of
cases
i
i
2
3
5
2
1
1
2
2
1
]
2
3
1
1
1
15
Clinical
progress
19 Day
26
45-- IS
53—70
86-100
l.4-l.6Yrs
2.0
2.',"
2.7
4.0—4.3
6.4
8.8
9.1—9.9
10.2
11.3—11.7
14
16
18
Control
Liver
(ppm)
;<> ;.
'. "' 1'
ori. 7
38 S
30 . 2
23.6
8 3
0.3
4.3
3.7
3.7
0.4
17.7
2.3
0.7
1 3
0.4
0.9
o— '2
Kidney
(ppm)
14 1 0
47 .5
S3.'! '
70.2
33.9
36.9
19.6
9.4
VD
11.8
11.3
1.0
7.4
21.6
7.6
10 1
0.2
3.1
0 — 3
Brain
(ppm)
11
12.7
5.,<
i.l
1.0
0.4
0.7
O 1
0.7
0.3
1 8
2.6
1.4
1 ,:.
0.2
2.3
0— '1.05
kidney had returned to normal,
ppm) compared to the normal
342
-------
.Kidnev
•Liver
•Brain
No. casesi i
Figure 1. Recent changes in the
level of mercury in visceral organs
of long-term Minamata disease
autopsy cases
us Year
Figure 2. Changes over time in the
level of mercury in the brain of
Minamata disease autopsy cases
A study of the mercury value in various organs during this period showed
that it differed with the organs. With respect to the liver, mercury ingested
in a large amount during the initial stage decreased at a relatively rapid
pace, but a large level remained until about three months, gradually return-
ing to normal after one and a half to two and a half years. In the case of the
kidney, a very high value was noted at the early stage, gradually decreasing,
as in the case of the liver. However, probably because of the excretory
function of the kidney, the level remained rather high, then decreasing to
half in 70 days and returning, while always maintaining a higher value than
the liver, to normal (0-3 ppm) in one and a half to two and a half years.
A unique case was that of the brain. In the early stage, the accumula-
tion of mercury was fairly low, rising to a peak in about a month, before
gradually decreasing at a very slow pace. Even after three months, the level
was higher than normal by two digits. In some cases, the level was still
high about a year and a half later, and did not return to normal even after
two and a half years, still being one digit higher than normal (see Figure 2).
Specifically, a high value of mercury accumulation was noted in the liver and
kidney, but it returned to a normal value, depending on conditions. The
level in the brain may be fairly low at first, but excretion of mercury, once
it accumulated, was rather difficult.
343
-------
It is known that methyl mercury
can be accumulated in a considerable
quantity, because it is easily per-
meated into the organ in general, and
does not cause any marked disorder.
In the case of the brain, it encount-
ers difficulty because of the blood
brain barrier. However, once even a
small amount gains entry, a serious
disorder is created in tissue cells,
posing a difficulty in eliminating
any accumulation.
In our cases of autopsy, we
studied those in which three years or
more had elaposd since affliction.
Some showed a normal value in the
liver and kidney, but we could not
obtain definitive results because most
reflected scattered mercury values,
probably due to their residence in the
Minamata district (see Figure 3).
As for the value of mercury in
the liver, it had returned to the nor-
mal range in many cases, but some re-
flected an abnormally high value
(35.0 ppm), with cases in which the
period of affliction was unknown re-
cording 7.99 ppm. The mercury value
in the kidney likewise decreased after
3 years or more, but there were fewer
cases of the level returning to normal,
with most showing 10 ppm or more.
TABLE 2, MERCURY LEVEL IN VIS-
CERAL ORGANS OF MINAMATA DISEASE
AUTOPSY CASES
•
o
a
Q>
co
cd
O
1
2
3
4
5
6
'i
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
Autopsy no.
:;i:>9
277 i
3350
2791
277(1
3201
3349
2775
320S
3388
3355
3290
3497
30ir-
3732
3567
3216
3130
3298
4292
3794
5663
548 1
4473
4312
4951
5360
5583
5946
6013
5363
5346
4437
5339
5952
5972
5987
x
•H
,J
70.5
38.2
33.8
3! f>
39.5
42.1
34.7
36 2
32.6
30.0
22 0
21.3
26.0
8.3
0.3
6.4
2.1
5.4
2.0
5.7
0.4
0.5
35.0
2.3
1.0
0.1
0.9
1.3
0.4
0.93
S.o
0.2
0.3
0.8
0.4
s
a.
a.
•\
t^
HI
•g
•H
&
lit 0
47.5
68.2
OP . 0
40.5
10G.O
61.2
21.2
49. S
22.6
42.0
36.3
37.4
19.6
9.4
12.8
3.i
5.9
17.6
11.3
1 0
2.3
12.6
21.6
10.7
4 6
10.0
0.2
3.1
2* . 1
5.5
0.3
1.4
2.5,
e
P.
a.
»i
a
•H
CO
M
m
9 6
15.4
24.8
7.S
9.0
21.3
7.8
9.5
4.9
6.4
4.6
2.6
2.8
5.3
1.0
0.4
1.3
0.1
2 2
2.0
0.7
0.3
0.6
3.0
2.6
2.6
0.1
2.1
1.5
0.2
2.3
2.1
1.2
0.04
0.08
0.06
0.03
Control (15 cases) o—2 0—3 0—0.05
344
-------
Some registered 10 ppm or more even
after 10 years, or even 21.6 ppm,
with a recent autopsy case in which
the period of affliction was un-
known recording more than 28 ppm.
It was considered necessary to
determine at a later date the ques-
tion of whether such high values
were the legacy of mercury accumu-
lation at the onset of disease
.Kidney
.Liver
•Brain
No. cases
Year s
2 2
Figure 3. Changes over time in the
level of mercury in visceral organs of
autoosv cases
or a phenomenon created by residing in a contaminated district.
The level of mercury in the brain was noteworthy. Out of 37 cases of
biopsy, the mercury level was determined in 35 cases. Of these, only two
cases, i.e., one case in which the period of affliction was 13 years, and
another recent case in which the period was unknown, showed a normal level,
with some reflecting a one- or two-digit value higher than normal even after
10 years or more. It indicated that the mercury value in the brain could not
return to normal if one resided in a contaminated district and could not be
ignored, even if it were a small amount compared to that in the liver and
the kidney. It should be borne in mind that the accumulation of mercury
in the brain is the result of methyl mercury, and that organic mercury cannot
infiltrate the blood brain barrier.
IV. SUMMARY AND COMMENTS
In their earlier, brief report on changes in the amount of mercury in
visceral organs, Takeuchi and his associates [8] indicated that the brain
undergoes a different sort of accumulation and change from that of the liver
and the kidney. Further, Irukayama and associates [5], based on animal ex-
periments, found that the accumulation of methyl mercury in the brain was
slower than in other visceral organs during the early stage of administration,
but its excretion was still slower. More recently, Shiraki and his associates
345
-------
[6] reported that, when a monkey was administered a single dose of
methyl mercury, a great amount began to infiltrate into ordinary organs im-
mediately after administration, as observed by autoradiography, but gradually
began to increase in the brain after more than a week.
We carefully studied the progress of initial symptoms by concentrating
on a greater number of autopsy cases, sufficient to observe the level of mer-
cury in visceral organs in human bodies with Minamata disease, associated
with methyl mercury poisoning. In so doing, we referred to the earlier re-
ports of Takeuchi and associates, as well as to recent information that has
come to light.
1) Changes during the initial stage (acute stage)
Observation of cases in which death occurred during the early stage or
acute stage of poisoning revealed that the kidney showed the highest level
of mercury 19 days after affliction, followed by the liver and the brain;
however, the level in the brain was extremely low as compared to that of the
liver, being about 1/8, and about 1/15 of that of the kidney. That still
would be about 192 times or more above the normal level of the brain, assum-
ing it to be 0 - 0.05 ppm. Organic mercury and inorganic mercury can accumu-
late in the liver and the kidney, but inorganic mercury cannot infiltrate
the brain. Since only alkyl mercury can cross over the blood brain barrier,
it can be assumed that the accumulation in the brain of biopsy cases con-
sists of mercury from methyl mercury. Thus, the effects of mercury accumula-
tion on the brain should be fully studied, even though its level may be
lower than in the liver or kidney. Moreover, methyl mercury is known to
strongly disturb and even cause the death of brain tissue, especially nerve
cells, but does not kill liver or kidney cells, even though it may cause
damage (Takeuchi [7], Eto [9], Suko [10]). This was the cause of death of
our case.
Twenty-six days to one month after affliction, it was found that the
mercury level suddenly declined in the liver and the kidney, but still
346
-------
remained high in the brain. This reaffirmed the findings of Takeuchi,
Irukayama, and Shiraki, indicating that a similar trend existed in the human
body, as in animals. It can be assumed from pathological observations of
the brain that the accumulation of mercury in the brain during this period
has a decisive effect on cranial nerve cells.
About two months after affliction, the level of mercury in the liver and
the kidney was about half that of the early stage, which agrees with the
findings of a Swedish academic group about a biological 70 day half-life.
However, there were little or no changes in the level of mercury in the brain,
showing virtually no decrease after two months.
Three months after affliction, a considerable decrease was noted in the
kidney and the liver, but some differences were seen in the degree of change
in both, indicative of the difference in the nature of the organs. The level
of mercury in the brain finally started to decline, reaching almost one half
between two and three months after affliction. However, its level was more
than 116-fold over the normal level, causing concern about its effect on
cranial nerve cells over a three-month period.
2) Changes during semi-chronic period after
one to two and a half years
The cases during this period do not necessarily mean semi-chronic cases
in which acute cases who survived later died of recurrent diseases, but that
the symptoms persisted throughout that period. The case extending almost
two and a half years involved a fetal infant who was initially stricken while
the mother was 8 months pregnant, for a total affliction period of 2 years
and 7-8 months. In this case, the level of mercury in the liver had re-
turned to normal, and to virtually normal in the kidney, indicating that the
mercury accumulation in visceral organs, in general, can be eliminated after
at least two and a half years. The level of mercury in the brain at this time
was 0.4 ppm.
347
-------
It should be remembered, however, that even a small level of mercury develops
symptoms in fetal cases as compared to adults, as has been established by
comparison of clinical symptoms of the mother and through the study of af-
fliction of fetal-type Minamata disease.
In the case of adults, even methyl mercury in an amount sufficient to
precipitate affliction and death will decrease and return to normal in vis-
ceral organs after two and a half years, except in the brain. Even in fetal-
type cases, where a relatively small amount is involved, mercury continued to
persist in the brain.
3) Cases three to four years later
Cases in which the patients were stricken for a period of three to four
years developed during the days when the mercury issue was at its peak, and
the intake of tish and shellfish was strictly prohibited. Thus, the level
of mercury in the liver and kidney was slightly higher than normal, being
near the upper limits of the normal value. The level of mercury in the brain
during this time showed a high value, 14 - 42 times that of the normal value,
in both adults and children.
This was generally true, even after six or eight years.
4) Changes after ten years or more
With the alleged decrease of mercury contamination since around 1965,
and the cessation in 1968 by the Chisso Corporation of the acetylaldehyde
process, coupled with lax enforcement of regulations against consumption of
fish and shellfish, some people of the contaminated districts again began
to eat them, which probably was the reason for further changes in the level
of mercury in visceral organs. According to the survey of Fujiki and his
associates [11, 12], the mercury level had decreased to 1/20 of that during
the prevalent period of Minamata disease. Neverthelss, a high value was still
348
-------
noted in some fish and shellfish, and examinations of human navel regions
revealed that methyl mercury level which reached its peak in 1951 during the
prevalent period continued to show a high value until 1968. It gradually
decreased thereafter, but was found to still persist in 1970. This confirmed
that the return of the mercury level to normal range in certain cases was
not true in all cases. With the foregoing as background, there is a need to
study cases in which 10 years or more have transpired since affliction. Most
were either chronic cases or mild cases at the time of prevalence which later
were accompanied by complications; there were very few serious, acute cases
which took on added complications.
Hence, there were many who died not from recurrent ailments, but from
other types of disease. The knowledge thus acquired should benefit a future
study of patients with mild or moderate degrees of affliction.
Considering such phenomena, we examined the level of mercury in visceral
organs 10 years after Minamata disease affliction. Although there were in-
dividual differences, a high level still remained in the liver, kidney, and
the brain. The fact that a high level persisted even after 10 years, al-
though it was supposed to return to normal in the liver and kidney after about
two and a half years from the early to middle stages, raised a question as to
whether it was the legacy of mercury ingested 10 years ago. Irregularity in
the curve reflecting mercury level changes was also peculiar. It may be that
the accumulation of mercury observed 10 years later reflected the recent
dietary habits of the residents. This theory is supported by a case (No.
4321) having a level of 20 ppm or more in the kidney, and by the recent case
(No. 5346) in which a level of 28.1 ppm was recorded.
Notwithstanding, the mercury level in the liver was normal in many cases,
and slightly greater in the kidney than in the liver, exceeding the normal
levels in some cases. The level of mercury in the brain continued to be 10 -
150 times greater than normal even after 10 or more years.
349
-------
Mercury in the brain is the result of entry of methyl mercury, and once
there is an accumulation, it is very difficult to remove, based on observa-
tions two or three years after the initial stage. What does it portend if
there is hardly any decrease in succeeding periods? Since it has been estab-
lished that a small amount may be excreted in two or three months, it would be
difficult to believe that it would persist even after 10 years. It could be
that, even though the biological half-life in the brain may be drawn out, an
accumulation could manifest itself through a balance between new accumula-
tions and excretion. At any rate, it should be recognized that such a level
of mercury is found today in the brain of Minamata disease cases among resi-
dents of contaminated districts.
Cerebro-biological half-life
The foregoing was a description of the level of mercury found in the
brain, liver, and kidney of biopsy cases. In an attempt to seek the average
base point between the lapse of time and the number of cases of autopsy, we
established the attenuation curve over time of the mercury level by the ex-
ponential functive curve and, using the latter as base line, mathematically
obtained the biological half-life. There was apprehension that the use of
an average method when there was a high initial value in the mercury level in
the liver and the kidney would mathematically distort the true biological
significance, because of the obscure treatment of the base point. We decided
to calculate the biological half-life of mercury in the brain, because the
average values are stable in the case of the brain, the ingestion of mercury
in the brain is similar to that in animals during experiments, and the base
point is stable. Another point of consideration was that the biological
half-life in the brain was tied closely to the disease, because methyl mercury
caused primarily disorders of the cerebro-nervous system; further, that methyl
mercury compounds entered the blood brain barrier slowly in the initial stage,
accumulated slowly, and were excreted slowly.
Additionally, it was a good chance to calculate the half-life, because
in cases of acute stages (19 - 100 days) or early stages of Minamata disease,
350
-------
the intake of fish and shellfish was not so free as now for therapeutic and
other reasons. Accumulation of mercury attributed to new contamination has
been observed in long-term cases of autopsy, due to recent, renewed ingestion
of fish and shellfish at the affected sites. It was found that it took about
230 days from the onset of disease to half-life.
The case of the brain is described (see Table 1).
TABLE 1
PVdaysF1'p-p-r
46.5 1C. 3
61.5 12.7
93 5.8
510 4.1
72u 1.0
fv?0 0.4
lotaki)
av. value *=^j -,
n) zi
: 2.791
2.541
1.75S .
1.411
0
-0.916
z ^1.264
XI — X
-339
-324
-292.5
126.5
334.5
494.5
i zi — z
1.523
1.277
' 0.494
0.147
j -1.2G4
! -2.156
t
;
,
c*i-:o:
114.921
. 104. 9"6
S5 . 556
16.002
111.890
244.530
677. S75
a r=s=
3oo.I2
f.vi-z}:
2.236
I.b31
0.224
0.022
1.593
1.045
10.469
1 ~320
i, vi- .1 ,/ '.zi— z )
- 513.65
- 413.75
- in. 50
-r U-..6!)
- 422.^.)
— luuo.14
— 254i>. 19
- 424.37
A graphical presentation of the distribution of specimens provided
(xi, yi) indicates ppm attenuation of Hg over a period of time (Figure 1,
line A) . The exponential function curve
b' = i-b, .'.b = Iog b')
close to the broken line formed by the specimens (xi, yi) , is obtained.
The manner in which this is obtained is to estimate an approximate curve
1 • , and then determine b1 , a.
Take the coefficients of both areas of the approximate curve y=t-vav as
y = log z. In other words,
z — log y --loe' b'c--1 =log b' i log car — b~^x
351
-------
Thus, the equation developed by this manipulation, z = ax + b, represents
the straight line at the plane formed by the axis of x (number of days) and
z (log y = z).
Against the specimen (xi, yi), zi = log yi is placed. Thus, a new
specimen (xi, zi) is obtained (dark line, Figure 2). We can determine a, b
0 200 400 000 800 X
Figure 1
200 400 600 \\800
1
Figure 2
so that the distance will be the minimum between the straight line y = ax + b,
having x, z as the axis of coordinates and various specimens (xi, zi). (Refer
to the section on minimum self-multiplication straight line, Introduction
to Easily Accessible Statistical Mathematics.) In other words,
a x ,
However, when (xi, zi) is indicated as 1 < i < N:
N
N
=
-------
1 N
'= i - (Ji-j)Cii-;)
-> i — i
(coefficient of correlation)
In the case of the brain, j-.:^.:>. z--?i.'.">i, ' ••• '•••''••'. a *=?]. 321, r- = --iV-."..
From the foregoing, the minimum approximate straight line z = ax + b
relative to (xi, zi) was obtained. In the case of the brain, it is
.,-_ - -M m >..,»«.' ;!.-!- (the straight line graph is indicated as the straight line
in Figure 2). As log y = z = ax + b , thus,
This is one of the approximate curves according to the exponential function
relative to the broken line graph (Figure 1, line A) of specimens (xi , yi)
(see Figure 2) .
The method of obtaining B.H. (the period from onset
to half life)
If xn were the number of days of maximum ppm of Hg, the maximum value
V is determined by :
In the case of the brain, x~ = 46.5 resulted in .<•„ 2— fi 3:;:> . Next, solution of
is made for x. In other words,
log v"- -- Iojj(b'e=-r)-log o'-i-
=--b-fa.x (log b'= li)
,. ,= IoB(-)-b
From the foregoing, BH x- was
In the case of the brain examined, x-.^-'W was obtained,
353
-------
In other words, the maximum value *0 is determined by:
a = r *-2 = (-0.956) x-I'?2;-, «.--".00376
a A loc.li.
333.5+1.261—2.712
XQ = 46.5.
Thus, x is
o
-[log (6. 325) -2.712J =2Jf).84
(Above by Shoichi Sato, Assistant Professor, Department of Physics,
Kumamoto University.)
Comments; Methyl mercury damages visceral organs to a relatively mild
degree. Pathologically, several disorders have been attributed to it, but
not as clinical symptoms. However, it affects the nervous system tremendously,
almost beyond comparison. This indicates that methyl mercury is closely re-
lated to metabolism, existing only in either the brain or the nervous system,
and we are pursuing a separate study to clarify its structure. Such matters
are associated with the fact that a relatively large amount of mercury in
the liver or the kidney produces little disorder, whereas a very small amount
in the brain would have a marked effect.
Kitamura and his associates have linked the level of mercury accumulation
in human beings with poisoning symptoms. This may be fine from a hygienic
concept, but we thought that , in order to uncover the relationship between
the occurrence of cranial changes known as poisoning symptoms, it was better
to concentrate on the intake level of alkyl mercury. Thus, based on our
earlier findings, an examination of the relationship between the intake level
of alkyl mercury and cranial changes disclosed the following (see Table 3) .
354
-------
TABLE 3. ALKYL MERCURY INTAKE LEVEL REQUIRED TO PRODUCE POISONING SYMPTOMS
(MINAMATA DISEASE) (TAKEUCHI AND ASSOCIATES)
Humans and animals
e
o
-H
o
•H
M-l
PI
10 vears
Maximum no effect
level
According to this table, a person 50 kg in weight will develop an acute
affliction by daily intake of 35 mg of alkyl mercury when the aggregate dose
reaches 1000 mg. A dangerous level would be reached when a daily intake of
3.5 mg reaches a total of 100 mg. According to Kitamura, 100 mg would cause
affliction in human beings, and when biological half-life is considered, it
would require 10.5 days at a daily dose of 10 mg to attain a 100 mg level;
28.7 days — at 4 mg; 40 days — at 3 mg; 465 days — at 1 mg; further, that
a daily dose under 1 mg would never reach 100 mg, because of half life. In
other words, Takeuchi's dangerous level and Kitamura's affliction-poisoning
level are in virtual agreement.
355
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Since serious cases of Minamata disease have developed acute symptoms
within one to two months, such findings would mean that a daily dose of three
to four milligrams was being ingested by the individual, and that chronic
patients had taken about one milligram per day for over one year. The level
of mercury in the brain of patients after death averaged about 10 ppm
(10 rag/kg). As the weight of the brain of the patients was about 1100 g,
that would mean about 11 mg accumulation in the brain. A minimum value of
2.8 rag would cause death.
On the other hand, one tenth of the level is said to cause affliction.
This would mean that approximately 1 ppm or a minimum of 0.28 ppm would
develop poisoning symptoms in the brain of human beings in biopsy cases.
Thus, this affliction level is more than 20 times the normal level of mercury
(0 - 0.05 ppm) in ordinary persons, a significant matter when considering
the level of mercury in the brain of Minamata disease autopsy cases.
Observations in the foregoing manner lend credence to the claim that
methyl mercury infiltrates the brain and slowly accumulates therein, causing
affliction when the level reaches an average of 1 ppm or more. Such observa-
tions can probably be used to demonstrate that such developments are also
possible in recent chronic affliction cases as well.
As a result of our latest study, chronic and late symptom cases are con-
tinuing to be found in the Minamata district, after it was established that
affliction can be due to contaminated fish and shellfish in Minamata Bay.
The wet level of methyl mercury in such marine life averaged 0.25 ppm; there-
fore, if an afflicted person had consumed a large quantity, he would have
ingested an average of 300 g in the same district. Even assuming that he
ingested a maximum of 1000 g (possible for a fisherman), the daily intake
would be 0.25 mg (mercury). In other words, a person ingesting 0.25 mg methyl
mercury daily would develop chronic affliction after several years, or more
than 10 years.
356
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If 1/10 of the amount represents a no effect level, that would mean
0.025 mg is the limit. Assuming that the average weight of a Japanese is 50
kg, that would mean 0.0005 mg/kg, much less than the 0.07 mg/kg which we
believed to be the case in acute or semi-acute affliction, making even 1/140
dangerous. We must, therefore, change our thinking concerning mercury.
This means that the safe permissible level for an individual weighing
50 kg is 0.175 mg (mercury) or less of methyl mercury per week.
V. CONCLUSION
Study on the accumulation and level of mercury in visceral organs based
on autopsy of methyl mercury poisoning cases (Minamata disease) disclosed the
following facts.
1, The level of mercury in visceral organs in the case of Minamata
disease depends on the type of organ; it is greatest in the kidney in the
early stage, and then in the liver. There was very little in the brain.
2. The level of mercury in visceral organs changed with the passage
of time, the type of change being different for each organ.
3. In the kidney, there was a marked accumulation in the early stage,
which rapidly decreased and reached one half in about 70 days. At least two
and a half years were required to return to almost normal, but accumula-
tion remained in many cases.
4. In the liver, the initial marked accumulation rapidly decreased,
and was reduced to half sooner than in the kidney. The level returned to
normal after two and a half years, and there were fewer cases of accumulation
remaining as compared to the kidney.
357
-------
5. Initial accumulation in the brain reached a peak after about a month
and decreased very slowly thereafter. It took 230 days from the date of
affliction to be reduced to half.
6. Accumulation of mercury in the brain is thought to be due to methyl
mercury. Because of the blood brain barrier, the level of accumulation was
very low when compared to those of other organs. However, when compared
with a normal brain, it was 200 times or more in the early stage, and one to
two digits higher in value thereafter.
7. The level of mercury in visceral organs of recent autopsy cases in
which the patient had been stricken for 10 or more years underwent no definite
changes. This was thought to reflect the living habits of residents of con-
taminated districts at that time.
8. The high mercury level in visceral organs of recent autopsy cases was
not thought to be due to mercury contamination more than 10 years ago —
rather, a reflection of subsequent contamination.
9. With reference to comments, an average wet weight of 1 ppm or more
with a minimum of 0.26 ppm mercury in the human brain will develop an afflic-
tion, and 5 ppm or more — death.
Thus, the level of mercury in the brain should be treated separately
from that in other visceral organs.
10. The no effect level of methyl mercury in the human body is thought
to be about 0.025 mg (wet mercury weight)/day.
358
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REFERENCES
1. Takeuchi, T. , et al. A Pathological Study of Minamata Disease in Japan.
Acta Neuropath., Vol. 2, 1962, pp. 40-47.
2. Takeuchi, T. Pathology of Minamata Disease.; Experiments with Organic
Mercury, Particularly with Methyl Mercury Compounds: Similarities
Between Experimental Poisoning and Minamata Disease. In: Minamata
Disease. Shuhan Co., 1968, pp. 141-252.
3. Takeuchi, T. Biological Reactions and Pathological Changes in Human
Beings and Animals Caused by Organic Mercury Contamination.
Environmental Mercury Contamination, ed. Hartung and Dinman. Ann
Arbor Sci. Publ., Inc., 1972, pp. 247-289.
4. Kitamura, Masaji, et al. Accumulation of Methyl Mercury in the Human
Body and Its Effect. Research Council Report Concerning Internal
and External Reasons for Toxic Neurological Afflictions, 1971.
5. Irukayama, K. Minamata Disease — Methyl Mercury Poisoning. Assem.
Formosan Med. Assoc. (Taipei), 1970.
230
6. Shiraki, H., et al. Time-Dependent Distribution of Hg-mercury Com-
pounds in Rat and Monkey as Studied by Whole Body Antoradiography.
J. Hyg. Chem, Vol. 17 (2), 1972, pp. 93-107.
7. Takeuchi, Tadao. Pathology of Minamata Disease; Study on Minamata Dis-
ease — Organic Mercury Poisoning Symptoms (Research Team, Kumamoto
University). Shuhan, 1966, pp. 194-282.
8. Takeuchi, Tadao, et al. Minamata Disease after 10 Years and Its
Pathological Changes. Japan New Medical Bulletin, No. 2402, 1970,
pp. 22-28.
9. Eto, Mitsuaki, et al. Unpublished.
10. Suko, Shuji, et al. Unpublished.
11. Fujiki, Shiroshi, et al. Survey and Study Concerning Mercury Contamina-
tion and Its Change in the Vicinity of the Minamata District: Epi-
demiological, Clinical Medicine and Pathological Study Concerning Mina-
mata Disease at the end of 10 Years. Team Report, 1972, pp. 1-5.
12. Fujiki, Shiroshi, Shizuko Tajima and Akiko Omori. Changes in the Level
of Mercury-Caused Contamination in the Minamata Region. Japan
Hygiene Journal, Vol. 27 (1), 1972, p. 115.
359
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11. CLINICAL, PATHOLOGICAL OBSERVATIONS ON ABNORMALITIES AND PATHOLOGICAL
CHANGES IN THE AREAS OF MOUTH AND TEETH OF MINAMATA DISEASE PATIENTS, PARTICU-
LARLY ABNORMALITIES OF FETAL DEVELOPMENT
Second Seminar, Pathology, Department of Medicine,
Kumamoto University
Team member: Tadao Takeuchi
Research assistant: Guniku Aoki
I. PREFACE
The fact is gradually being established that methyl mercury adversely
affects newborn infants and adults, especially their nervous system and a
part of the visceral organ tissue. Further, upon discovery of fetal Minamata
disease as one form of Minamata disease, it was established that methyl mercury
permeated the placenta and affected the fetus. Takeuchi and his associates
[8] assumed, from the standpoint of four types of methyl mercury disorder —
fetal, embryonal, gene distorders, or hereditary — that only the fetal type
existed in human beings, and that only disorders occurring subsequent to the
4-5 month fetal period made their appearance. Gene disorders have been
proven [5, 6] expermentally, using drosophilae and onions. Further, the
obstruction of synthesis of DNA or RNA was shown through the studies of Otsuka,
Sakai and Kojima [4]. Sakai [10] established that, in the initial stage of
sperm formation in mice, there was an inhibition of division of the mother
cell. Whether this is true in the case of human beings is still unknown.
Meanwhile, Murakami theorized, on the basis of an experiment using
phenlyl mercury and teeth abnormalities in fetal Minamata disease, that teeth
disorders may also be caused by methyl mercury.
360
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Faced with the urgency of clarifying whether such a phenomenon occurred
in Minamata disease patients, we decided to conduct a study focused on Mina-
mata disease, particularly on congenital Minamata disease. Since Murakami
[3] had indicated that embryonal disorders among congenital Minamata disease
cases may be in the area of dentistry, we directed our efforts especially to
the mouth and tteth.
In the area of the mouth and teeth, no extensive studies have yet been
conducted on pathological changes and disorders precipitated by organic mer-
cury, being limited to matters involving saliva flow or teeth misalignment
among Minamata disease patients [9]. Ikejiri and his associates indicated [1],
on the basis of examination of the mouth of fetal Minamata disease patients,
that a high incidence of decayed teeth and incomplete enamel formation was
seen in those patients.
Hence, we tried to uncover the abnormalities of the mouth of fetal,
juvenile, and adult Minamata disease patients by examining patients clinically
diagnosed as having Minamata disease, and creating and studying study models.
Bsed on our findings, we reviewed the abnormalities of the mouth and teeth,
areas affected and their conditions.
II. OBJECT OF SURVEY AND METHOD
The object of our latest survey was 18 Minamata disease patients hos-
pitalized at Minamata Municipal Hospital, Myosuien. Of these, 8 were diag-
nosed as either juvenile or adult Minamata disease patients (hereinafter
termed simply as Minamata disease patients) and 10 fetal Minamata disease
patients. Of the latter, two were excluded from our survey, as one of them
was a 15-year old male youth who was uncooperative and excited during our
examination, and the other was a 65-year-old woman who had all dentures and
appeared to have no abnormalities in the soft mouth tissue. Therefore, the
actual number of patients examined was 16: 7 Minamata disease patients
(1 male, 6 female; aged 22 - 72), and 9 fetal Minamata disease patients
(4 male, 5 female; aged 15 - 18).
361
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Examination of the patients' teeth and of the hard and soft tissue of
the inner mouth was made. Study models of the teeth of three Minamata disease
patients and six fetal Minamata disease patients, all of whom had been co-
operative, were completed so that, together with findings related to the mouth,
we could conduct a detailed study. For comparison and reference purposes, we
referred to school health statistics for 1970, and a survey report on the
people's dental disease situation for 1969.
III. FINDINGS
1. Results of examination of the mouth of Minamata
disease and fetal Minamata disease
Table 1 and 2 reflect the results of examination of the mouth of adult
and juvenile Minamata disease patients and fetal Minamata disease patients, ba
based on diagnosis and study models. An explanation of each item follows.
1) Hard tooth tissue
Initially, studies were made of those with decayed teeth, and whether
treatment was received or not. Decayed teeth were classified into 3 cate-
gories as to whether or not treatment was received and/or teeth were missing
(filled teeth excluded), and overall results were expressed by the acronym
DMFT — for decayed, missing, and filled teeth. They are shown in Table 1.
All or 100% of those examined had decayed teeth. The number of un-
treated decayed teeth ranged from 1 to 16 in all of the cases. Out of 9
fetal Minamata disease patients, 4 had not received treatment for 10 or more
teeth, and 6 of this group had never received any treatment. It was a fairly
high rate, compared to ordinary individuals in the same age bracket. In the
adult Minamata disease patients, a greater number had received treatment, but
there was also an increase in the number having missing teeth. DMFT was 5 -
19 teeth in the fetal patients, or an average of 10.5 per person, a very high
362
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Table 1. OBSERVATIONS CONCERNING THE MOUTH OF MINAMATA DISEASE PATIENTS (a)
HARD TOOTH TISSUE, SOFT TISSUE, OCCLUSION
f
M
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1
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7
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14
15
Name
Naka, Chi
Mori, Hi-e
Iwa, Su-ko
Naga, Isamu
Mori, Tomo
Oni, .Yu
Ka, Ta-ko
Kane, Yu
Han, Kazu
Ki'ta, Sa-e
Kita, A-ko
Fuchi, Ki-no
Yama, Sada
Mori , -me
Yama, U
16 Saka, Ma-yo
Age,
sex
15, F
15, F
15, F
16, M
16, F
16, M
17, M
17, M
18, M
22, F
24, F
55, F
62, F
68, F
68, M
72, F
Hard tooth tissue
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364
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TABLE 2. OBSERVATIONS CONCERNING THE MOUTH OF MINAMATA DISEASE PATIENTS;
(b) ABNORMALITY OF POSITION OF TEETH AND OTHERS
Case
no.
Observations concerning the mouth
1
2
! ~ , filled; <• missing and unrestored.
•• missing and unrestored; filled.
(/remaining; >> root remaining; ^-2^ filled.
31 'centripetal distortion; ,,,",, ,". shift to tongue side; • shift
to lip side; centrifugal shift of arched teeth alignment of lower
jaw; a c conical teeth; '; ;-- filled.
11 shift to lip side; ,7 shift to cheek side; f" ^ filled.
!j_j_5_ shift to tongue side; _<_ centripetal distortion r?,: -. filled.
5 mm gap between 4 and ,,', between * and ' 3 ; fc missing and unrestored;
i —= * centripetal distortion; 5 shift to cheek side; <• root remains;
I - filled.
I > •> .—-— . ————— • ———
8 ! L shift to lip side; " „ missing; '" .. bridge affixed; «^~ filled.
9 / centripetal distortion; _a centrifugal inclination; " I shifts to
tongue side; _!. centrifugal inclination; c •• •. -.: shift to lip side;
I c conical teeth; ^5 ' filled.
10 i L centripetal distortion; A shift to lip side; * ;~ centripetal
inclincation; ", centifugal inclination; T76-5-*T shift to tongue side;
= filled; 6 missing and unrestored.
11 ! VJ. centripetal distortion; - " •,- shift to tongue side; 3 centripetal
jinclination; r « missing and unrestored.
12 | 4-centripetal distortion; s_ 355 missing; "!J bridge;
J shift to check side; Sl filled.
13 ^eavy tartar coat; . \ \\ \ I -, ^VvWeA Pt ri missing; l denture;
] :; fined.
I
i'j_L_.-_i_il5_-u bridge affixed; *- succeeding teeth damaged;
<; i missing.
(Table continued on following page)
365
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TABLE 2. (continued)
Case
no.
15
16
Observations concerning the mouth
i C
11 s. p- AVi I'-.V,,'- missing; T,~ bridge damaged.
rate compared to 2.5 teeth among middle school students of "S" district, as
reported by a survey of the Houth Hygiene Academy [2]. Adults also reflected
a high DMFT rate, but theirs cannot be compared with that of the fetal
patients because of the age factor.
As for tooth enamel, we looked for the degree of roilkiness or color
and for the presence of reddish pits. We found that incomplete enamel forma-
tion existed in alnost all of the fetal patients. Specifically, yellowish-
brownish discoloration of the enamel was seen in 8 out of 9 cases, and almost
half manifested either milkiness or pits in the enamel (Photos 1, 2, 4, 7).
In Case no. 9, a shallow pit was clearly seen in 1/2 of the neck of the tooth
(Photo 7). Among the adults, one case manifested a milkiness of enamel, but
none had pits. Four out of 7, however, showed yellowish-brownish discoloration,
3 of whom had moderate degress of discoloration (Photo 8). As described above,
incomplete formation or development of the enamel was easily visible, the
degree of incompleteness and incidence of being being marked in fetal Minamata
disease patients.
Other abnormalities of the hard tooth tissue were deterioration of the
grinding surfaces and indentation or extension of the roots of the teeth.
These were detected in more than half of the fetal patients and in two adults.
They may be due to convulsive actions of the Minamata disease or bad habits,
such as teeth grinding, but we shall not discuss them here as to their link
with clinical symptoms.
366
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2) Soft mouth tissue
As for the soft tissue, we directed our efforts to inflammation of the
gums, swelling and degree. Gingivitis was noted in all of the cases, although
its degree varied (Photos 1-8). Serious gingivitis was seen in 4 out of 9
fetal patients, and in 3 out of 7 adult cases, there being no marked differ-
ence degree between the two groups. Compared to ordinary patients, it was
very serious and of great incidence. Considering that 45-19% of ordinary
patients examined (1970) had periodontal problems, it can readily be recog-
nized that the rate is considerably higher for Minamata disease patients. A
moderate degree of swollen gums was noted in 2 fetal patients, and a mild de-
gree in 2 adult cases. No other significant changes were noted.
3) Occlusion
We looked for malocclusion, if any, and its degree, using the study
model prepared from 6 fetal Minamata disease patients and 3 adult Minamata
disease patients. Here, we classified occlusion into the three categories
of front teeth area, molar area, and teeth arch alignment for convenience.
a) Front teeth area
First of all, in the front teeth area, we studied the degree of deline-
ation, as measured from their center, of the lower jaw from the upper jaw.
Normally, they are positioned exactly in the center. However, in 8 out of 9
Minamata disease patients examined, there were deviations either to the left
or right. An almost normal position was seen in only one fetal patient.
The proportion of deviation was 4 cases each on both right and left sides.
Next, we studied whether the front teeth of the upper jaw overlapped
the front teeth of the lower jaw. Although there were differences as to de-
gree, overlapping was noted in 7 out of 9 cases. In 2 of the fetal patients,
a marked overlapping, or so-called deep over bite, was noted. In 6 of such
367
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9 .
L,
368
-------
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11
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369
-------
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370
-------
22
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371
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.28'
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372
-------
;^.......... ...^ -J1 ..I
Description of Photos
Photos 1-2. Case No. 1. Milkiness of teeth and reddish, medium pits; heavy
yellowish-brownish discoloration; serious inflammation of
edge of gums.
Photo 3. Case No. 3. Moderate yellowish-brownish discoloration; moderate
inflammation of edge of gums; mild deterioration of grinding
surfaces; b[ b, root remaining; 2j 2 filled.
Photos 4-5. Case No. 4. Serious inflammation of edge of gums; moderate
overbite; 212 conical teeth.
Photo 6. Case No. 5. Moderate, reddish pits; heavy yellowish-brownish dis-
coloration; serious inflammation of edge of gums; moderate over-
jet, \l filled.
Photo 7. Case No. 9. Moderate reddish pits and serious yellowish-brownish
discoloration; serious over-jet accompanied by open bite;|.c_
• conical teeth; 2|2 filled.
Photo 8. Case No. 13. Moderate yellowish brownish discoloration; serious
inflammation of edge of gums; marked tartar coat.
Photos 9 - 11: Case No. 4. For this case and cases indicated below, molds
give view of bite area with mouth open, frontal occlusion, and
bite on left side. Observations are outlined in Tables 1 and 2.
(Descriptions continued on following page)
373
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Description of photos (continued)
Photos 12-14 — Case no. 5; Photos 15-17 — Case no. 6;
Photos 18-20 — Case no. 7; Photos 21-23 — Case no. 8;
Photos 24-26 — Case no. 9; Photos 27-29 — Case no. 10;
Photos 30-32 — Case no. 11; Photos 33 - 35 — Case no. 12
cases, the front teeth on the lower jaw were covered so much that they could
hardly be seen (Photos 15 - 17).
Observation of the degree of protrusion of the front teeth of the
upper jaw relative to the front teeth of the lower jaw revealed 2 cases of
serious over-jet among the fetal patients. In other words, Case no. 5 has
a 5 mm gap between the front teeth of the lower jaw and those of the upper
jaw, and 7 mm in Case no. 9 (Photos 12 - 14, 24 - 26). Also, a moderate over-
jet was noted in an adult Minamata disease patient.
Other tnalocclusions in the front teeth area involved frontal projection
of the upper jaw in 9 fetal patients, wherein the molars were in contact dur-
ing the bite, but the front teeth did not and were open. These cases also
were accompanied by a deep over-jet (Photos 24 - 26). Further, in 12 adult
cases, the front teeth in the upper jaw came in contact with those of the
lower jaw at their ends (Photos 33 - 35).
b) Molar area
Assuming that the arched teeth alignment of the upper jaws was in a
normal position when the molars were in a biting position, we studied the
position of the lower jaw in relation to the upper jaw. At this time, our
concept was that the normal pattern consisted of the centripetal apex on the
cheek side of the first molar of the upper jaw fitting in the groove on the
cheek side of the first molar on the lower jaw; that forward position of the
lower jaw constituted centripetal occlusion of the lower jaw, and that the
backward position of the same constituted centrifugal occlusion of the lower
jaw. In the case of fetal patients, 4 out of 6 manifested either centrifugal
374
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or centripetal occlusion on the left or right sides, with only 2 cases being
normal. A somewhat lighter degree was noted in adult cases, with 2 out of 3
showing centrifugal or centripetal occlusion on either the left or right side.
Next, in determining the surface of the molars, our concept was that
the normal position was for the upper jaw to overlap the lower jaw, and that
the opposite occlusion position was for the molars on the lower jaw to pro-
trude toward the cheek. Among the fetal and adult patients, there were 2
cases and 1 case, respectively, of only the molars on the left side mani-
festing opposite occlusion (Photos 13, 16, 34).
c) Arched teeth alignment
In normal persons, the arched alignment of teeth is naturally para-
bolic. Occasionally, however, an abnormality develops due to the shift of
the front teeth to the lip side, and of the molars to the tongue side. In
other words, the arched alignment appears to be V-shaped, constituting a
so-called V-type arched alignment (Photos 9, 12, 15, 24). Such an abnormality
was noted in 10 adult cases, but noteworthy was the fact that one individual
had conditions similar, age-wise, to those of fetal cases (Photo 27).
Other abnormalities of the arched alignment of the teeth were con-
strictured arched alignment due to shift of the molars to the tongue side, as
observed in Cases 4 and 10 (Photos 9, 27). These 2 cases were accompanied by
V-shaped arched alignment in the upper jaw. In Case no. 7, a gap was noted
in the arched alignment, due to uneven growth of the jawbone and teeth
(Photos 18 - 20).
Among the fetal Minamata disease patients, only 8 were entirely free
of abnormality of arched alignment of the teeth, most of them showing V-shaped
arched alignment of the upper jaw, or occasionally constricture of the lower
jaw (Photos 9 - 11, 27 - 29), or accompanied by a gap in the arched alignment
(Photos 18 - 20). In adult cases, all except Case No. 10 were completely
375
-------
free of abnormality. In other words, a morphological abnormality was noted
primarily in fetal patients, which was rather interesting from the standpoint
of tissue formation.
4) Filled teeth and milk teeth
It has been generally stated that eruption of new teeth ends with the
second molar around the age of 10 to 14 [2], Of those over 15, 4 out of 9
fetal patients had filled teeth; specifically, Case nos. 3. 5, 6, and 9 had
filled teeth 2 -• '" • : • >and 2 -j > respectively. The average number of teeth
among the fetal patients were 27.1. Three cases — Case nos. 3, 7, and 9 —
still had milk teeth — '• h- ° , and | c.
5) Other abnormalities
With respect to abnormal positions of teeth, centripetal or centrifugal
distortion was noted in 4 fetal patients and 3 adults. As for shifts to the
tongue side or to the lip-cheek side, there were 3 cases each among the fetal
patients, and 2 cases each among the adult patients. Another abnormality was
centrifugal or centripetal inclination, involving 2 or 3 cases.
Morphological abnormality of the teeth was seen in fetal Cases nos. 4
and 9, manifesting conical teeth at 2 [2 and |_c, respectively (Photos 9 and 24)
Pyorrhea was not observed in any fetal cases, but was found in 3 adult
cases.
376
-------
2. Ailments of the hard tissue, according to area
affected, and abnormal teeth positions in Minamata
disease patients
1) Hard tissue ailments and their treatment
Teeth ailments, according to the area affected, and treatment were re-
viewed on a statistical basis on all cases examined. Because of occasional
difficulty in determining whether a tooth not existing in the arched align-
ment was a missing tooth or a filled tooth, we treated it as a filled tooth
for convenience. The results are shown in Table 3. We are presenting the
data merely as information, because of the small number of cases involved.
Among the Minamata disease patients, an average of 48%, or nearly half,
had teeth ailments, primarily decayed teeth. Teeth (including filled teeth)
most susceptible to disorder were ^ I .-', \ , the most sound were •* - 9i3 ,
with other in between. The rate of treatment for decayed teeth was 26.4%
(12.7% for fetal cases alone), with untreated cases running 20%. No compari-
son was made of these findings between fetal and adult cases, because of the
small number of cases and age differences.
2) Abnormal position of teeth
All the teeth of 9 persons on whom models were prepared were examined
by classifying the abnormality into the three groups of shift, distortion,
and inclination. The results are outlined on the right side of Table 3.
In all Minamata disease cases, the abnormal position involving a shift
to the tongue side was preponderant, registering 10%, followed by a shift
to the lip-cheek side, with 4.5%, manifested primarily in fetal patients.
This can be regarded as a highly unique abnormality in fetal cases. Centri-
petal distortion was noted in 4.5% of all cases, and either centripetal or
centrifugal inclination —about 1%. There was believed to be a need for a com-
parative study of these abnormal positions by examining more cases.
377
-------
TABLE 3. HARD TISSUE AILMENTS AND ABNORMAL POSITION, ACCORDING TO
TEETH, IN MINAMATA DISEASE PATIENTS
0)
V4
u
•a
•H
Vj
Jj
•0)
CU
O.
JJ
4-1
CJ
,— 1
U
01
4-1
•a
Oi
r- 1
r-l
•H
fn
T
14
1
1
2
1
11
13
1
1
1
1
12
59
1.3
F
Q
1
1
1
1
3
Q
1
1
1
1
9
43
C
4-1
0)
V
4J
13
1
0
4
5
0
,
1
2
1
1
1
1
2
i
2
/
77
14.8
F
0
5
o
\
4
0
3
5
3
?
1
9
3
4
t
6
1
2
1
1
1
0
o
\
1
D
60
C4
T F
'.j
)
2
1
9
1
1
i,
1
6
1
1
26
5.3
^
0
0
0
1
1
0
,")
1
6
0
0
17
% of total no. teeth (288) of 9
persons on whom molds were made
Abnormal position
Shift Distor-
l
1
Tg L-C
i
T
l
2
v
3
9
1
J
1
1
1
1
o
1
9
i
O
1
2
29
10. n
F
i
~^
•
0
r«
0
1
r
l
T
;*
i
•'•
?
i
i
o
I
F
1
-
9
]
i
1
tion
Cp
T
!
1
F
l
1?
l
i
l
,j
o
1
Cf
T
I
1
i
F
Inclina-
tion
Cp
T
1
F
0
0
0
Cf
T
1
ir, 13 n u 7 i: i 3 o 2
.
F
l
0
l
,,( J, ,| j .0
JO 7
Notation: Tg — tongue,side; L-C — lip-cheek side; Cp
Cf — centrifugal; T — total; F — fetal
centripetal;
378
-------
IV. SUMMARY AND COMMENTS
Minamata disease patients examined consisted of 9 fetal cases, aged
15 - 18, and 7 adult cases, aged 22 - 72. Case No. 10, a 22-year-old woman,
exhibited conditions similar to those of fetal cases, age-wise, including the
condition of her mouth. There were relatively few disorders of the teeth
in adults, not considering changes due to age. But several abnormalities were
noted in fetal cases. We decided, therefore, to study each aspect of our
findings. Table 4 is a comparison of statistical findings concerning the
mouth of Minamata disease patients with those reported in other references.
TABLE 4. STATISTICAL COMPARISON OF MOUTH AILMENTS OF MINAMATA DISEASE PATIENTS
AND OTHERS
Item
% decayed teeth
% treatment of decayed
teeth
DMFT
Those with periodontal
tissue ailments
Malocclusion (front
teeth area)
Use of toothbrush
Brushed daily
Brushed occasionally
Never brushed
Minamata disease (in-
cluding fetal type)
100%
26.4%
12.2% (only fetal type)
10.5 teeth (only fetal
type)
100%
50% (only fetal type)
0%
18.75%
81.25%
Ministry of Welfare survey
(1969)
85.66%
55.0%
21.30% (middle school
students)
5.8 teeth ("F" middle
school, ace. to
Ikejiri and others)
2.5 teeth (elementary and
middle school stud-
ents, Survey Comm.,
Dental Hygiene Academy)
13.36% (age 21 or below)
79.68%
11.81%
8-13%
379
-------
Among ailments of the hard tooth tissue, decayed teeth was the highest
among Minamata disease patients, with 100%. This was remarkably high, com-
pared to 85.66%, registered in the survey of human teeth ailments for 1969
[2]. DMFT per person among all Minamata disease patients examined was 11.8
teeth, a breakdown of which was fetal patients — 10.5, and adult cases —
13.0. According to Ikejiri and his associates [1], DMFT in 1970 was 5.8
teeth at "F" middle school in a Minamata disease prevalent area. Further,
according to a report prepared by the Survey Committee of the Dental Hygiene
Academy [2], DMFT of middle school students of "S" district, which we used
for comparison, was about 2.5 teeth. This showed that the rate was highest
in fetal patients, and also high among "F" middle school students in the
disease prevalent area. Considering that the district is mercury contaminated,
there could be some relationship between decayed teeth and organic mercury
contamination. The percentage of decayed teeth treated was 12.2% in fetal
cases, or almost 1/2 of that of 21.30% of middle school students, according
to school health statistics for 1970 [2].
With respect to enamel, there was at least one case among fetal patients
of milkiness, reddish pits, and yellowish-brownish discoloration. Since the
figure was high as to the degree of incompleteness and incidence when compared
to ordinary patients, it was noteworthy in relation to the previously de-
scribed incidence of decayed teeth.
As conditions for occurrence of decayed teeth, there is believed to be
a complicated decaying process involving pathogenic, environmental, and host
(property of teeth) factors, as in other ailments. It is wholly possible
that secondary factors, such as inability to use toothbrush because of accom-
panying disorders of the motor function or mental-intellectual disorders of
Minamata disease patients, lack of sense of hygiene or awareness of decayed
teeth, or decreased concern for treatment, would be a cause for decayed
teeth or gingivitis. On the other hand, serious incomplete formation of
enamel was noted, especially in fetal patients. Aside from the participation
of secondary factors, it is well known that incomplete enamel formation abets
380
-------
tooth decay. The question, then, was whether, during the formation of devel-
opment of the fetus, the mercury contamination had some effect on tooth for-
mation and growth, particularly on enamel formation. Even if there were
such a possibility, we do not possess sufficient data to prove this point
at this time.
Based on observations of the condition of the bite from study models,
it can be stated that serious malocclusions exist in fetal Minamata disease
patients. Most noteworthy was that in the front teeth area there was a
serious degree of overlap of the front teeth in the upper jaw in 5 out of 6
cases in fetal patients, two of whom also manifested a serious overbite
(Photos 9-11, 15 - 17). One case also indicated a serious over-jet, along
with open bite (Photos 24 - 26). Serious malocclusion of the front teeth
area, as viewed from the side, was indicated in 50% of the fetal patients —
a remarkably high rate when compared to 13.4% (age 21 or below) cited in the
survey ireport on human teeth ailments for 1969. In addition, virtually all
of the cases disclosed eccentric bite to either the left or right.
As for malocclusion in the molar area, abnormal positions in the front
or back or with respect to the arrow-shaped surface were noted in almost half
of the Minamata disease patients examined, with two having a combination of
the above.
With respect to the abnormality of the arched alignment of the teeth,
most noteworthy was the V-shaped arched alignment in the upper jaw of 4 out
of 6 fetal patients (Photos 9, 12, 15, 24). Some manifested a gap or con-
stricture in the arched alignment in the lower jaw, with 1 case showing a com-
bination of the latter and V-shaped arched teeth alignment. In adult cases,
the degree of malocclusion was slight as compared to fetal cases, but the
condition of Case no. 10, a 22-year-old woman, was serious and comparable
to that of the fetal patients (Photos 27 - 29).
While we have discussed malocclusion in Minamata disease patients, the
distinction between normal and irregular cases was occasionally extremely
381
-------
difficult because even a normal bite showed some changes. Our method of
morphological classification of the arched teeth alignment, for example, may
be inaccurate because of visual measurement. We therefore wish to defer
consideration of the question of measurements until another time.
The cause of malocclusion can generally be classified into hereditary
and environmental factors [7]. Today, even hereditary aspects have been
clarified with respect to certain cases of malocclusion, but we wish to direct
our attention to the latter factor as the cause of malocclusion. Amidst the
environment are congenital and a posteriori causes, each containing numerous
other causes. It would be clinically difficult to determine which one of
these factors is responsible for malocclusion. However, when considered in
the light of Minamata disease, we tend to believe that disturbance of nutri-
tion and growth of the fetus by methyl mercury contamination naturally retards
the formation and growth of the teeth, and also precipitates uneven develop-
ment of both upper and lower jaws and peripheral soft tissue. Additionally,
a posteriori factors would emerge, abetting various forms of malocclusion.
We wish to caution that, among fetal patients, there are still some who have
bad habits, such as toying with their fingers, tongue, and lips [9]. There
probably is a need to consider these matters as well.
Next, filled teeth were noted in four of the fetal patients, who had an
average number of 27.1 teeth. We consider that this number of teeth repre-
sents no major difference when compared with an average of 27.1 teeth among
"F" middle school students, as reported by Ikejiri and his associates [1].
Three of the fetal patients still had milk teeth — '• i> and . The fall-
out of milk teeth was late in these fetal patients, and beyond the average
length of time. It may be due to the absence of succeeding permanent teeth
or other abnormalities, but we could not probe further on the basis of clini-
cal examination alone. Moreover, it is known that the presence of milk teeth
is a factor responsible for the aforementioned malocclusion [7]. In addition,
various degrees of abnormal teeth positions and morphological abnormality of
conical teeth were noted in Minamata disease patients. As explained in the
case of malocclusion, we believe that we cannot disregard the direct or
382
-------
indirect effects of methyl mercury as a continuing factor. A comparative
study of these abnormalities in position, according to area, and morpholo-
gical abnormalities would probably be necessary by examining a greater
number of cases.
As explained above, it was found from the study of the mouth and study
models of the Minamata disease patients that several characteristics exist in
Minamata disease patients. Those characteristics appearing in fetal Minamata
disease were: 1) malocclusion, especially overbite, over-jet, and abnormal
arched teeth alignment; 2) incomplete enamel formation; 3) existence of milk
teeth. Among them, there was nothing to indicate any unusual abnormality
attributable to abnormal development. However, there were many which could
be considered abnormal growth in the course of teeth formation. Factors in
the course of development during the fetal period played an important role.
However, embryonal factors could not be determined. Abnormal development of
the fetus is still believed to be an important factor.
Thus, it can be pointed out that complete disturbance of development of
the arched teeth alignment and the recurring effects of nerve disorders com-
bined to precipitate various secondary pathological changes. Such secondary
pathological changes probably were manifested as numerous cases of decayed
teeth, gingivitis, and deterioration of grinding surfaces.
Conclusion
Examination of the mouth and of study models of 9 fetal patients and
juveniles and 8 adults among Minamata disease patients led to the findings
described below:
1) We found characteristics peculiar to Minamata disease patients,
particularly in fetal patients, but were unable to pinpoint any unusual
pathological changes attributable to abnormal development.
383
-------
2) We found, in fetal and juvenile Minamata disease patients, abnormal
developments in the teeth and mouth structure in the course of growth during
the fetal and subsequent periods. The abnormalities consisted of:
i) Serious malocclusion. Overbite, over-jet or open bite was found in
3 out of 8 fetal and juvenile patients. In the molar area, centrifugal,
centripetal, and opposite occlusion were noted in about half of those examined.
With respect to abnormal arched teeth alignment, V-shaped arched alignment in
the upper jaw was found in 4 cases.
ii) Indications of incomplete enamel formation were noted, although its
degree varied, in all fetal and juvenile cases, being marked especially in
fetal patients.
iii) Among fetal patients, 3 cases still had milk teeth, 4 cases had
filled teeth, and 2 cases had conical teeth. However, the average number of
teeth was 27.1, showing no great difference from that of the control group.
3) Also, secondary pathological changes were noted in Minamata disease
patients, due to a combination of motor function and mental-intellectual
disorders.
i) In these cases, a high incidence of decayed teeth was noted in all.
DMFT 10.5 teeth among fetal patients was rather high compared to the control
group.
ii) Quite serious cases of gingivitis were noted in all Minamata disease
patients — 2 or 3 having swollen gums.
iii) Deterioration of grinding surfaces was noted in nearly half of
all Minamata disease patients; also, a heavy tartar coat was seen among adult
patients, the incidence being greater than in other symptoms.
384
-------
We wish to express our appreciation to Professor Noboru Ohashi,
Chief, Minamata Municipal Hospital, the staff of Myosuien and
patients for their assistance and cooperation in this study. We
also wish to thank Professor Yoichiro Otsuka, parttime lecturer,
Second Seminar, Pathology, of this university, for his advice and
supervision.
REFERENCES
1. Ikejiri, Shigeru, Hisayasu Uji and Shunichi Ito. Observations of the
Mouth of Fetal Minamata Disease Patients. Dental World Outlook,
Vol. 37 (1), 1971, pp. 49-53.
2. Japan Dental Association. Data and Commentary for the Supervision of
Mouth Hygiene. Japan Dental Association Journal, Vol 24 (12),
1973, pp. 33-52.
3. Murakami, U. The Effect of Organic Mercury on Intrauterine Life.
Drugs and Fetal Development. Ed., Klingberg, Abramovici and Chenke.
New York, Plenum Publ. Co., 1972, pp. 301-336.
4. Otsuka, Yoichiro, Ken Sakai, Hidetoshi Kojima and Tadao Takeuchi.
Effects of Methyl Mercury Chloride on Cell Multiplication, Particularly
on Cell Fission and Nucleic Acid Synthesis. Unpublished.
5. Ramel, C. Genetic Effects of Organic Mercury Compounds. I. Cytological
Investigations on Allium Roots. Hereditas, Vol. 61, 1969. nn. 908-710.
6. Ramel, C. and J. Magnusson. Genetic Effects of Organic Mercury Com-
pounds. II. Chromosomes Segregation in Drosophila melanogaster.
Hereditas, Vol. 61, 1969, pp. 231-254.
7. Takahashi, Shinjiro. Orthodontics. New Edition. Tokyo, Nagasue
Bookstore, 1966, pp. 74-105.
8. Takeuchi, T. Biological Reactions and Pathological Changes in Human
Beings and Animals Caused by Organic Mercury Contamination.
Environmental Mercury Contamination. Ed., Hartung and Dinman.
Ann Arbor Sci. Publ., Inc., 1972, pp. 247-301.
385
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9. Tokuomi, H. Minamata Disease. Study Group of Minamata Disease,
Kumamoto University, 1968.
10. Sakai, K. Effect of Methyl Mercuric Chloride on Rat Spermatogenesis,
Kumomoto Medical J., Vol. 25 (3), 1972, pp. 94-100.
386
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12. OPTICAL-ELECTRON MICROSCOPIC STUDIES ON TASTE BUD DISORDERS CAUSED BY
METHYL MERCURY CHLORIDE
Second Seminar, Pathology, Department of Medicine
Kumamoto University
Team member: Tadao Takeuchi
Research assistant: Morio Sonoda
I. PREFACE
Takeuchi and his associates have reported on characteristic and unusual
pathological changes, primarily in the central nervous system, at every
opportunity [1]. Takeuchi and his associates [6, 7, 10] and also Eto [8]
have further reported on pathological changes in the peripheral nerves, while
Matsun.oto and his associates [3, 4], Kameda [9], and Miyagawa [5] provided a
detailed, clinical, microscopic report, all on disorders of the sensory
nerve system.
Apart from disorders of the nervous system, certain pathological
changes in visceral organs in general were said to appear in Minamata disease
(Takeuchi). About the same time as this study, it was clarified by Takeuchi,
Shigenaga, and Sato [11] that there was also a disorder of the islets of
Langerhans. Meanwhile, many of the Minamata disease patients complained
about a disorder of the sense of taste, and Nozaka and his associates [2]
have reported that about 80%, clinically, have disorders in the sense of taste.
Since a disorder of the cerebral cortex is involved, judging from Minamata
disease cases, the taste nerve cannot be said to be dissociated. Yet,
generally speaking, there were not serious changes in the neurons in the
brain stem or the thalamus. However, a disorder of the taste nerve endings
was believed possible; therefore, we decided to study its receptor, the taste
bud, and nerve endings. Since, from our experience with the gastrocnemius
muscles in the human body, we knew that optical microscopic studies cannot
387
-------
be fully accomplished unless electron microscopic changes were observed, we
experimentally conducted an optical and electron microscopic study of methyl
mercury on the taste buds.
II. EXPERIMENTAL MATERIALS AND METHOD
For experimental animals, we used Wistar strain white mice, weighing
about 100 g, and orally administered 3 mg/day (mercury volume 2.4 mg/day)
methyl mercury chloride mixed with margarine to each animal, continuously or
intermittently. For control, healthy white mice of the same strain were
fed the same feed, but without the methyl mercury chloride.
On six mice used for optical microscopic studies, the total mercuric
dose administered successively was 7 mg (A), 26 mg (B), 55 mg (C, D, E),
58 mg (F). When about a 40 mg level was reached, the animals were stricken
(see Table 1 and Figure 2). The tongues of the animals that had died there-
from or were slaughtered were fixed in formalin, and an ordinary microscopic
specimen prepared therefrom was examined.
Animals used for the electron microscopic studies were treated simi-
larly, but in separate experiments. Four mice (Nos. 1-4) were examined.
No. 1 was daily administered 2.4 mg/day for six days for an aggregate dose
of 14 mg; No 2 — 2.4 mg/day for a total of 58 mg; No. 3 was administered
intermittently whenever there was a decrease of body weight, and was slaugh-
tered 16 days after it was stricken on the 25th day — aggregate dose was
43 mg. Like No. 3, No. 4 was treated intermittently until the 8?th day,
and left alone for the ensuing 16 days. On the 37tn day, an intersecting
phenomenon occurred. The total dose was 77 mg (see Table 1 and Figure 3)
Preparation of the electron microscopic specimens was done according
to Mr. Kitamura's [12] method. The experimental animals were anesthetized
for about 5 minutes with ethyl, and just before they reawakened they were
injected with 0.2 cc/100 g of hexabarbital natrium in the dorsal muscles.
388
-------
TABLE 3. METHOD OF ADMINISTRATION, DOSE AND NUMBER OF DAYS ELAPSED
A
B
C
D
E
F
No. 1
No. 2
No. 3
No. 4
Method of
adminis t rat ion
Daily
Daily
Daily
Daily
Daily
Daily
Daily
Daily
Intermittently
Intermittently
Onset of
affliction*
_
nth ,
9 day
27 (21 mg)
16th day
48 (38 mg)
22nd day
66 (53 mg)
21st day
63 (50 mg)
,,th ,
16 day
48 (38 mg)
-
18 (J4 mg)
-i r th ,
16 day
42 (38 rag)
25th day
48 (38 mg)
37th day
75 (60 mg)
Total number of
days elapsed
5 days
12
23
23
23
24
6
24
41
Aggregate dose
MeHg
15 mg
36
69
69
69
72
18
72
54
'
103 94
Hg
7 mg
26
55
55
55
58
14
58
43
77
Milligram numbers in parentheses ( ) for MeHg have been converted
to indicate amount of Hg.
Ten minutes later, the stomach was cut open, the aorta and cervical vein
exposed, the blood flow stopped on the descending aorta at a point just
above the branching area of the kidney artery, the artery wall incisioned,
about 300 cc of 3% glutalaldehyde solution (0.05M, pH 7.4, with cacodyalte
buffer) was pressure injected in reverse flow, and when the previously ex-
posed cervical vein became inflated, it was severed with a razor and the head
was biotically irrigated (see Figure 1). Following irrigation, the tongue
was removed and severed into small fragments lengthwise. After 1 hour of
fixing in glutalaldehyde solution, post-fixing was carried out with 1% osmium
389
-------
Figure 1
A * Appearance of intersection
of lower limbs
Control
10 20 30 0
Figure 2. Changes in body weight of animals for
electron microscope use
y
250
200
150
100
50
N'o.1
No. 2
No 4
"~ ' • 'control
A;Appearance of
intersection of
lower limbs
10
20
30
iOO days
Figure 3. Changes in body weight of animals for
electron microscope use
tetroxide (0.1M, pH 7.4, with veronal buffer). Then water was removed,
enveloped with epon, a 1 micron slice was made with ultrotome of LKB, and
toluidine blue-stained optical microscopic specimens were prepared. After
observing them, the required portion containing the taste bud was trimmed
390
-------
and a thin slide was obtained. Upon double staining according to the Raynolds
method, it was examined with Hitachi electron microscope HU-11A
111. EXPERIMENTAL FINDINGS
1) Optical microscopic observations
A (total dose, 7 mg): As compared to the control (Photos 1, 2), the
epithelial and innate layers were marked by mild atrophy, as a result of which
the groove of the taste bud was somewhat wider. Swelling and vacuolar changes
of nuclei of taste bud cells and mild nuclear fusion were noted. As a result,
some irregularity in the size of the nucleus, as well as a mild degenerative
fusion of cytoplasm, was seen. Partial changes were observed in nerve fibers
in the innate layer, and the Schwann's cells were enlarged (Photos 3, 4).
Some of them on the epithelium of the mucous gland in the muscular layer
were swollen (Photo 15).
B (total dose, 26 mg): No marked changes were noted in the epithelium
in general; however, mild atrophy was seen in the epithelium of the taste bud
and the groove was somewhat wider. As for taste bud cells, the size of
nuclei varied, some were swollen, and chromatin condensed into granular forms
or were concentrated. Also, cell bodies undergoing fusion were scattered,
and interstitial cells were scanty (Photos 5, 6). Partial changes were noted
in nerve fibers in the innate layer, as well as an increasing trend of
Schwann's cells. Partial changes were seen in glandular cells of the mucous
gland, and a mild change in the epithelium of the serous gland.
C (total dose, 55 mg): There was marked degenerative atrophy in the
epithelium of the taste bud area, and the groove was considerably wider.
Degenerative changes in the taste buds were serious, there being great
atrophy. In the taste bud cells, there was an increase of small nuclei into
which chromatin had concentrated, but, on the other hand, there was a marked
degenerative enlargement of the cytoplasm. There was also atrophy of the
innate layer, and a mild increase of nuclei substances. While not serious,
391
-------
there were partial changes in the nerve fibers between the surface and deeper
area of the innate layer (Photos 7, 8). Serious changes were observed in the
epithelium of both mucous and serous glands.
D (total dose, 55 mg): Moderate atrophy was seen in the epithelium of
the taste bud area, with degenerative atrophy being marked in the taste bud.
Taste bud cells were undergoing pyknosis or fusion and obliteration, thus
making the inside of the taste bud brighter and sparse. Fat tissue was on
the increase in the innate layer; there was degenerative enlargement of
nerve fibers, and enlarged Schwann's cell nuclei. The nerve fibers in the
basal portion of the innate layer were fairly intact, but there was an en-
largement of Schwann's cell nuclei (Photos 9, 10). Moderate degree of degen-
erative swelling of the epithelium of the nucous and serous glands, as well
as fusion, was seen.
E (total dose, 55 mg): There was marked atrophy in the epithelium of
the taste bud area, and a rather severe epidermoid keratosis in the surface
layer. Atrophy of the taste buds was even more serious, there being a space
between the surrounding epithelium and its border of the taste bud. Most
of the nuclei of the taste bud cells were undergoing serious pyknosis or
fusion and obliteration; the cells themselves were in the process of disin-
tegration and obliteration, and the taste bud was contracting markedly
(Photos 11, 12). Degenerative disintegration of some glandular cells was
observed in the epithelium of both mucous and serous glands.
F (total dose, 58 mg): Mild atrophy of the epithelium of the taste
bud area, and a relatively marked irregularity in the size of taste bud cells
were noted. A considerable number of taste bud cells was swollen. Inter-
stitial cells were scanty and light. There was atrophy in the innate layer
(Photos 13, 14). Nerve fibers were visible in the lower area of the innate
layer, the medullary sheath being swollen. Moderate changes were noted in
the epithelium of mucous and serous glands (Photo 16).
392
-------
TABLE 2. DEGREE OF PATHOLOGICAL SYMPTOMS OF TONGUE
Pathological
changes
! Animal code
I
A
Ji
C
n
K
F
Control
Upper
face
membr
; Atrophy
(-f)
+
-H-
•u-
fu
-•
-
sur-
of
ane
1 Hornifi-
cation
_
—
4-
(j-)
•fl-
-*-
_
-
Ta
Atrophy and
reduction
in number i
-r
-f
-H-
-ff
*
+
-
ste b
•o
§ c<
Nuclear
degeneration
disintegratio
-r
-4-
ttf
-f*
•Kf
-H-
-
ud
Irregularity
of size C
of nucleus
-L
•H-
4H-
4f
4!f
-Fr
Innat
Atrophy
4-
-f
-H-
4-
TTt
44.
i — —
:e lay
o
Degeneration i
nerve fibers
(- '
-*
44
--
-rf
-H-
-
er
4-1
to
Increase in i
-.
—
—
i
—
—
!
- i
Secr(
gl*
TJ
g
Epithelial^
degeneration
of mucuous gl
-
-•
_j.
—
-
2tory
md
^j-
%
Epithelial!
degeneration
of serous gl
—
( )
^^
-'
-
r
Cell
infiltration
—
—
—
—
i -tr
-
-
TABLE 3. AVERAGE NUMBER OF NUCLEI IN A TASTE BUD
1
f-l
~~~. cu
CO
Animal code °
A
B
C
CO
a
^-|
O 1 0)
-H
4-1
ca
<
•i
3
&
0)
4J
CO
cfl
4J CO
<4-l 3
O .Q
V-l
(U
1
3
^
2S
21
'} 1
CO
i-l CO
-H 3
CU CU
O iH
O
M-l 3
0 C
0
01
c>0 J-J
cd cu
cu "B
!> 3
<^ fi
254 t
228 1!
177 ri
co
3
cu
H
O
3
C3
D
E
F
Control
16
26
S6
195
271
393
-------
Table 2 is a summarization of the foregoing (see Table 2). It shows
the extent of differences in marked pathological changes, depending on the
level of methyl mercury administered. Also, as Table 3 reflects, a remarkable
difference was noted when we counted the average number of nuclei in a single
taste bud, in view of their decrease in the taste buds (see Photo 3).
2) Electron microscope observations
Following epon enveloping and preparation of a 1 micron slide, we
examined the toluidine blue-stained specimens. In No. 1 (total dose, 14 mg;
Photo 17), the boundary of each cell was relatively distinct. In No. 2
(total dose, 58 mg; Photo 18), however, all taste bud nuclei were moderately
transparent and swollen, the nuclei had no difference in shade, presented a
uniform oval appearance, and cell boundary was indistinct; compared to No. 1,
the taste bud was in a state of atrophy. Changes similar to those described
under optical microscopic observations in 1), above, clearly became evident
as dosage was increased. The taste bud area of this specimen was trimmed,
and an electron microscopic photograph was made thereof.
We wish to describe below the pathological changes in the taste bud as
they occurred, depending on the period of administration and dose.
In the initial stage of administration (No. 1, 14 mg Hg, administered
for 6 days), there was no marked change in Class I cells (dark cells, sup-
porting cells), and Class II cells (light cells, taste cells) among taste bud
cells, but a small vacuolar space was seen between cells, and electron den-
sity of cell nuclei appeared to be somewhat increasing, making differentia-
tion between Class I and Class II cells somewhat difficult (Photo 20). In the
spaces between cells, changes in the movement of and increases of microvilli
was seen (Photo 21). An irregular but distinct pathological change was noted
in a part of the ground substance of filaments. About this time, a similar
change was observed in the axon of the peripheral neurite, but no changes
were seen in neurotubules.
394
-------
,t
''*•
* i
..
I. .;''•'',
' *"' ~~'
j , \
.
I I
,( «
/
'•»
c>
"* • I
•» »
If
J4.
395
-------
A
. •- >.
* >'
S • *,' !
"1
* '-'"'.--
,* *
'•*"
X ' •
'.""*
«» > « .'9
'•'•tf '
O
S- J ,• '• •:S:^v-
•'* •'
" S
396
-------
i. «
"t';
:..io *
••'v
:/v...-^\:;:-;%- •.-*-
..*,V- ,
v.
^ «-*vu n
397
-------
-... -J . ,»»"' , .' • '.
13'. "••
" '>,.:••'••
I - \
--'I
%J \ •-.
'•
\
-
398
-------
17
•• i
r V
.'4
-> .».
19
399
-------
• ..•&:;—;•-•::>,••
4CO
, .. •
•'• ,-v^,. -.r .. , ;. •.;:..Vfjw.^v:..v-: -••' .',- x~
%^^*^i*.^:^{^>i4^
-------
--3
-.* "'> - .
y ,' i. ••.. - -.
'
- •_;,<* - •",,, ' >
*•* '*'"' ':V', .'• .;,' ••.')
/ -23
.-• -*-»
401
-------
•; "'(•, \ '
t '
".A ' ., f
•>
••V
si\ \ r
-.v:
402
-------
- ••»• •
I- '•
;'.<•'.'••«
t ... ~; .. \ i • ,
X •
c.
--
>f> s-
" *
'*»< t v.', /
. v-<
»•*
403
-------
t—•'•
s
•Vk
I:1*.
IK-.,
" *•
•V " ' •'
r
it .,
*-'v
^'•' ••'.
*
•- -» . *•'••""*
u
h'^
"A
'f^'^>'-.
.X, * t B«r • '•>*•%
W
/.s- ,. .. -,.-. -
ft ^ : '•'•• • •»-''
-------
Photos 1-2;
Photos 3-4:
Photos 5-6:
Photos 7-8:
Photos 9-10:
Photos 11 - 12:
Photos 13 - 14:
Photo 15:
Photo 16:
Photo 17:
Photo 18:
Photo 19:
Description of Photos
Control case (low and high magnification of the taste bud)
Case A (fifth day); nuclear enlargement and fusion is seen
in the taste bud cell; the cell body is swollen
Case B (twelfth day) ; degenerative change is fairly distinct
in the taste bud; in the taste bud cell (primarily taste
cell), there is pyknosis of the nucleus and nuclear destruc-
tion; some are undergoing degenerative disintegration as
cell bodies become swollen
Case C (23 day); marked degenerative atrophy of the taste
bud; taste bud has been reduced in size because of degenera-
tive disintegration of taste bud cells
Case D (23rd day); although the same number of days has
elapsed as in the case above, there is greater degenerative
atrophy, probably owing to larger mercury dose: degeneration
and disintegration marked in taste bud cells; nuclei under-
going pyknosis in remaining taste cells; vacuolar degenera-
tion in cell bodies
Case E (23rd day); virtually identical observations can be
seen in the taste bud as above; some atrophy in the sur-
rounding epithelial cells; relatively serious keratosis in
the surface layer
Case F (24 day); milder changes than above; the process of
degeneration to disintegration of taste bud cells can be
seen in each
Salivary gland (tongue gland) of Case A; degenerative swell-
ing is seen in part of the mass in the epithelium of the
serous gland
Salivary gland (tongue gland) of case F; prominent degenera-
tive swelling on serous gland, extending in the mouth
Control case of toluidine blue-stained, epon-covered,
one-micron slice; Class I and II cells seen in the taste bud
Toluizine blue-stained, epon-covered slice from Case No. 2
(24th day); degenerative atrophy of the taste bud; distinc-
tion between Class I and II cells (taste cells) impossible;
nucleus of taste cells transparent and border indistinct
No. 3 (41st day); part of apical, formative substance of taste
cells near the tip of the taste bud; vacuolation of filaments;
partial vacuolation of smooth-surfaced vesicle; possibly
serious disorder of receptor structure (electron microscope,
10,000 x 2.5)
(Description of photos continued on following page)
405
-------
Description of Photos (continued)
Photo 20:
Photo 21:
Photos
22 - 23:
Photo 24:
Photo 25:
Photo 26:
Photo 27:
Deep area of taste budy of No. 1 (sixth day) ; basal membrane of
taste bud normal, but some spaces between taste cells- increased
electron density of nuclei (electron microscope, 2000 x 2.5)
Enlarged view of No. 1; slightly irregular transparency in ground
substance of some of the filaments; neurites partly visible, but
no marked changes; identical changes in their filaments (electron
microscope, 10,000 x 2.5)
No. 2 (24 day); most serious changes seen in filament, with
ground substance becoming transparent and appearing to be worm-
eaten, and there being obliteration of cristae; among marked
cases, some filaments undergoing vacuolation, leaving only their
external membrane. In Photo 22, no change was seen in coarse-
surfaced vesicles, but as shown in Photo 23, there were maceration
and obliteration of ribosomes in some cells, Vacuolation was
also seen in smooth-surfaced vesicles (electron microscope,
10,000 x 2.5).
No. 4 (103rc^ day); two taste buds; increased electron density of
nuclei of taste cells evident in comparison with that in surrounding
epithelium; marked vacuolation of taste cells also seen (electron
microscope, 2500 x magnification).
No. 2 (24^ day) ; marked vacuolation of filaments in taste bud
cells: also vacuolation of vesicles; part of neurite running
laterally between two taste cells (center); increase as well as
destruction of filaments, with some becoming transparent and
appearing to be worm-eaten (electron microscope, 10,000 x 2.5)
No. 4 (103rd day); shows 4/5 of single taste bud; mild changes
during this period, but marked vacuolation visible through elec-
tron microscope; decrease of taste cells; increased electron
density of nuclei and concentration thereof; vacuolation of fila-
ments; enlargement of vesicles; decrease and obliteration of ribo-
somes; irregularity of Golgi apparatus and enlargement of Golgi
sac; formation of dense body (electron microscope, 2500 x 3)
Enlargement of taste cells of No. 4; marked vacuolation of forma-
tive substance of cells; sound filaments are few, with most being
transparent and undergoing vacuolation; enlargement and vacuola-
tion of vesicles; irregularity of Golgi apparatus; enlargement
of Golgi sac; concentration of nuclei; decrease of filaments
(electron microscope, 6000 x 3).
406
-------
As the dose was increased and days passed (Nos. 2-3), Class I cells
disappeared in the taste bud, and only Class II cells were visible. Further,
there was some increase of electron density of the cells, clearly manifesting
pathological changes when compared with the surrounding epithelial cells of
the taste bud. In Class II cells, marked changes appeared in the filaments;
there was a loss of cristae, and the ground substance of the filament was
transparent and appeared to be worm-eaten. They were gradually undergoing
vacuolation, forming large vacuoles covered by a filament membrane (Photos
22, 23). As for vesicles, microvacuolation of smooth-surfaced vesicles
appeared, and irregular enlargement of Golgi vacuoles was seen in the Golgi
field. No marked changes were noted in the cells, except for increased elec-
tron density. There was an irregular increase of microvilli located between
the cells, and a wider space between such cells. No marked changes were
observed in the basal membrane of taste buds, and some irregularity was noted
in the filaments.
In neurites, similar changes were seen in filaments in the axons, but
no marked change was noted in neurotubules.
When the dose of methyl mercury was further increased and as days passed
(No. 4), marked changes generally appeared in the taste buds and no distinc-
tion could be made between Class I and II cells; there was a greatly in-
creased electron density as compared to the surrounding epithelium, as well
as vacuolation (Photo 24). In taste cells, the nuclei were concentrated,
chromatin was changed, and the double structure of nuclear membrane was dis-
torted and spaces were created. There was a loss of cristae in the filaments,
enlargement of vacuoles due to transparency of the stroma, and creation of many
large vacuoles. Destruction or fusion of vacuoles was also noted, there being
great changes in vacuoles (Photos 24, 26). Their changes were remarkable
when compared to those in surrounding epithelial cells. There was a great
increase of microvacuolation in the vesicles, especially in smooth-surfaced
vesicles, forming relatively small spiny cells in some places. The structure
of the Golgi field was irregular, and spiny cells were seen (Photo 27).
There was no irregularity of RNA granules. Although no marked changes were
407
-------
seen in the dense body of lysosomes, they indicated a tendency to increase
to some extent. A marked decrease and irregularity was noted in filaments,
and in taste cells under going great changes, the process of cell deteriora-
tion caused by spiny cell formation was seen (Photo 24). Mild changes were
also noted in peripheral cells, with some becoming spiny.
In neurites, degeneration of spines in the filament was noted, with
neurotubules being indistinct.
IV. SUMMARY AND COMMENT
Nozaka and his associates have clinically indicated that there were
both olfactory and gustatory disorders in Minamata disease patients. However,
no light was shed on how such disorders developed. In the cerebral cortex,
thinning and fallout of nerve cells occur, but not completely, with most
nerve cells remaining except in extremely serious cases. Therefore, a study
was required to determine whether peripheral factors were involved in
gustatory disorders.
Using mice, we studied the changes in the taste bud, which is the taste
receptor, by orally administering methyl mercury chloride and experimentally
eliciting toxic symptoms similar to those in Minamata disease.
In eliciting poisoning symptoms, we considered the three features claimed
by Takeuchi and his associates. Symptoms appeared when the dose of mercury,
starting at a minimum of 21 mg per animal, was increased to a maximum of 60 mg.
In the case of continuous administration, symptoms developed even at a level
of roughly 38mgper animal. As for the period of administration, the minimum
was 9 days, but symptoms developed usually after 2 to 3 weeks, and in one case,
after more than a month. The administration of organic mercury was continued
even after the initial symptoms appeared. The total mercury level administered
was a minimum of 26 mg per animal to a maximum of 77 mg per animal, over
a period of 12 to 77 days. Pre-symptom cases examined were those which had
been administered 7 mg per animal for 5 days.
408
-------
Morphological changes in the taste bud tissue of these animals were
visible under an optical microscope. After 5 days, the inside of the nucleus
of the taste bud cell was already transparent, and the cell body was en-
larged. At the end of 12 days, degeneration of these cells was apparent,
with emergence of nuclear pyknosis, partial fusion, spiny formation on the
cell body, enlargement and swelling. After a lapse of 3 weeks, there was
degenerative disintegration of the taste bud cells, nuclear pyknosis, nuclear
destruction, fusion and obliteration, with some cell bodies becoming swollen
and disintegrating. As a result, there was a decrease of taste bud cells,
marked degenerative atrophy, and even contraction and loss of the taste bud.
Compared to the relatively profound pathological changes in the taste
bud, the surrounding epithelium was hardly affected. Only vacuolar changes
and some atrophy were noted. In some cases, there were fairly strong in-
stances of keratosis.
In peripheral nerves in the innate layer, changes could not be seen
using ordinary stains, especially HE, but through the use of KB stain, swell-
ing of the axons were visible. Changes in Schwann's cells could not be de-
termined, optically.
No serious changes were noted in the salivary gland. However, a future
study is needed, since some glandular epithelial changes and degenerative
disintegration of glandular cells was seen.
An electron microscopic study showed changes in neurites of the taste
bud and nerve endings. In the taste bud, changes were apparent at the end
of 5 days, progressively becoming serious. In other words, Class I cells
(dark cells, supporting cells) could not be differentiated from Class II
cells (light cells, taste cells), and taste cells occupied a larger portion
of the taste bud. In the taste cells, localized light areas in the electron
density in the stroma of filaments appeared, and as the light area enlarged,
the stroma had holes as if eaten by worms. Simultaneously, the cristae was
409
-------
obliterated, and spiny formation on filaments increasingly developed. The
filaments formed spines completely, leaving only the outer membrane, became
enlarged, and then burst. As for vesicles, the ends of smooth-surfaced
vesicles became enlarged, underwent microvacuolation, and gradually became
vacuolized. In the coarse-surfaced vesicles, RNA granules had fallen and
free ribosomes were disarrayed and decreasing. On the other hand, changes
also occurred in the membrane structure in the Golgi field, with disconformity
of the membrane, vacuolotion, and gradual obliteration. In the nucleus, its
electron density generally increased at the outset, but there was a change
in homogeneity and its structure was obliterated, with the double structure
of the nuclear membrane being ruptured. In such a fashion, the taste cells
tended toward degenerative disintegration, as the filaments decreased.
While peripheral cells of the taste bud have offered some resistance,
degenerative changes commencing with vacuolation of filaments also occurred
in taste cells.
Neurites on nerve endings were faily well preserved, but were affected
as taste bud orders progressed. With respect to changes in the neurites,
the axon structure was clearly visible at the outset, but there was a gradual
vacuolation in the filaments as in the case of taste cells. This was later
followed by changes in neurotubules, and swelling of the entire neurite was
seen.
Outside of the taste bud, changes were generally mild. While there was
a little pitted vacuolation of filaments in epithelial cells, most filaments
were sound, and no serious disorder was seen in the cells.
As explained above, it was found that in the case of methyl mercury
poisoning, pathological changes were induced in the sensory receptor, which
is the final apparatus manipulating the sense of smell. It was also found
that a cell disorder commencing with the destruction of filaments in the
taste cells, which are most important to the taste bud, ultimately induced
cell disintegration and obliteration, causing a decrease in the number of
410
-------
taste buds. At the same time, it caused chages in neurites, making it impos-
sible for taste buds to perform their functions as taste receptors.
Although it had been known that sensory disorders were involved in Mina-
raata disease, little was known concerning receptor disorders in the periphery.
Cell disorders caused by methyl mercury in the retina, the visual receptor,
and the Corti's organ, the hearing receptor, have not yet been established.
There is believed to be no great change, but further study will, of course,
be required. The revelation of cell disorders in taste receptors, as described
above, will probably necessitate a study of other sensory receptors.
V. CONCLUSION
A study was made of pathological changes induced in taste receptors by
experimentally evoking organic mercury poisoning symptoms in mice by oral
administration of methyl mercury chloride. The following results were
obtained:
1. Methyl mercury developed a disorder in the taste bud of taste re-
ceptors, and induced degenerative disintegration of taste cells. As a result,
there was a decrease and obliteration of taste cells, and the taste bud con-
tracted and was obliterated.
2. Optical microscopically, taste cells developed changes such as
nuclear pyknosis, nuclear destruction, nuclear fusion, as well as enlargement,
swelling, and fusion of cell bodies.
3. Electron microscopic differentiation between Class I and Class II
cells was difficult. In taste cells, which are Class II cells, there was
transparency with holes as if eaten by worms of the stroma in filaments, a
loss of cristae, ultimately vacuolation and disintegration of the filament.
Changes also appeared in the vesicle and Golgi apparatus, with greater elec-
tron density, uniformity, and finally, vacuolation of the entire cell.
411
-------
4. In nerve endings, degenerative changes appeared at the outset in
filaments, similar to those in taste cells, with changes in neurotubules
following later.
5. Outside of the taste buds, there were few changes in the epithelium.
Vacuolation was induced in part of the filaments, but there was no cell
disorder. As a result, the taste bud disorder was clearly visible.
Observations concerning the inducement of disorders in the sensory
receptor caused by methyl mercury in the taste bud were significant. Our
study was the first to explain pathological changes in the receptors.
We wish to express our profound gratitude to Mr. Mitsuaki Eto,
lecturer, Second Seminar, Pathology, and to Ms. Katsuko Izumi,
assistant, for their cooperation, and to Professor Katsuya Kita-
mura, Kyuahu Dental College, and Mr. Toshiro Kubota, Large
Microscope Laboratory of our university.
REFERENCES
1. Takeuchi, Tadao. Pathology of Minamata Disease, Minamata Disease
(Compiled by Research Team, Dept. of Medicine, Kumamoto University),
Shuhan, 1966, pp. 194-282.
2. Nozaka, Yasuji. Taste Disorder, Minamata Disease (Compiled by Research
Team, Dept. of Medicine, Kumamoto University). Shuhan, 1966,
pp. 147-148.
3. Matsumoto, Fuo, and Kameda. Pathological Study of Toxic Polyneuropathy
(I); Experimental Formation of Polyneuropathy Through Methyl Mercury.
Progress of Neurology, Vol. 13 (3), 1969, pp. 660-669.
4. Matsumoto and Kameda. Pathological Study of Toxic Polyneuropathy (II);
Electron Microscopic Observations Concerning Degeneration and Regenera-
tion of Nerve Fibers Caused by Methyl Mercury Chloride Poisoning.
Latest Medicine, Vol. 25 (4), 1970, pp. 939-950.
412
-------
5. Miyakawa, T., et al. a) Experimental Organic Mercury Poisoning,
Pathological Changes in Peripheral Nerves. Acta. Neuropath., Vol. 15,
1970, pp. 45-55. b) Regeneration of Peripheral Nerves. Acta
Neuropath., Vol. 17, 1971, pp. 6-13.
6. Takeuchi, et al. Electron Microscopic Observations During Biophia
of Peripheral Nerves Under Conditions of Methyl Mercury Poisoning
(Minamata Disease) in Human Beings. Twelfth Meeting, Japan Neuro-
pathological Association (Tokyo), 1971.
7. Taeuchi, T. Biological Reactions and Pathological Changes of Human
Beings and Animals Under Condition of Organic Mercury Contamination.
Intern. Congr. Environ. Mercury Contamination, 1970. Ann Arbor, 1970,
pp. 1-30.
8. Eto, Mitsuaki. On Pathological Changes of Peripheral Nerves in Mina-
inata Disease in Human Beings, Especially on Its Electron Microscopic
Observations. Progress of Neurology, Vol. 15 (3), 1971, pp. 606-618.
9. Kameda, Kosei. Pathological Study of Toxic Polyneuropathy (III). Op-
tical Microscopic and Electron Microscopic Study on Regeneration
Following Peripheral Nerve Disorder Caused by Methyl Mercury Chloride
Poisoning. Kumamoto Medical Hournal, Vol. 45 (10), 1971 pp. 985-999.
10. Takeuchi, et al. Electron Microscopic Observations During Biophia
of Gastrocnemius Nerve in Fetal Minamata Disease. Kumamoto Medical
Journal, Vol. 46 (11), 1972, pp. 706-719.
11. Takeuchi, Shigenaga and Sato. On Pathological Changes in Islets of
Langerhans in Minamata Disease Biopsy. In this report.
12. Kitamura, Katsuya. Neurohistological Study on Degeneration and Re-
generation of Taste Buds. Kyushu Dental Association Journal,
Vol. 18 (3, 4), 1965, pp. 1-40.
413
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VI SUMMARY
These research studies on Minamata disease in the Minamata district
and the surrounding area have clarified somewhat the conditions of
mercury pollution, health conditions of the inhabitants, the incidence
of the disease, the progress of the disease, and the fundamental know-
ledge of clinical treatment for the disease. Following is a summary of
the important results in this report.
414
-------
1. ihe situation of mercury pollution in dinamata district and the
surrounding area.
Fish and shellfish from outside or around Minamata bay have recently
served as the main protein source of food for the residents. Seafood taken
from the area was, therefore, examined for mercury content. The mercury
content in the fish taken from outside Minamata bay (around the Koiji island),
is remarkably decreased from the value measured in 1961. The highest mercury
content in the fish by wet weight was 0.530 ppm. and the highest methyl
mercury content was 0.440 ppm. The lowest value was 0.182 ppm which was
higher than those of other districts. If 200g of the seafood containing the
highest mercury levels were eaten daily, the diet would exceed the level
estimated to be harmless by Dr. Kitamura as presented in his table on the
toxic effects of mercury; however, it would remain below the level of
poisoning. In the polluted area, generally, shellfish were more contaminated
with mercury than fish. In the heavily polluted area in Minamata district,
there have been patients having mild symptoms of Minamata disease from 1965
to the time of this survey. Visceral organs from autopsy cases with Minamata
disease had high mercury levels, considering the bio-half life of mercury
in viscera. It is also known that the bio-life of mercury in the brain is
longer than in the viscerral organ. Therefore, it will be recommended that
no more than 200g of fish and shellfish contaminated with mercury from the
area of Minamata bay can be eaten daily.
In Minamata district, the relationship between the distance from
Minamata bay and the methlymercury content of fish, taking into account fish
species, was examined. Even though there were some differences of mercury
content among fish species, in general, methyl mercury content was highest
in fish taken from Minamata bay and its neighboring sea. Next high values
were found in fish from the mouth of Minamata river, the hairtail fishing
area in Minamata bay, and the Kurata area. According to the distance from
415
-------
Minamata bay, methyl mercury content in fish was gradually decreased in
the Yatushiro Sea. Fish from Midoriura and Yatushiro districts had
remarkably low levels of mercury. Therefore, fish from these areas seem
to be less dangerous than that from the Minamata bay area. In contrast
to these areas, mercury pollution in the Ariake sea area is a new problem.
In the Ariake sea area, fish and shellfish taken from the coast of Yushima
Island and the mouth of Midori River contained somewhat high values of
methylmercury as compared with those from other areas. The value was not
so high as the value estimated for Koiji Island, but nearly equal to that
for the mouth area of Minamata River. This suggests that there has been
an additional source of mercury pollution in the area when the low value of
mercury content in the fish from Yatushiro area and the ocean stream is
considered. Even though the number of people studied and the experimental
error for the survey were taken into account, the mercury content of hair
from many residents of Minamata district was high while the mercury content
of hair from people living in the Goshonoura area was relatively low. In
Minamata district, the highest value of total mercury found in the male was
14.82 ppm of which 11.37 ppm was methyl mercury; in the female, the highest
value for total mercury was 10.44 ppm of which 9.21 ppm was methyl mercury.
These values indicate that the mercury pollution in the area is below the
poisonous dose level at this time. However, many people having high mercury
contamination were found. This fact is indicative that the people in this
area have been exposed to mercury pollution. In contrast with the Minamata
area, only one person having 4.65 ppm methyl mercury in the hair in the
Goshonoura area was detected and all the others were found to have less than
1.35 ppm. The results suggest that Goshonoura area has not been polluted
with mercury recently.
416
-------
2. Health hazard of residents in Minamata district.
From the epidemiclogic survey, two remarkable points were recognized.
1) Death statistics in the Minamata district during the past 24 years
from 1948 to 1971, show that the average span of human life in the Minamata
area is lower than that of the Ariake district, chosen as a control. The
average age of death was 50.36 ± 28.91 in the male and 52.50 ± 29.49 in the
female. The average age of death in females in the Minamata area is remark-
ably younger than that of females in other places. This trend is also observed
in statistics for every five year period. The age of death in females
observed in Minamata district was younger than that at any other place in
Kumamoto prefecture. The average life span in Goshonoura area from 1963 to
1967 was significantly shortened. The rate of death in infants and the
stillbirth rate were observed to be the highest in the Minamata area, second
highest in the Goshonoura area, and third in the Ariake area. From the
classification of the causes of death in the area, many deaths by external
factors or by infectious diseases were reported in the Minamata area.
The external factor category included many accidental deaths by drowning.
2) The screening method used for the detection of Minamata disease
included examinations for sensory impairment, constriction of the visual
field, disturbances of movement, and hearing and speech disturbance.
The method was effective with about 80% sensitivity and 60% specificity
for detection of the disease. It was obvious that some patients were
not identified; therefore, some problems remained in the method of the
clinical screening for diagnosis of the disease. Later clinical examina-
tion of the patients who did not appear to have Minamata disease did
demonstrate Minamata disease or health injury.
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3. Incidence and distribution of Minamata disease
For the survey for detection of Minamata disease, Yudo, Dezuki, and
Tsukiura in Minamata district were selected as the heavily polluted
areas and Arashiguchi in the Goshonoura district was selected as a
slightly polluted area. For control areas, Akazaki, Sunoko, and Oura
in Ariake district were chosen as non-polluted areas, but they were
found to be polluted areas by this survey. For the first year survey,
1119 persons (520 male, 599 female) of 304 families in the Minamata
district; 1871 persons (902 male, 969 female) of 459 families in the
Goshonoura district; and 1180 persons (570 male, 610 female) of 278
families in the Ariake district were examined.
Upon screening by questionnaire and general clinical investigation
for symptomatic analysis, persons who needed further precise clinical
examination for Minamata disease were found to number 315 (33.7%) in
Minamata district, 135 (8.5%) in Goshonoura district, and 29 (3.1%)
in Ariake district. There were some changes in the above recorded
numbers up to the second year's survey.
Persons who had been clinically examined by neuropsychiatrists before
the general clinical examination included 245 in Minamata, 134 in
Goshonoura, and 26 in the Ariake district. Among the above recorded
persons, the numbers diagnosed as "probable" cases of Minamata disease,
were 191 persons (78.0%) in Minamata, 25 in Goshonoura (19.4%), and 8
(30.8%) in Ariake district. After the further clinical examination,
the persons who were diagnosed as "very possible" cases of Minamata
disease, were recorded as 20 persons in Minamata district, and 34 persons
in Goshonoura district.
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When the persons with the "probable" or "very possible" Minamata disease
diagnosis were summed up in these areas, there were 211 persons (86.0%)
in Minamata district and 59 (44.0%) in Goshonoura district. We found
10 persons (38.5%), including two questionable cases, having very similar
symptoms of Minamata disease in Ariake area in the survey. Furthermore,
20 persons in Minamata, 30 persons in Goshonoura, and 9 persons in Ariake
district were reserved for precise examination.
(Note: The number recorded above as having Minamata disease is going to
increase later, because the neuropsychiatric clinical survey has been
continued to detect the disease as a follow-up to the general clinical
diagnosis).
Of the persons who underwent precise general clinical examination,
there were 195 in Minamata, 39 in Goshonoura, and 33 in Ariake district.
Some people who lived in the local area in places inaccessible to the
transportation of clinical instruments were called in and diagnosed at
the university hospital. There were 150 persons out of 195 persons
(77.0%) who were diagnosed at the hospital as having Minamata disease.
(Minamata disease was confirmed in 64 persons at survey time, 81
persons at the end of March, 1972). Minamata disease was suspected in
20 persons. Therefore, when the number of suspected cases was added to the
number of persons diagnosed as having Minamata disease, the total number
became 170 patients (87.2%). In Goshonoura district, 16 patients (41.0% out
of 39 persons were diagnosed as having i-linamata disease. One patient was
confirmed and 8 suspected cases were found. The total number of patients was 24
persons (61.5%) in this area. The number of persons reserved for
further precise clinical examination was 24 in Minamata and 9 in Goshonoura
district. The numbers may be increased when further examinations are
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completed. In the survey, 5 patients (21.7%) having the same symptoms
as those for Minamata disease were found in Ariake district. Out of
the 5 persons, 3 persons were diagnosed as similar to Minamata disease
cases and 2 persons had suspicious symptoms. In addition to these, 9
persons were reserved for further clinical examination. The Ariake
area had been thought to be a non-polluted area until the survey was
undertaken. However, from this survey, it was clear that the area
was also polluted with mercury. The pollution in this area seems to
be slight at the present time; the methyl mercury content in fish taken
from the area was not so high. The fact also suggests that it seems to
be difficult to think about the disease as constituting an outbreak.
By epidemiological survey, if the patients of the Ariake area have a
disease similar to that of patients in Minamata caused by organic mercury
poisoning in the past, the incidence of the disease in Ariake would be called
the third outbreak of Minamata disease, following the second outbreak of
Minamata disease as reported in Niigata prefecture in Japan. As this
is an important finding, the problem in the Ariake area has to be made
clear and be resolved by future work. At the same time, it will be
necessary also to detect the source of methyl mercury pollution in the
area. On the coast of Yatsushiro-sea, many persons having health
disorders were found in the fishing village or around the area, and
many persons having complaints of nervous symptoms were affected with
mercury pollution in the Minamata area which had been heavily polluted with
mercury. These incidences were fewer in the Goshonoura area located on
the coast opposite the Minamata area. This fact suggested that the
mercury poisoning in the area depended on the eating of much fish and
shell fish contaminated with mercury. To the contrary, other points
made by the research survey concerning mercury poisoning in the Ariake
area might be considered.
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Concerning the change of incidence and of Minamata disease itself,
the situation is not so clear, because the disease was mainly diagnosed
by patients' complaints. There were some diseased persons before and
after the great outbreak during the time from 1953 to 1960. After 1965,
diseased patients have appeared every year. This fact is indicative that
the chronic or delayed type of the disease would be present. These
problems shall be examined and clarified by autopsy of this type of patient.
In the field of pediatrics, 9 children (9 in Minamata and 0 in
Goshonoura) were suspected of having the disease. Adding to this number,
2 children were in the "probable" category of diagnosis, and 5 children
were reserved for policlinical diagnosis. In total, 76 children related
to 29 patients as offspring or as brothers or sisters of children born
with MinaTiata disease were recorded. Thirty-six patients out of the 79
children were examined and abnormalities were found in 13 children. Six
out of 13 children has sensory impairments or disturbance of movements.
4. The clinical medical study on Minamata disease and the detection of new
clinical symptoms.
To diagnose Minamata disease or methylmercury poisoning, it is important
to find the characteristic and specific clinical symptoms of the disease
and also to develop new methods for detection of the symptoms. It is
impossible to diagnose the disease with the simple combination of the
individual symptom or of several nervous symptoms. For example, our
studies showed that there were about 30 chemicals which can cause
constriction of the visual field, and there were many chemicals which
cause sensory impairments of peripheral nerves. There are also many
poisons which involve disturbance in movements. Therefore, it is
important that the combination of the appropriate characteristic symptoms
be used to diagnose the disease.
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In addition to those observations, the most important thing is the
application of an epidemiological survey or chemical examination for
mercury pollution before clinical medical diagnosis. In our recent
experience it was possible to diagnose the disease. With the data
collected from epidemiological surveys and from accurate chemical
analyses for mercury pollution, we were able to diagnose Minamata
disease, even if patients' symptoms were slight. The fundamental, new
findings of electron microscopical observations of biopsied tissue
of the peripheral nervous system are also helpful for the diagnosis
when used in parallel with the epidemiological survey.
The characteristic main symptoms of Minamata disease are recognized as
sensory impairments, constriction of visual field, cerebellar antaxia,
dysarthria, and hearing difficulty. Some other symptoms were also
reported. The research group, however, found some additional important
symptoms in ophthalmology. In addition to centripetal constriction of
the visual field, we found the subsided visual field, abnormality of
eyeball movement, and disorder of short sight reflex. The patients
having centripetal constriction of the visual field were also found to
have scattered disintegrated dark points located in the center of the
constriction of visual field in high incidences. Squint eye is characteristic
in children born with Minamata disease. Lateral squint caused by visual
disturbance in the diseased children was found and was effectively
treated by new clinical treatment. These neurophthalmological symptoms are
caused by disintegration of nerve cells in the cerebral postcentral-cortex.
This symptom is important for the detection of the presence of cerebral
cortex disturbance. Therefore, the symptom is an important reference
for diagnosis. For these ophthalmological symptoms, we designed a new
instrument that detects centripetal constriction of the visual field and
the movement of the eye ball at the same time. The new instrument
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developed by us was named Kumamoto University's Neuro-ophthalmometer
and it can be used for the diagnosis of many people in a short time.
The machine will be very useful for mass diagnosis and for clinics
for the residents in the area. The otorhinolaryngological survey
showed that hearing ability, sense of equilibrium, and lingual, taste,
and smell senses in cases of Minamata disease were functionally
disturbed in general. The impairment of hearing associated with the
disease appears to be caused mainly by the disturbance of the retro-
labyrinth, of its auditory center in the brain, and of the peripheral
auditory nerve. However, this presumption has not been confirmed up
to the present time, because in our histopathological examination of
the inner ear, especially the organ of Corti, no change was found in
these organs. Recently, cats experimentally poisoned with methyl -
mercury were examined and it was found on histopathologic examination
that the cells in the organ of Corti remained intact. Another finding
in the case of poisoned cats was that methy!mercury could not pass
into the fluid of the cochlea. These results help to clarify the
origin of auditory disturbances and will be helpful also in clinical
treatment. However, in the case of chronic Minamata disease, the
source of disorder in the auditory organ still remains obscure.
Taste sense is very important for daily eating habits. The origin
of the dysgensia in Minamata disease is not only related to the loss of
nerves in the respective cortical center, but also related to the
damage of peripheral gustatory cells such as gustatory buds, a finding
which was clarified by histopathological examination in this experimental
study. In another study using autoradiography with 203 Hg-methylmercury,
it was demonstrated that 203 Hg was incorporated into gustatory bud cells.
In the course of experimental animal study, the gustatory bud cells
were degenerated, atrophied, and decreased in their number. The kind of
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experiment in the acceptor of peripheral nerve damaged by methylmercury
was the first study. In future work it will be examined whether damage
to acceptors of the other sensory peripheral nerves is present or absent.
Through study up to the present time, no damage was found in the cells
of Corti organ in the inner ear and in the cells of retina in the eye.
Therefore, peripheral acceptors such as smell, pain, the pressure, and
thermal sense will be carefully examined in future study. It is already
known that severe damage to peripheral fibers of sensory nerves were
observed in the intoxications. Other important neurological symptoms
were mental and emotional disturbances in sensation which were generally
recognized in almost all cases of the disease which were referred for
diagnosis. These symptoms were reflected by cortical disturbance of the
cerebrum, particularly of the frontal cortex. The disintegration of nerve
cells in that area cannot be negligible. In mild cases of the disease, it
is difficult to differentiate from geriatric change. However, in such
cases, methylmercuric poisoning must be suspected because other neural symptoms
such as defect in character and other mental disease were observed.
Epilepsy was also observed in rare cases of the disease. In the severely
diseased case with marked damage to the patient, the progressive paralysis
and total disability was observed. On autopsy, including the cases which
had been studied during the first year of this survey, it was found that
the symptoms seemed to be caused by the damage of a wide area of the
cerebrum, mainly from the loss of nerve cells of the cortex and diffuse
atrophy in the central cerebrum. When the change in the cerebral cortex
due to aging is added to Minamata disease, it is possible that the
delayed type of the disease will appear. Persons whose nerve cells were
slightly affected and injured by methylmercury show earlier geriatric
changes. This tendency was also confirmed by the epidemic logical survey
and by the autopsy. The premature geriatric changes caused by methyl -
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mercuric poisoning will be reflected in the clinical diagnosis of the disease.
All symptoms revealed by this survey were put in a computer system and
were used to facilitate diagnosis. It could be pointed out by the
survey that a new standard of clinical diagnosis for slightly affected
patients will be necessary.
Among the clinical symptoms, pain in the joints and muscular atrophy
were also found in this survey to be common characteristic symptoms
of the disease. However, we did not have adequate study of the causal
factor for these symptoms. These symptoms will be analyzed and examined
with comparison to the neuromuscular disease in future work.
5. Could the methylmercury disease be inherited by descendants of
patients in the Minamata district?
There were cases of congenital Minamata disease. However, the
congenital disease is a kind of fetal disease, not an embryonic disease.
Therefore, it cannot be called true congenital disease. However, molecular
biology experiments and other studies suggested that methylmercury
inhibited RNA syntheses and DNA syntheses. In experimental mice
exposed to methylmercury, the division of spermatocytes into the
spermatids was inhibited by the chemical effect on the process of
spermatogenesis. Researchers in Sweden, who studied the root of onion
and drosophila, found that methylmercury damaged chromosomes, resulting
in genetic variation in descendants. They also found that chromosomal
change in le cocytes appeared in the methylmercury poisoned animal.
However, in our research survey in the Minamata district at this time,
we could not find any evidence of genetic damage or genetic variation.
Through the survey, we found some instances of structural chromosome
breakage in congenital Minamata disease. However, the occurrence seems
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to be in the natural range, since such breakage found in the diseased
children were also recognized in normal control children. Deformity
was not found in the congenitally diseased children. Dental examination
revealed much abnormality in the oral cavity. However, the abnormality
was only determined as abnormal growth in the period of a fetus, but
not as abnormal embryonic development. During our survey of congenitally
diseased children and newborn babies from the families affected with
Minamata disease in the area heavily polluted with mercury, no abnormal
development and no deformity were found. The results mentioned above
indicate that contamination of pregnant women with methy!mercury could not
cause genetic or embryonic abnormality, but could damage the fetus.
These facts could be explained by postulating that methylmercury could
pass through the mother's body and could not affect the embryo in the
early stage, prior to the formation of the placenta, and then the
methylmercury could pass through the formed placenta into the fetus and
damage the nervous system of the fetus. For this reason, therefore, it
is reasonably acceptable to call this disease infantile or fetal Minamata
disease rather than congenital Minamata disease.
6. Relationship between the mercury content and the occurrence of Minamata
disease.
There are several findings concerning the relationship between the amount
of mercury intake and the occurrence of symptoms of poisoning. The
relationship between methylmercury intake and mercury or methylmercury
accumulation in the body has to be considered.
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From the results of experimental poisoning and the findings of autopsy
of the disease, Dr. Takeuchi estimated that the total amount, 1,000 mg,
of mercury compounds by the oral administration for several months would
be the toxic dose which essentially caused Minamata disease for the
person having 50 kg of body weight. The total amount 100 mg of mercury
(one-tenth of 1,000 mg) will be a risk dose for the disease in the same
way. In Dr. Kitamura's study, poisoning symptoms could appear when
mercury accumulation in a body reached 100 mg and the lethal dose seemed
to be 1 ,000 mg of mercury in a body, considering about 70 days estimated
as the biological half-life of methyl mercury.
Our research study in this time showed that there were many differences
among the mercury accumulation in various organs. Therefore, it suggested
that the extent of damage in the organs by the contamination with mercury
could be varied depending upon the amount of mercury accumulation in
these organs. From the examination of mercury content in the case of
autopsy of the human body receiving methyl mercury by oral administration,
it was found that the highest content value was in the kidney, the second
highest content in the liver and remarkably low content in the brain.
In the early stage of the disease, the mercury content in the brain was
less than about one fifteenth of the content in the kidney and one-eighth
of the content in the liver. This value in the brain of the diseased
persons, was high, being about 192 times the values of 0.^0.005 ppm
detected in normal brains. In spite of the various mercury contents in
organs, the fatty degeneration in the kidney and the liver was only
observed by the histopathological examination in the cases of acute and
subacute disease. In contrast to these visceral organs, pathological
changes in nervous tissue were especially severe. Among the nervous
tissues, the visual central nervous area in the cerebral cortex and
the deep area of the cerebellar cortex were commonly damaged. In severe
cases, the damage spread out into the entire area of the cerebral cortex,
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but some extent of the first slight changes were scarcely observed in
diencephalon, in mesencephalon, and in spinal cord. Therefore, there
were some special relationships between the amount of mercury intake,
the accumulation in the individual organ, and the response of tissue
cells. However, it is not so simple to discuss the relationships among
them, such as the relationship between the appearance of symptoms and
the total mercury content. Mercury accumulation in the brain can be
considered as the total amount of mercury which is derived from the
methylmercury compounds which have passed through the brain blood barrier.
From the findings in autopsy cases, poisoning symptoms will appear when
the mercury content in the brain reaches beyond 1 ppm, and the patient's
death will occur when the content reaches beyond 5 ppm. Dr. Tsubaki
indicated that the disease would appear in persons having more than
40 ppm mercury content in their hair.
In the case of humans, biological half-life time of mercury content
in the kidney was estimated as about 70 days and in the liver was a
little less than 70 days. Contrary to the findings in these organs, bio-
half-life of mercury in the brain was remarkably different. Mercury
accumulation in the brain was very slow and delayed after mercury intake
into the body. The maximal content was found at about the 40th day after
mercury intake. The decreasing pattern of mercury content in the brain
was different from other organs. After two months from the date of
maximal accumulation, little decrease was observed, after the disease was
apparent. One half decrease of mercury content in the brain was found
approximately 230 days after the disease was apparent and one-third
decrease was found one and one-half years later. After two and one-half
years, mercury content in the liver and in the kidney of diseased patients
had generally returned to normal level, but in the brain, mercury still
remained ten to one hundred times higher than the normal value. Therefore,
this observation requires a revision of the table presented by Dr. Kitamura
-------
which estimated the relative value between the mercury accumulation
and the intake on the basis of 70 days as mercury bio-half-life period.
It means that a lesser amount of mercury contamination in the body
than the dose of mercury poisoning reported by Dr. Kitamura seems to
be enough to cause the disease or the death. It will be revised to
show that if a person had been taking 1 mg mercury daily, it would take
465 days to reach 100 mg of the total amount of mercury accumulation in a
body according to the table presented Dr. Kitamura, but a shorter period
would be enough to cause the appearance of disease symptoms by our
estimation as mentioned above. Dr. Kitamura's other suggestion that the
daily intake of 1 mg mercury would be harmless for the human body, must
be changed. From the recent autopsy cases of the Minamata disease patients
previously recognized or other diseased patients in the Minamata district,
the mercury content in the liver was found at normal levels and somewhat
high values were found in the kidney, but high values in the brain of
1-^2 ppm mercury were found in many cases. This fact indicates that the
condition of the human body exposed to mercury pollution still remains
above the poisoning dose level.
Epidemiologic surveys also support that there have been many Minamata
disease patients in every year since 1965. Therefore, contamination by
very small amounts of methyl mercury for a long period, would make it
possible to accumulate mercury in the brain in large enough amounts to
cause poisoning, nevertheless significant mercury accumulation in the liver
and in the kidney could not be detected. For this reason, a more precise
study will be necessary to establish the relation between the intake of
small amounts of mercury for a long period and its poisonous effects.
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7. Occurrence of a chronic type of Minamata disease—a chronic Minamata
disease.
It is essential for the occurrence of Minamata disease that the
accumulation of methylmercury in the brain has to reach the toxic dose
level. Therefore, when a person is given a large amount of methylmercury,
the mercury accumulation in the brain will be rapid and an acute type of
disease will appear. Severely ill patients have mostly died within
a period of 100 days after onset. In such cases, mercury content in
the brain at death was found to range from a high of 24.8 ppm to a low
of 2.6 ppm, with 10.31 ppm being the average value. When a person
receives lesser amounts of mercury, the latent period of the disease
will be prolonged and the subacute type of the disease will appear.
In this case, no deaths will be found due to mercury poisoning.
With still less mercury contamination than that mentioned, it will
take a longer period for symptoms of mercury accumulation in the brain
to appear as described above. Since 1961, patients with Minamata disease
seemed to be almost entirely of the chronic type. Among the autopsy cases,
many have been recently found of the chronic type and very few cases
were found of the subacute type. In these chronic type cases, it cannot
be clearly recognized when they were suffering from the disease and the
typical symptoms appeared later. Such chronic type of the disease is
called chronic Minamata disease. In cases of the slightly ill patients,
we found that many were cured after the clinical treatment in the early
stage of the disease. However, in the two years survey in this time
(the first and the second year's research), some cases showed a satisfactory
progress into a cured condition, but some cases took a turn for the worse.
These facts suggest that the problem about the relationship between a small
amount of methylmercury pollution for a long period and its accumulation
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in the brain still remains obscure. Another study was made to detect
subclinical or inapparent Minamata disease and to clarify the picture
by examination of autopsy cases and the estimation of mercury content
in organs. Subclinical Minamata disease was sometimes revealed by
detectable symptoms during the aging process. This type of case is
different from the delayed type of Minamata disease reported by
Dr. Tsubaki. The subclinical Minamata disease was detected only in
middle-aged people, but not in young people, and could be called
a delayed type of Minamata disease in aged people. This type of
Minamata disease should be differentiated from the symptoms of the
diseases of old age.
The general pathological changes of chronic Minamata disease in
the nervous system, such as brain, spinal cord, and peripheral nerves,
were precisely described in a separate report. In the cases of chronic
Minamata disease, pathological changes were observed in the nervous
tissue cells, similar to those generally observed in mercury poisoning.
The secondary degeneration in the nervous tissue was generally recognized
as corresponding to central nervous system damages of a chronic nature.
For example, a marked disturbance in the precentral cortex caused
secondary degeneration in the pyramidal tract. Secondary degeneration in
the cornuposterior of the spinal cord was found in a case with severe
disturbance in the sensory nerve, especially in the posterior tract
of the peripheral nerve. The severe disintegration of the cerebral
cortex cells caused diffuse demyelination in that area. These pathological
changes were the same as those reported earlier.
In cases with high mercury content in the brain, because of progressive
thinning and disintegration of the cerebral cortex atrophy or more often the
loss of cells was seen. During these pathological changes, active chromato-
phagocytes appeared and chromatin increased in the nerve cells. Therefore,
these pathological changes are difficult to differentiate from aging plagocytic
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changes. For differentiation between aging and Minamata disease, the
locality of changes and the demonstration of mercury will be helpful.
8. Additional findings of pathological changes in organs—diabetic changes
General disturbances in organs in cases of acute or subacute Minamata
disease were observed as fatty degeneration in the liver and in the kidney,
hypoplasia of the bone marrow, and gastrointestinal catarrh. These
pathological changes in organs were slight. In the cases of chronic
Minamata disease, death usually resulted from other diseases and the
disturbances in organs by methylmercury were difficult to find. No
common pathological changes in organs caused by methylmercury was observed
in the chronic cases. Ho specific change was found in the kidney. Among
the pathological changes in the chronic cases, the disturbances of islands
of Langerhans in the pancreas were found. The B cells in the islands of
Langerhans are usually rich with zinc and are related to metal metabolism.
The cells in the islands of Langerhans were affected by methylmercury
poisoning and lead to the degenerative disintegration, resulting in a
decrease in the number of cells in the islands of Langerhans and bringing
about their compensatory reorganization. In remarkable cases, damage was
found similar to the pathological changes observed in diabetes mellitus.
The change is an important finding since it was found commonly in all
autopsy cases of Minainata disease in adults, in infants, and in fetuses.
During the reorganization and compensation, the islands of Langerhans
functioned to the extent that diabetes mellitus could not be found by
clinical examination. However, severely diseased patients revealed
typical diabetic symptoms and with increased sugar content in the blood.
Therefore, mercury pollution could cause diabetic disease.
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9. Metabolic pathway of methyl mercury in a living body and fundamental
studies on the prevention and clinical treatment of Minamata disease.
The difficulty of treatment of Minamata disease has been pointed out.
However, from the study at this tine, a promising treatment was found for
the external squint of the eye (strabismus) in congenital Minamata disease.
At the present time, there has been mercury pollution in some areas, and it
is supposed that mercury poisoning is going to occur again. In such
circumstances, we have to provide methods to prevent mercury accumulation
in the brain and to promote excretion of mercury from the body. For that
purpose, the study of the metabolism of methyl mercury in the body is very
important.
1) Metabolism in the living body.
Experiments showed that Methylmercury changed into methyl mercuric chloride
in the stomach and combined with aminoacids (expecially cysteine) digested
in the intestine. The methyl mercuric cysteine was absorbed into the
intestinal mucosa, stayed there for some time, and then entered directly
into the liver without entering into the lymph by passing through the portal
vein. Some of the methylmercury compounds in the liver were excreted with
bile and the remainder circulated in the blood stream. ;>lethylmercuric
chloride administered by other than the oral route was mostly incorporated
into circulating erythrocytes , but some of it became bound to cysteine and,
as methylmercuric cysteine, entered into the bile. Methyl mercuric cysteine
continued circulating between the intestine and the liver for a long period.
It was found that methylmercuric acetylcysteine existed in the bile. Methyl -
mercuric chloride and me thy line re uric cysteine in the blood are not excreted
into urine. However, quite a bit of methylmercuric acetylcysteine is excreted
into urine through the kidney. This fact suggests that methylmercury combina-
tion with closely related aminoacids have different metabolic pathways in the body.
43:
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The ami no base of methyl mercury combined with the acetylradical is difficult to
reabsorb in the kidney and easy to excrete with urine. This methylmercury
mercaptan seemed to behave as a mercaptan complex for the detoxication
mechanism. The mechanism may be applicable in the future to promoting
methylmercury excretion in urine and to establish a method of clinical
diagnosis for methylmercury poisoning. On the other hand, a small amount
of methyl mercuric cysteine in the blood can pass through the blood-brain
barrier and thus into the brain. It is reasonable to assume that
methylmercury can directly enter into the brain since methylmercury is
soluble in lipid substances. Methylmercury cannot pass through the blood
barrier of the brain when methylmercury is chemically bound with hemoglobin
of erythrocytes. Methyl mercury bound with hemoglobin will be able to pass
only when it dissociates from hemoglobin, ilethylmercury dissociated
from hemoglobin seemed to be bound with cysteine in the cysteine pool
in the body and entered into the serum of the blood and then transferred
into the brain. It is more suggestive, therefore, that a small amount
of methylmercuric cysteine enters into the blood and accumulates in the
brain during methylmercury action on the nerve cells. These mechanisms
and metabolic pathways of methylmercury are also suggested by our
recent experiments.
2) Fundamental findings for clinical and preventive treatment—development
of drugs for treatment.
i. The oxidized forms of pyridoxine-4-thiol and pyridoxine-5-
thiol , are similar in structure to vitamin 86 and have -SH[ radicals which
can react easily with methylmercury. Uhen these chemicals were administered
by oral, subcutaneous, and intravenous routes, the mercury content in
the organs, i.e. brain, liver, was decreased and mercury compounds were
excreted into urine and feces. The strength of the effects decreased in the
order of pyridoxine-4-thiol, pyridoxine-4-thiol oxidized form,
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and pyridoxine -5- thiol. When pyridoxine —5- thiol was oxidized in
the body, it changed to pyrithioxine which had the effect of activating
metabolism in the brain. The pyridoxine -5- thiol had little effect on
the excretion of mercury, but would have very good effects as a remedy
for mercury poisoning. Therefore, pyridoxine —5- thiol will be studied
further. If it should be acceptable for the treatment of humans poisoned
with mercury, it could decrease the mercury content accumulated in the
brain and could be useful in the prevention of and as a remedy for the
disease.
ii. Methylmercury is excreted into bile over a long period, and
thus remains in circulation between the intestine and the liver. There-
fore, if there were some method to prevent reabsorption into the portal
vessel from the intestine, methylmercuric cysteine could be stopped from
entering the blood stream. To prevent methylmercury excretion into bile,
chemicals with strong binding affinities for methylmercury have been studied
for their effects on methylmercury excretion into bile. When a resin having
-SH radical was administered, it was found that the mercury content in the
liver was decreased but not the mercury content in the brain and in the
kidney. Therefore, we are looking for some other synthesized resin with
-SH radicals. Up to the present time, the effect of the synthesized
resin with the -SJJ_ radical was not better than the effect of powdered hair.
The hair powder will be more useful for the treatment to mercury poisoning.
iii. For possible use of the drug in diagnosis, we are studying
the drug's effect on methylmercury excretion into urine. During the course
of the study, we have found that pyridoxine-4-thiol has a strong effect on
excretion of methylmercury into urine and also has the effect of decreasing
the methylmercury content in the brain. Therefore, the chemical looks
promising for use in the diagnosis of small amounts of methylmercury
contamination in the body.
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The results and the new findings mentioned above are still being
investigated in experimental animals. However, there is no doubt that
the findings have fundamental importance for treatment with the drug.
10. Methylation of inorganic mercury
It is well known that methyl mercury is synthesized from inorganic
mercury in some microorganisms or in some fungi. It has also been
reported that methyl mercury is possibly synthesized in the liver of some
fish. However, in the natural field, it was not completely understood
how to change the inorganic mercury in the mud from the Minamata bay
into methylmercury. The results obtained at this time showed that
inorganic mercury can react with active methyl radicals in the municipal
sewage or in the drainage from the factory. In this case, if the inorganic
mercury is mercury sulfide, methylmercury cannot be synthesized. However,
under aerobic conditions, the mercury sulfide can be changed into an active
form of inorganic mercury and can be synthesized to methylmercury.
Actually, a great amount of inorganic mercury was found in the mud from
the Minamata bay. Most of the inorganic mercury compounds cannot change
into organic mercury compounds, but it is possible that the inorganic mercury
can be changed into methylmercury under aerobic conditions or in the presence
of ultraviolet light. Therefore, in the Minamata bay areas, polluted with
mercury, methylmercury poisoning will be prevented only by eliminating the
above condition or by removing the inorganic mercury in the mud.
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VII. Closing Remark
During the past two years, we made a great effort to study and
survey mercury pollution in Minamata district and the surrounding areas
and also the progress of Minamata diseased patients. The results
obtained were separately reported in the first year and in the second
year, and were completely described in this report. From the study,
it is suggested that the inorganic mercury in the mud from the Minamata
bay will be chemically changeable into methylmercury compounds under
some conditions. At the present time, it must be considered that many
problems ?re presented in the prevention of methylmercury intoxication
in these areas ^nd in the medical treatment for Minamata disease.
However, some problems remained to examine or study in future work.
The results and findings obtained will be greatly useful in preventing
the occurrence of Minamata disease in detecting the subclinical patients,
and in treating residents having health effects due to mercury poisoning.
We hope that the area of Shiranui Sea and Ariake Sea will be kept in a
good and healthy natural environmental condition.
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ACKNOWLEDGEMENT
The research was greatly supported by Hr. Sawada, Governor of
Kumamoto prefecture and the related officials and was greatly assisted
by the Mayors of Minamata City, Goshonoura Town, and Ariake Town and
related officials. It was also greatly assisted by all residents in
surveyed areas.
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