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TRANSCRIPT
UCHIVES
FISHERIES AND MARINE SERVICE
Translation Series No. 3507
Chronic optico-neuropathy due to envirnomental exposure of organophosphate pesticides (Saku Disease)
by Satoshi Ishikawa
Original title: Manse• Yukirin Chudokusho no Ekigaku, Rinsho oyobi Jikkenteki Kenkyu
From: Nippon Ganka Gakkai Zasshi 77: 1836-1841, 1848-1852
Translated by the Translation Bureau( KH/PS) • Multilingual Services Division
Department of the Secretary of State of Canada
Department of the Environment Fisheries and Marine Service
Biological Station St. Andrews, N.B.
1975
19 pages typescript
•
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AUTHOR - AUTEUR
Satoshi ISHIKAWA
TITLE IN ENGLISH - TITRE ANGLAIS
Chronic Optico-neuropathy due to Environmental Exposure of Organophosphate Pesticides (Saku Disease)
TITLE IN FOREIGN LANGUAGE (TRANSLITERATE FOREIGN CHARACTERS) TITRE EN LANGUE ÉTRANGÉRE (TRANSCRIRE EN CARACTÈRES ROMAINS)
Mansei Yukirin Chudokusho no Ekigaku, Rinsho oyobi Jikkenteki eenkyu
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Nippon Ganka Gakkai Zasshi
REFERENCE IN ENGLISH - RÉFÉRENCE EN ANGLAIS
Acta Soc. Ophthalm. Jap.
YEAR ANNÉE
DATE OF PUBLICATION DATE DE PUBLICATION
VOLUME ISSUE NO.
NUMÉRO
PAGE NUMBERS IN ORIGINAL NUMÉROS DES PAGES DANS
18 36-18838, 1839 0 1840 ,1 841 ,1 848-1 851 ,1852
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....^^^sa`.iléii^^, _.
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C1TYVILLE
pttawC).t Urit.
JU L3 1 1975753382 JnPt-nese
Chronic optico-ncuropathy chic to Environmcntal r^posure
of Organophosphate Pesticides (Saku Disease)
--Clinical and rxperimental study
Satoshi ISHIKAWA
D%nrfinent of Ophthalmology, School of .1•fedicine, Kitasato Unic•ersiy.
Sngmnihara-shi
OROAItTOPHOSPHATL PESTICIDE
This pesticide is an organic compound with phosphorus
as its neucleus and the structure of this substance is€
RO ^ ii^- XR'
RO
^^ '^ D[S TRADUCTIONS
SECRETARIATD ETATD^EPAI7TMENT OF THE SECRETARY OF STATE ^d ^i,^
^c_0ro
mEô
.0
1836
1837
R is a short alkyl and X is either 0 or S. R' is typically an alkyl
^sessinçr an arninatic ring, carboxyl ester, amide,
thi.oether etc. In this report,
mainly the following substances are discussed. L' D50 expresses
mg/.Kg (oral route).
Ethyl.th ^.ometon
02HS0 I, _ LDS0^14.1
C2 5 0 (Dà.^syston, ekatin TD)
/P^-S-^CH?CH2SC?H5 (Mouse)
9UREAU
DIVISION DES SERVICES
MULTILINGUES
DIVISION ORANCN
DIVISION/DIRECTION
FiSheries Service
2
Vainido-thion
cH3o ° o^ÿ-s-cH^rH2sçxérr
CH36 CH3
LDzo=45.6(r.Ouse)(Kilvar)
Salithion
Ma'.athon
P-S-CI-iC00C^H5 ^CH 0" I `
3 çH2COOC2H5(Malathion)
These organophosphate pesticides inhibit cholin-
esterase.t (ChE), a somatic enzyme, and cause
accumulation symptoms of acetylcholine in the receptor organ.
Over accumulation of acetylcholine stimulates and paralyzes
transmission. For example, with regard to ciliary muscles,
mild ChE inhibition causes myopia and a acute inhibition ca4ses
either hyperopia or paralysis of adjustment. As to the
pupils,a mild inhibition causes miosis while acute inhibi-
tion causes rryâriasis. These organophosphates break down
inside the body into the forms of P-0 and P-S and these
substances are sometimes more toxic than the original substance.
In the case of parathione,it becomes the form of paranitrophenol
which is excreted in urine. TMien examining the patients,
^ocHLD50=91.33
r \\ (vLJuse)S
S LD,0=369
CH.,O \ 11 (mouse)
I
3
it is extremely important for the
diagnosis to ascertain the presence of these organophosphate
pesticides directly in the blood or in the urine or to find
intermediary metabolites. However, the studies in this field
are extremely behind schedule and the only lulown substances for which
the final netabolites Can be detected are: paranitrophenol
such as parathione and FPN, and the paranitrocresol sumithion
(phenitrothion).
METHOD 1848
I. Clinical Examples
The number of infant patients from May 31, 1970 up
to present is 310, of which 150 are males and 160 are females.
(The average age is 10.5 years old for both male and female.)
The number of adult patients is 111. (Average age, 50.) They
were the cases of organophosphate poisoning picked out from
7000 patients who visited the Asama Hospital during the past
three years conplaining of reduced vision. The total
number of patients at the Kitasato University was 81. The
controls were 100 infants and 1C0 admits frai the
Saku district and ,50 subjects among- the Kitasato University ordinary
outpatients unaffected by
this particular disease. 50 cases were selected
from those who received medical examination in Mogamihara
district. The details of examination method were already
reported by. Ishikawa. However, the difference from the forner
L.
time is that the determination of the amount of organo-
phosphate residue was made in blood or in urine using FPD
gaschromatography for all the cases at the Kitasato
University and the 63 cases frœthe Saku district.
method is discussed in the following.
Method of Determing Organophosphate in Blood and Urine by Gaschromatography (Fig. 7)
The structure of the gasdmxuatograph is shawn in the
figure. 2m1 of blood is put in a centrifugal tube fitted
with a ground stopper together with 5m1 of acetonitriles
acetone(218). It is shaken for approximately 10 minutes
and then centrifuelly separated tœezing centrifugation at
0 ° 0, 2,000 rpm) for 10 minutes. This operation is repeated
and a acetonitrile and acetone mixture is prepared.
Then, acetone suspension of microcrystalline powdered cellu-
lose for column chromatography : activated charcoal for column
chromatography (9:1) are packed in a chromatographic tube of
1.8cm in inner diameter x 50cm in length. Approximately
10m1 of the said extract solution is transferred into the
column and then eluted with 150m1 200m1 of 5% ethanol
acetone. The eluate is dried up under reduced pressure.
The residue is dissolved in of acetonitrile,
1 ml of n-hexane is added and mixed lightly. After centri-
fugation (2,000 rpm), the upper layer (n-hexane)
is discarded. This operation is repeated. The lower
layer (acetonitrile) is hardened by evaporation.
l
The residue is dissolved in 20m1 of acetone,?-mZ of
which is injected int a gaschromatograph.
100m1 of urine is put in a separatory funnel (300ml)
with 150m1 of benzene containing 25% ethyl acetate. It is
shaken for about 10 minutes and then separated. The lower 1849
layer is extracted by addition of 150m1 of benzene con-
taining 25% ethyl acetate. The extract solutions are mixed
and thus left _ standinçr after addition-of approxinately 25g of
sodium sulfate anliv&ide. After dehydration, it is passed
through a plaited filter paper and the filtrate is condensed
to about 10m1 under reduced pressure. Further operations
are . done in the same manner as for blood analysis.
For analysis in urine, the literature by Saito, Kubo and
others should be referred t 44) In each of the figures A. B and
C of Fig. 8, the standard curves obtained when we ran the
standard samples are shown. Substances are determined from
the retention time by comparing the retention time of these
curves and the data obtained from the blood of patients.
Regarding this gaschromatographic analysis, the author
received advice from Dr. Kanazawa, Head of Analysis Dept. of
National Research Institute of Agricultural Technology. The
gaschromatograph used is from Shimazu Manufacturing Co. and
a flame photometric detector (FPD) was employed. The above
operation is described as followsE
6
Liquid-liquid partition
Analysis procedure for Organophosphate in Blood
91P4 ?)4)0d
Extraction
Separation
Condensation
2m1 1) . 5m1 of acetonitrile (2s8vy) is
added- Ëo- i-los bv - 5 'minutes shafdng _ _ -
1) Freezing centrifugation, 2,000rpm. t0 minutes.
)
Condense to 411.
lml of nrhexane saturated With acetonitrile is added and mixed. - «h--hexane layer is re-moved.
1) Pour the above mixture into a 30cm long column chromatographic tube of 18cm in inner diameter in Which 1 cm of sodium sulfate anhydride is placed over 100m1 Cf••• aâtivated charcdal for Oolirrai • çhromatographY:MierCerïstalline Cellulose (1:9v/V). •
2) ElUte . With 150e.200M1 of 5% ethanol acetone at the rate of 5flemin:
,s1/ Column chromatography
Drying under reduced pressure
Liquid-liquid partition
Drying under reduced pressure
GC 1) Dilute to 100 1. Inject 5 1.
Analysis Data of Organophosphates in Blood
Fig. 9A is the curve obtained from analyzing the
blood of a normal subject. No organophosphate peak is
observed. B shows the curves of a patient. As corresponding
1.
0 ?
peaks, unknown, salithion, ethylthiometôn, methylparathion
peaks are observed. In Co there are unknown and sumithion
peaks. More detailed information should be obtained from
Tamai's report.77) The unknown peaks indicate metabol.ztes.
II. Experiment Using Animals
--2 Year Experiment on Chronic Poisoning Using Beagle Dogs--
Up to this date, there has been no parallel example
for this study condücted by the author and associates for 1850
over 2 years on chronic intoxication by administering small
amount of organophosphate. The animals used in the experi-
ment were all 6 months old purEbred beagle dogs. For
administration, ethylthiometon packed in capsules were given
orally every day except Saturdays and Sundays. 10 dogs
received dose administration and 5 who did not were used
as controls. The amount of ethylthiometon was determined. ....,,
according to Homma's experiment on subacute intoxication ^.
and after preliminary experiment using four mongrel dogs,
the amounts of 51,19, 10mg and 15mg/dog per day were determined
prior to the commencement of the experiment. During the
experiment, the dogs were weighod. No dose was ad-
ministered on weekends and holidays or on any other days off.
As far as the five dogs which are the main subjects of this
experimental data are concerned, there was little effect on
their weights regardless of the total amount of èthyl.thiometon
8
given or their final weight . The hematocyte cholinesterase
level on the final day of dose administration are shown.
The weight increase of the dogs during the period from 6
months to ale years after birth was approximately 1 to 1.5Kg.
When tentatively considering the weight of the dogs to be
10Kg, the average dose per day comes to be 0.5 ppm and 1.0
ppm for 2 dogs each, 1.5 ppm for 1 dog plus 5 control dogs.
To avoid mutual contamination between the dogs, the treated
and the untreated dogs were completely separated
and 37ept under the same environmental conditions with air
conditioning, constant temperature (23 °C), the same humidity
and constant light. - Also, contamination from food was
taken into consideration and special dog food was prepared
and given to the dogs. Clinical symptoms, blood, blood sugar,
liver functions, urine, feces, ERG, refraction, corneal
curvature radius, phacometry, diameter of pupil, the eye
point, eye ground and intraocular pressure were tested and
measured by Ishikawa, Ohtsuka, Suzuki and others at least
once every 3 moriths and the details were recorded in a computer
to be punched out when necessary. A part of the data
is shown in the table. Two years later, 20-30mg/kg of
menthyl ethoxyacetate anesthetic was administered for
pathological examination. Apart from this, the dogs were
well trained and no anesthetisia other than the local
*4. administration of benoxinate hydrochloride vas performed .
*** Refraction test was done after applying midor3n M at least
T.L.: In Japanese: "mintà-ru" ** II it "Benokishiru"
*** SI transliterated
9
five times at intervals 10 minutes. The Harteinger concurrent
rèfractometer was used for the measurement of refraction,
Zeiss ophthalmometer for corneal curvature radius, Alcon's
elecbxm ophthalmotonometer for intraocular pressure and
for phacometry and echogram, the Ohtsuka, Tokoro and others '
method was imployed.
For pathological examinatiOns, toluidine blue dyeing,
LFB, PAS and silver dyeing were perfonned after fixing
with hematoxylineosine and osmium.
Electron microscopic sampling was done by Kono, Uga
and others (Kyushu University) and in this experiment, a x-ray
microanalyzer, a totally new method developed recently, was
used. 78)
Electron microscopic examination, pathological and
histological examinations are recorded in detail in Kono's
report. 87) In this report, only the major observations are
presented as the author cannot review all of them. With
regard to pathology, the author was assisted ty
Professor Okudaira of Kitasato University,
L . •
10
Fig. 1 e Amount of Pesticides Sprayed and Number of 1838Occurrences (infants)
After 1960 and up to 1967, the ona y pesticide sprayed in theSaku district was malathion. However, since 1968, otherpesticides also were used. The nunber of cases after1966, increased almost in proportion to helicopter sprayedarea and then decreased. The population ofSaku City is shown at the top, and indicates no increase.
PaDalelten
5rli>•
Aa5000
U_] 4,IalA^on I7•. Do.ler)nvi Vam.latn„nlK.er•DI^.l^u^flL:.7 earaa. t15^ 3.01,1CCY.''i 6DUtli ♦ 3•< a^;^0a1
4000
3000
130•IO
IZ'ii Polianla
25
4^Î1 ^.^ 1100
:
2000
10m)
150
}I
535 36 3,` 7à 39
I960 1961 1961 1951 1964 :965 1966 196? 1962 1969 1900 1971
42 41 42 43 44 45 46
Fig. 2 c Rate of Cases Treated for OrganophosphatePoisoning at the Dept. of Ophthalmology at theAsama Hospital.
From 1966 to 1973 for infants and from 1970 to 1972 foradults, the rate of the cases treated was high betweenApril and August during pesticides spraying. The ratewas also high in November during the farmers' slack season.There is no such example for other diseases.
+11W 15
t 10 ^•Q) .)j .'to
Ri x
^.-w ^% f
° ^ I I I ne.Licopter
La17 rr;
CdI z 3 â•• Sq 6 7 9 9 10 11 Iz ;I
s4 ground spraying Month
^
1
.\^!A1ii';Tç.^t!.n.'u'^..R"tv4.wC_....YrOr_.i1-.anvK*..S^t^r.^.!"n++^.Yn>... . ..L..r..... • _ . . ..vrian .^. .. . .. . . . ...., y.v. ^T. .. ..
0.1
0.05
0.01
• 11
Table 1. Organophosphate Content in Blood of Saku Patients*
Number of Cases Corresponding Peaks Average count (PPm)
1 59 2 14
Salithion 0.265
Formothion
3 Ethyl \
0.040
4 MetheParathion
2 DDVP 0.425
4 5 2
0.070 S-seven
6
1 0.035
Diazinon 0.006
* Nothing was detected in 23 controls.
Fig. 3 s Organophosphate Count (PPM) in blood from Infant 1839 Patients in Saku.
Organophosphate count was made twice with the same patient in August and in November, 1972. 0 mark indicates the average and the standard deviation. The counts were 10 times higher in November. In the same patient, contamination was
detected in November though not in August. The effect of water, food and aerial spray of pesticides can be considered.
ppm August, 1 72 November, '72 mtd-imsn unwienn
•=ce: • . , ..T •
• 0.
0 • • • 8
1.01-
0.5
• •
g28s 8.
01.0.tgl
• . 000 •
8 •
008 e e •
o. • • .8
•
8 t
?",
12
Table 2. Epidemiological. Survey in Saku District (Infants)
Îçoumi
Saku City
Asashina
Mochizuki
Karuizawa
Oshirota
Nagato
Kitaomaki
Yachiho
Ko;noro
Tateshina
Shiota
Total
Population
No. ofatients(infants) Occur.-
OrganophosphatedPtected, ppm(min. - max. )
0 -4.29
0.05-2.140o -0- 540 -1.821 -2-300
0 -0.280 -0,28
0.56-0.83o0
0.751-0.99
7,60049,000
6,200
12,000
13#0008,700
5#5005P 5005: 4oo
39,000
8,300
25,000
14•1,100
rencerate(per1,000)
30 3.9169 3.4
16 2.5
25 2.1
25 1.910 1.1
4 0.74 0.7
3 0.6
..21 0•51 0.12 0.1
310 2=19
Averagé)
n)puteox, ( per.5ons)
.
!ru,..e.
i,4 :
\
„
.ur
p
cch.
tpfhd, p
mc
,
...w.lamSt_
2....-->y ....,...
, . 39000 „.
l• .7. • Içornc. -7;f7,71.9 OS heed. ,t-
H [ 'II...J/0e\ . X ft RI , I.2L ''-'•
■ Flio:to, I-nni-uPo fAa83Q71.X`<;3 :i----
I: EH • k, • -., . 0 ,-r----=‘-if .1c 1 2 -'-'-.- -
1<it( —11.10DiL . • • ' 8 ' 4- 0. Ins--
6 mc à: 770- . • -egeil 0 _ .-:1?....› .,ewer f•---
lviamuratt■ 7 ''• • •• c_À-3
sehhzoki
Pidelit,// Mt neamA ,er.rd.
1 •
0 g
An (À) r.Mfi7R
;-, el-ideeife—/e " Ze
0 ti 00 •le 0
f Le,Z.0
.5.40D mt. Tittesh ■ nel 0.28 k -01111
1.90 01r. 4.29 I Ilapi ewer .
noon 4, ntA: 7129 '
0.56
rel t . 0
tcee,
1 2
3 4 5 6
7 8 9
13
Fig. 4 t Result of Epidemiological Survey .Population - underlined. Residual organophosphates in
drinking water (ppm) and the districts where outbreak of cases was reported are indicated. Centering around Saku City, occurrences are frequent and many cases are found in districts along the Chikuma River and its tributary streams.
Table 3. Organophosphates in Blood from Patients at 1840 Kitasato University
Number of Cases Corresponding Peaks
51 Salithion
34 Ethyl N Methyl/ parathion
19 DDVP
7 Diazinon
5 Ethylthiometôn
3 Sumithion
2 . S-seven
1 Formothion
1 Bitex
Average count (P1m)
0.145 0.719
0.455 0.038 0.018 0.070 0.030 0.030 0.010
Fig. 5 :
14
Organophosphate Count in Bloodof Organophosphate Poisoning patients treated at theKitasato University (vertical axis) andMonthly Changes (January to December)
pp. i n
1.0
0.1
0.01
0.001I 2 3 4 5 6 7 8 9 10 I I 12 rrnntfl
p,
Fig. 6 s Serum Cholinesterase Level in Patients inSaku District. In both infants and adul.ts,there was a decrease from Ivlarch to S.eptembd^with the minimum level in July.
e
0.85
ControJ.s a 100, 1. Os^r
1 ^ 1 0.11
1 `% I IÎë5)`1
12 n.< number of months(eüi,;,s , (1 970-1973)
1841
,^w:.• •t.^!*c^-^sv.u,>,r_.^,,^ .s..,r . ,.. _..., . . . ^.: .,..,^,... ..„.._......,.....^F..,...._.,-.,--._-..-.... ... _. ...... ... ....,. ... , . . _,._., ...,,.._....
R
(75)
0-0 f%
o---a Tnfan s!°.Y, c^--.^ 4 i ' 1 `05) Patients
l ( ) a");, / AdultlAü(rti ]OOY, 1.0510.21
1 ^ ) Numbe^
6i (9F)
(52) ^.^5)1 pf (208)
it
1 /
U42) ^13) K i
(206) Of reaC7.7..nÇl^
jl2'•5
n ^tinR. ^
Di rnotho ate-
DDVP Ekal in
Cyanox
Sunii1Won
) EMylporalhion
rmorean
ï ,1
1 Poston. Papthion
tI çn Cod 1 -- Battery
'
t r; F 10 Collector — Glals Mildew r . Oolical F u ll er
_ _
I ! Pho lo rnli er .
D i pl o ro x
1 5
Fig. 7 Block diagram of Gaschromatograph 1848
Amp .{
Recorder
I ,r ) il
c• 2'8..1:net L
i - H2 1 High-Voltage •
Column N2 L Sorrier Gas' I
DoIumil CIPment Injection Port
Fig. 8(A) Retention Time of Standard Samples Obtained by Gaschromatography
150° C — 5° C/min I 20mln
.Fig. 8(B) s 'Retention Time of Standard Samples Obtained 1849 by Gaschromatography
Di- Syston Ihipthyl parathion
Il Jj I I Vin jl iphote S-Sevon Ep
Exhaust , s Heater
.„
150.D — - — 5C/min I 20m in
16
• Fig. 8(C) t Retention Time of Standard Samples Obtained by Gaschromatography
Salit hion Diazon
Ant hion
• Amiphos
150 ° C 5%/min 1 . 20min
Fig. 9(A) t Result of test for organophosphates in blood 1850 of a normal subject.Noorganophsphate peaks are detected.
r—Y
Fig. 9(B) Result of test for organophsphates in blood of a patient with serious intoxication. Unknown peak, salithion, ethylthiometon, methylparathion peaks are observed.
o
F.
r •
c
WW
Me
thyl pa
rath
lon
•...taa.-•L:.e^aial_r.s'a.,4ïa ....^:..^si_^:_,. ..^._:.:3:b^:::^laCiA^r^'.1.^t+^.::'?ti;^^:^.rr.:ifS'a`.S.i^z3"l.'.^FL:S^_'""...s:.Nf.„.u,^..^a .̂zryu^T_a.wn.41_..C3.^ - ::2u.Y^..K^:he.W..]:e.L^ti:.tY.t^.:.&a::^'3nduvJS.3?.'sG'f r.i.+=.szl^lY ^1.iann,ï-ti.'w..ï.=ÿ{
17
Fig. 9(C) t A patient with moderate intoxication.Unknown peak and sumithion peak are observed.
Ir'
L-
il
18
0
Fig. 10 s Neuropathic symtoms (Patients in Saku DistrictsChildrens 100 casesg controls, 100 subjectsAdults: 51 cases; Controls, 50 subjects. )Tendon reflex, disorders in sensory system,coordination disorders and disorders in muscularsystem are observed in each case.
Patients coo, Contr,91*o, M
1E1C iiY 7
1.1.1 u'1 I i q:
1i JL
rl`,•1 h^^T
0 10 20 30 10 ^r--- r- -
......_._..._...._..._..._......W .......: W^ E::^;x
............ ^::: ^ ^^`
ZJ..::^._._....y ..................:...::^. ^::::^ ^ . ^ . . ^:":^:-
0 10 20
r^ 4•11 Infants I:.̂ .:.:m ..: ^u. Adults
I-
10
AcceleratedTendon reflex ^ Disappeared
Abnormal reflex
Reduced consciousness of bodily positionSensory system I Reduced sense of vibration
Numbness
Coordination ( Inability to stand on one footl Dysdiadokokinesia
Muscle atrophyMuscular system Fibrillary contraction
Reduced muscular strengthInability to walk
/ 0 10 20
Infant 0:u patients U-1 MIMM Controls
1I n
FIJ fi
eit Ji
el
eb:t
if
91:if
555555:•23:3
General fatigue Loss of s Lremgth
Forgetfulness Reduced capaciIT for a.ttentibn 00 20 30 40
zmhnv
/1 • (;
50 60
o
eiesei
e-1.4(11 *ee ›tz
1;11 el
ME§-;::;•M
_eft U 4
Patients
:fl Li uontrols
(22)
, 19
Fig. 11 z Autonomie Neuropathy Symptoms 0e2 Patients in 1852 Saku District
4R
Excessive drinking Car sickness Excessive perspiration Constipation Headache Diarrhea Low blood pressure Dizziness Nausea Tremors Goose skin
Fig. 12 s Clinical Symptoms of Patients with Chronic Organophosphate Intoxication (according to Metcalf)
Reduced vision Blurred vision
Headache
Muscular pains
Excessive perspiration