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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DACTYLOGRAPHIÉES

10 77 1 9

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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