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CENTRAL NERVOUS SYSTEM EFFECTS OF CHRONIC
EXPOSURE TO ORGANOPHOSPHATE INSECTICIDES

J. ROBERT DILLE, MD.
PROGRAM ADVISORY OFFICER

PAUL W. SMITH, Ph.D.
CHIEF, PHARMACOLOGY-BIOCHEMISTRY BRANCH

FRDERAL AVIATION AGENCY
CIVIL, ABROMEDICAL RESEARCH INSTITUTE
AERONAUTICAL CENTER
OKLAHOMA CITY, OKLAHOMA
OCTOBER 1963


An: electroencephalogram showed paroxys-
mal'3:7 per second slow waves (theta waves)
of approximately 50 microvolts present most
prominently in feads Fr,, Fr, Ci, and C,, less
prominently in leads 0,, 0,, T, and T.; and
absent in leads T, and T,. Occasional high
voltage bursts (above 100 .V) appear in leads
Fe., Fes, €,, and C. There were no significant
changes with hyperventilation and
photostimulation.

DISCUSSION

It is commonly accepted that the toxic ac-
tions of the organophosphate pesticides result
from their inhibition of the cholinesterase cn-
zyme. Unlike the carbamates and a varicty of
other chemicals and drugs which exert a tem-
porary oF transient effect on the activity of this
enzyme, the organophosphates cxert a persist-
ent action because of the formation of a chem-
ical bond between the phosphorus-containing
radical and a receptor site on the enzyme it-
self. The rate at which phosphorylation takes
Place following contact organophos-
phate and enzyme varies from compound to
compound, as does the firmness of the bond,
The rate of this reaction, along with many
other factors such as size of dase, route of ex:
powre, enzymatic transformation of the toxic
material in animal tiseues, and the rate of ox-
cretion, contributes to the rate of depression
of cholinesterase activity and the time of onset
ted severity of such symptoms as occur The
firmness of the phospate bond is the controlling
factor in determining whether some spontane-
whether econpey of fall aethty depends ce
wi tecovgry of full activity or
tirely on de novo synthesis of a new comple

ment of enzyme. : kh
increases will

time, and this factor tly influences the
success of efforts to vate the enzyme by
means of 2-PAM of other, similar antidotes,
ber edit Puede gs eee oe
te compound given ‘or or par.
enterally, the activity of plasma’ (pseudo)
inesterase can fall to near zero in one hour,
that of red cell (true) cholinesterase will
reach a similar level in two hours, The red
cell activity is believed roughly to parallel that
in nerve, muscle and gland, A rapid fall of

enzyme activity usually coincides with a rapid
onset of acute symptoms. Following a single
exposure, recovery of from 13% to 19% of the
pre-existing enzyme activity can occur within
24 hours. Plasma activity thereafter retums to
normal in 30 to 40 days, and the erythrocyte
level in about 90 davs,

A considerable lack of precision is inherent
in the methods most commonly used for ron-
tine measurement of cholinesterase activity.
Therefore the values of 20% and 12% reported
by the second pilot as having been obtained
in that sequence, five or six days apart, do not
necessarily Indicate a real decrease in activity
during this period, especially since the deter-
minations seem to have been made in different
laboratories,

The peripheral autonomic and somatic motor
responses to acutely toxic doses of organophos-
phates are in actuality, therefore, the res;
of these, systems to accumulated acety! ~ ine.

» the responses to the pre-
Sietable effects of plea edited
acetylcholine, the differences 1g primarily
quantitative, but there may be exceptions.
Vv the heart is usually slowed by acetylcho-
phates may cause acceleration
pitation and dbcomfort In the pre-
ton instead. This may be due to
nausea sufficient to overcome the expected
brad; or to stimulation of the adrenal
glands resulting in release of catecholamines,
Dilation of the pupil may occur instead of the
predictable myosis.
A more detailed account of the symptomatel-

line,
with

of te polsoning is to be
fond in tl ase yn Durham and
Hayes’ and the article by and Shaw,
Each of the subjects ted in this re~

experienced man; these acute
omedicing their active as oariultura
pilots, Case 2 in particular recounts many epl
sodes of nausea, retching, vomiting and abdon-
inal cramps, and the muscular weakness which
indicates an advanced stage of acute toxicity.
Case 1 was reported at one time to have ex-
perienced anginal pain, but this may well have
been identical with the sensation of “Ughtness”
in the chest of which the second subject com:
plained, Atropine {san effective antidote
against the majority of these acute effects, a

-4-


CENTRAL NERVOUS SYSTEM EFFECTS
OF CHRONIC EXPOSURE TO ORCANOPHOSPHATE
INSECTICIDES

J. ROBERT DILLE, M.D.
PAUL W. SMITH, PRD.

The organophosphate cholinesterase.
inhibitors, which were first introduced durin
World War HI as potential agents of chemi!
warfare, have yie! & variety of derivatives
which are now among the most widely used of
all pest-control agents,

As carly as 1941 it had been established that
the high toxicity of these was due

used In the treatment of such clinical states as
and myasthenia gravis, whero per
viteney of action can be an advantageous

organophosphate
poisoning vary in rapidity of oneet, severity
and duration depending on com:
ee . pal pers nk Aa pedir
are

peripheral and depending upon their
Pe erttceal symptoms are; in genera,

’ .
more “yore and Immediately acaperitating
than are the central effects, phd until about

ten years ago the latter had received little at.

tention, At about that time it began to be
realized that cholinesterase inhibitors could

luce sensorinotor, behavioral person:
ality changes, but there was no general agree
mentyas to their potential severity and
importance,’

ttlo has been written about this prublem in
the intervening years, but recent reports, pare
ticularly that of Gershon and Shaw,’ have

firmly established the psychiatric

tion 29.3 (d) (i) (ii) of Part 29 of the Civil
Air Regulations (now Section 67.13 (a) (1)
(it) of the Federal Aviation Regulations), A
current psychiatric evaluation was. obtained
and accompanted his appeal to the Civil Alt
Surgeon for reconsideration,

-l-


ACKNOWLEDGMENTS

The authors are deeply indebted to Harry L. Gibbons, M.D., for
the first case and to P. C, Tang, Ph.D., who performed the electro-
encephalographic studies on the second case.


0 ee

In January 1955 he began applying a mixture
methylparathion and DDT on a plantation
in Perm, The living quarters were quite near
the mixing and loading area and the odor of
insecticide was said to be constant. He re-
led that nautea and diarthea were preva-

t among the twenty pitcts employed. In
March he sought voedical advice, as told that
he had liver and kidney damage and was ad-
vised to stop spraying.

He resumed spray in July 1955. During
the next six ee he experienced gastro-
intestinal complaints about every ten days, He
reported that this is a common experience of
acrial applicators in his country and that the
ute of a mixture of atropine, sugar and char-
coal for relief of symptoms {s widespread. Dur-
ing 1957 he sought medical advice for nausea,
chills, and tightness in the chest. He was ad-
vised to rest a few days before he retumed to

ying.

On September 26, 1961, his clothing was
saturated with a mixture containing methyl

thion, toxaphene and when 1!
tank of his alrcraft was tly overfilled.
He washed his face, shouklers and hands and

‘continued flying. Three trips later he was “too
sick to fly” with nausea, abdominal cramps,
dizziness, chest tightness, extreme weakness of
hands and legs, and a rash on his wrists, He
alized for five days, He reports that
20%, his liver was en-
larged and liver tests were “abnormal.” His

flying but a of symp-
toms on the day, He yras advised against
further aerial application 4

security for the next six months (through March
1962). An EEG obtained in January 1962 ap-
peared to be normal although he experienced
dizziness during photic stimulation,

win May 1962 he was re-evaluated. At this
time his cephalin flocculation was + (48 hrs.),
his thymol turbidity was 3 units, and his brome
sulfalein was 5.5% retention after 43. minutes.

He retumed to aerial application in July in-
tending to work only two days per week, He
experienced nausea and weakness on the sec-
ond day and went to the hospital outpatient
department where he was given the mixture of
atropine, sugar and charcoal, En route home
he experienced dizziness, He retumed to the
hospital and obtained a blood count which he
reports showed 11,500 WBCs per cubic milli-
meter, He was denied stiy medical support for
further social security benefits, He was in-
formed that a tonsillitis could be responsible
for the elevated white count; he,. therefore,
urierwent a tonsillectomy, After recovery he
attempted a retum to working one day per
week but ex m the same symptoms, He
stopped work in late August I
contin, time of his craminton bee his chief

twas of recurring acute
anxiety. His usual geniality been marred
by sudden outbursts of temper the past two
years. He feels “closed In” and jences
sweating and difficulty breathing when alone
in a car or a On one trip he fad to
land because of his Fymptoma He he once
enjoyed flying at alti up to 12,000 feet,
he now hecomes symptomatic above 5,000 feet,
He is symptom-free in the presence of another
person, even a non-pilot. Ingestion of alcohol
is also noted to relieve his symptoms, He ad-
mits fear of being alone in a closed space as a
child but denies any recurrence of these symp-
toms until the past two years, He is now ex-
tremely sensitive to the odor of even low con-
centrations of chemicals and experiences nausea
ard chest tightness when he smells benzene,
wasline, ether, o¢ similar ts
pat medical history is non-contributory
except jor an ted appendectomy at
age 20, The cay hisses and review of sys-
tems are similarly non-contributory, There
werd=tio abnormal findings on physical
examination.

Laboratory studies were as follows: red
blood count, 5,340,000 cubic millimeter;
hematocrit, 52 per cent; lobin, 17.2 gm;
white blood count, 7,100 with normal differen:
tials total cholesterol (non-fasting), 318 mg.
per cent; thymol turbitlity (non-fasting), 5.2
units; urinalysis, normal,

A chest x-ray and an electrocardiogram were
normal,

=~3~


FOR
SCIENTIFIC AND TECHNICAL INFORMATION

CAMERON STATION. ALEXANDRIA, VIRGINIA

UNCLASSIFIED

a”


major exception being the Initial tremor and
later weakness of skeletal muscle.

With or without treatment, the acute signs
and symptoms usually subside within one to
six days although the activity of both plasma
and red blood cell cholinesterase may still be

low. It is also true that repeated exposures to
small doses of cholinesterase inhibitors may re-
duce enzyme activity to a low level without
the appearance of acute symptoms. The mech-
anism of adaptation to low levels of enzyme
activity is not known.

The nature of the central nervous system
symptoms depends upon the manner and de-
gice of exposure, Acute poisoning has been
reported to produce ataxia with stumbling gait,
headache, restlessnew, irritability, impaired
ability to concentrate, deperonalization, indif.
ference to environment, wild dreams, slurred
speech, tremor, convulsions, medullary center

lepression witl pres, cyanosis, coma anc
high-voltage, low-frequency clectrvencephalo-
graphic waves which are more pronomicu
alter hyperventilation,

Since both of our cases are typical of chronic
exposure, it is not surprising that neither of
them presented an appreciable number of these
symptoms at any time, Only. headache was
prominent in Case 1, and Case 2 showed onl
irritability, atasia and slow EEG waves wh
were of moderate amplitude and not appre-
clably altered by hyperventilation,

Chronic exposure is associated with anxiety,
uneasivess, giddiness, Insomnia, somnambulism,
lassitude, oe tinnitus, doris dizai-
hess, pyrex ysis, polynen.
This; Rental ‘confaion’ Gretional abut, de:

frewion with ing. sc teactiqn,
fanny ah fugue, inability to get along with
fa riencls, performance.

OF these, Case 1 preented the symptoms of
anxiety, uncasiness, and with weep-
Ing. Caso 2 complained of ‘dizziness, anxicty,*

emotional lability, frequent and severe dis.
agreemeents with family and associates and an
inability to-perform familiar tasks, ,

Since only close questioning of a non-
nagically-trained individual would reveal the
occurrence of certain of these symptoms, par
ticularly if they were transient, it is possible
that some may have been missed in’ these
histories.

Other reports have stated that recovery from
schizophrenic and depressive symptoms requires
from six to twelve months following removal
from further contact with the totic agents.
Sufficient recovery for discharge from medical
observation occurred in ten months in our
Case 1, but commercial flying was not at-
tempted for another two years. Symptoms
which prevent commercial flying still persist
in the second pilot six months after his last
exposure. Symptoms that persist after 90 to
129 days cannot be associated with low cholin-
esterase levels in the brain. There is some in-
dication in these and other histories that re-
covery may be a relative term and a degree
of recovery which would permit the resumption
of one occupation might not permit the re-
sumption of another.

The EEG pattern found in the second pilot
(Fig. 1) {s not inconsistent with the findings of
other authors” despte ‘ower amplitude and
the abszuce of changes with hyperventilation.
The Principal difference concems the duration
of the effects, which are reported in other
studies as seven days,’ eleven to eighteen days,”
and four weeks’, If the EEG changes ob-
served here are Indeed resklual from organo-
phosphate exposure, their persistence exceeds
six months, Slace experts differ in their in-

ation of slow-wave activity, it is not cer-
taln whether the EEG obtained one year earlier
and pronounced normal was different from
the current one. knowled

Tn the light of present jae, fk rust
be consklered more likely that the mild liver
damage found in both pilots was caused by
the thlorinated hydrocarbons to which they
were also chronically exposed,

It is interesting to speculate that our cases
were the victims of a combination of circum
stancesglmost perfectly designed to produce
their central nervous system involvement, They
operated in regions with long growing seasons.

nature of the crops and the insect pests
demanded the use of organophosphate insecti-
cides, Prolonged periods of guod weather and
& great demand for their services led to long,
uninterrupted periods of flying. All of these
factors combined to cause continuous contact
with the toxte materials for protracted periods,
and encouraged the practice, common among
agricultural pilots, of suppressing acute symp.


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Review-of the record revealed that he had
undergo.e eight months of psychotherapy for
an anxiety reaction with tension headaches
3% years prior to this examination. Just prior
to this treatment, he had failed to accept re-
alistically the death of his 93 year old father
and was greatly upset when one of his children
ingested a foreign body one month later, He
was actively engaged in the acrial application
of organophosphate insecticides immediately
preceding and during this treatment. When
little improvement occurred he was hospital
ized with a diagnosis of a neurotic reaction
with obsessive compulsive, phobic and depres-
sive syn.ptoms,

At the time of admission he complained of
angina and was unable to work despite the
assurance of physicians that no discase existed;
he was fearful of being alone, depressed, and
despondent with crying spells. He had no
suicidal impubes, insomnia, ideas of guilt of
pinishment, or depersonalization, The past
tmedical history, family history, and physical
examination were not significant.

Laboratory studics were as follows: hema-
tocrit, 43 per cent; hemoglobin, 15.4 gm;
white bleod count, 7,700, with normal dif-
ferential; BUN, 10.3 mg. per cent; fasting ghi-
cose, ILA mg. per cent; total serum proteins,
7.60 gm. cent; albumin, 427 ym, per cent
globulin, 3.33 gm, per cent; alkaline phospha-
tase, 3.3 units; bromsulfalein test, 12 per cent
retention in 45 min.; cephalin Mocculation, 24
brs: 2+, 48 brs: 2+; prothrombin time, 80
per cent activity; Kline, negative, No cholines-
terase determination was performed.

Baseline ar double Masters test_clectro
cardiograms. normal. No clectroencepha-
logram was performed.

A:chest x-ray was normal as were upper and
lower gastrointestinal sorties and oral

tography, y

He mere 19 clect treatments und
was disc after two months on iproniazid,
3s mes ly, and pyridoxine, 150, mys, daily,
The diagnosis was. psychotic depressive
reaction,

Ghis hospitalization was not reported until
the third annual physical examination for a
second class medical certificate following diss
charge. At this time he denied any commer:
clal flying during the two years immediately

S ecceneen

n

following his hospitalization, He reported 600
hours flying time in the preceding year and
denied any symptoms referable to the nervous
system.

The medical record including the current
Psychiatric evaluation was reviewed by the
Civil Air Surgeon’s Medical Review Board.
Since there was no disqualifying physical de-
fect present at this time and since the correct
diagnosis may have been that of “acute brain
syndrome probably resulting from exposure to
toxic chemicals,” a medical certificate was is-
sued with the stipulation that a current psy-
chiatric evaluation be obtained at the time of
his examination for renewal of his medical
certificate,

Case #3.

A 37 year old Latin American agricultural
lot visited CARI in Febmiary 1963 seekin;
Ip for recurrent bouts of acute Ansiety. wh
he believed to have resulted from fong ex-

posure to organophosphate insecticides.
He began acrial application in ier yd
ago after serving ten ycare as a
the Chilean Ale Force, One year later ho
moved to, Gastemmale where he still resktes,
how as an tor re~
veals the use of a wide try al to
Pwstly cotton wi thion,
DDT, touphene, endrin, and didn The
normal season {s from July through December;
the normal workday Is from 6:00 a.m, to 2:00
p.m.,, five to seven days a week upon

“tho weather, The farmer selects

chases the tnsecticide and furnishes the Lend.
ing strip and mixing facilities. The owner
operator employs « mixer and a flagman and,
when business warrants, may employ a second
pilot, “The pilot usually helps with the mixing
about every third day. The insecticide mix-
ture for cach of the 30 to 50 daily flights is
loaded in 1S minutes from an overhead tank.
Spillage is common and results tn discoloration
of the left wing and the ground, Review of
his personal habits revealed that he cleaned his
plane, inside and out, at the end of each day
and wore a respirator in which he changed the
filters every day and the cartridge every two
of three days,

-2-


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CENTRAL NERVOUS SYSTEM EFFECT:
OF CHRONIC EXPOSURE TO
ORGANOPHOSPHATE INSECTICIDES

Jd ws

FEDERAL AVIATION AGENCY
CIVIL AEROMEDICAL RESEARCH INSTITUTE
AERONAUTICAL CENTER
ORLANOMA CITY, OKLAHOMA

OCTOBER 1963


a

rm

NOTICE: When government or other drawings, speci-
fications or other data are used for any

other than in connection with a definitely related
government procurement operation, the U. 8.
Government thereby incurs no responsibility, nor any
obligation whatsoever; and the fact that the Govern-
went may have formated, furnished, or in any way
supplied the said dravings, specifications, or other
data is not tc be regarded by implication or cther-
wise as in any manner licensing the holder or any
other person or corporation, or conveying any rights
or permission to manufacture, use or sell any
patented invention that may in any way be related
thereto.

Yee


nes

toms with atropine and continuing their -work.
In the meantime, the more insilious central
nervous effects were developing.

These circunntances are not unique, and it is
almoit cesta'n that more such cases will appear.
Physicians in Latin America and the agricul-
tural regions of the United States are hecoming
alert tu the acute peripheral signs. and symp-
toms of organophusphate toricity, and recog-
nize them readily, It is now apparent that
they must be watchful for central nervous sys-
tem symptoms as well. They should be es-
pecially emphatic In warning pilots to avoid the
prolonged, chronte expowire which may lead to
mmychiatrle difficulties

The case of the second pilot of this report
Indicates that it fy scarcely powible to take ex-
coube precautions against such etpovure, since
he crntomarily ined a reepirator which he kept
in geal condition, had flawn a chned-cockpit
alrcralt since 1990 and was careful about the
clanlinew of both hie aircraft and his person.

Even this reed not be weprhing Of 23
subjects in one sturdy." all of whom «ved carbon-
(iter respiratory and worg rubber gauntlets and
eorrealls, 19 hed mikd to moderate symptoms,
four sad vernte symptoms but recoverrd, and
one died

-~7-

REFERENCES

|. Conference on Human Pnarmacodynamics

of CW Compounds, Chemical Corps Medi-
cal Laboratories Special Report No. 72,
Sept. 1955.

Durham, W. F., and Hayes, W. J., Jr.: Or-
ganic phosphorus poisoning and its ther-
apy. Arch, Environ. Health, 5:22, 1962.
Gershon, S., and Shaw, F_. H.: Psychiatric
sequelae of chronic exposure to organo-
phosphorus insecticides. Lancet, 1:1371,
196].

. Grob, D., Garlich, W. L, and Harvey,

A. M.: The toxic effects in man of the
anticholinesterase insecticide Parathi ion
(p-nitrophenyl diethyl thionop! te).
Bull. Johns Hopkins Hosp, aoe 1950.
Grob, D., and Harvey, A. M.: The effects
and treatment of nerve gas poisoning.
Amer. J. Med., 14:52, 1953.

Grob. D., and Harvey, A, M.: Observations
on the effects of tetraethyl pyrophosphate
(TEPP) in man, and on its use in the
treatment of myasthenia gravis, Bull. Johns
Hopkins Hosp., 84-532, 1949,

. Rowntree, D. W., Nevin, S., and Wilson,

A.: The effects of diisopropyl fluorophos-
phonate in schizophrenia and manic de-
pressive psychosis. J. Neurol, Neurosurg.
Psychiat., 15:47, 1950.

© 8 8 COVERNUENT PRINTING CRFICE- 194 O- nALT19