~

AL ELLE ELT CNET EE I OEE FRE Nee eye eR YE gdm Sone

It was necessary to give large amounts of so-
dium pentobarbital after endrin administration.

B. Experiments with succinylcholine, The
following experiments were carried out to avoid
the depressant effects of additional barbiturate,
Five dogs were given 3-10 mg of succinyl.
choline chloride (Ancctine* ) intravenously to
prevent convulsions, Three animals received
this drug several minutes before endrin, while
it was given after endrin to two, Artificial
respiration was necessary and the rate was
usually adjusted in an effort to maintain blood
pH within the physiological range, Except for
a tracheotomy and artificial respiration, these
animals were treated identically to those in
group 1-A,

C. Control experiments, Six animals were
treated as in 1-B, except that endrin was not
given.

Croup 2 — Effect of endrin on heart rate

Heart rate and systemic arterial blond pres-
sure were measured in ive dogs as in the
receding xroup, Succin ine was given as
scribed above, After lethal Infusions of en-
drin, heart rates were followed until the cardiac
effect was pronounced, Atropine (0.5 mg)
was then injected intravenously,

Group 3 —~ Effect of endrin on cerebrospinal
Nuid preenere
y

Cerel fluid '(CSF) pressure was

described shove. In additional dogs
sagital venous sinus presiire, obtained an
18 gauge needle in the sagital sinus

Brea ite the subarachnoid space and the
re
perkment This pressure was compared with

simultaneously obtained CSF pressure. Ia

one experiment CSF ite was maintained
Rear control pressure following endrin by with.

“obtained from Burroughs Wellcome & Co,

drawing spinal fluid. The Queckenstedt
was usually carried out before and after em
administration. Alcohol blank infusions w
also tested. All animals received succinylcho
to prevent convulsions,

RESULTS
Group 1 — General Systemic effects of enc

A, Initial experiments. Severe tonic-clo
convulsions ustally commenced within five
ten minutes after the beginning of endrin
fusion, Convulsions, as well as hyperexcital
ity to stimulation and copious, mucoid sali
tion, lasted until death, Convulsions could
initiated by a sharp sound. Because of te:
nical difficulties ensuing from the violent ct
vulsions and hyperescitability following end
administration, it was to give repeat
injections of sodium pentobarbital (25-50 1

Injection) every few minutes during ¢
Fine 60 minute post--i4rin period, Althou
barbiturate usually decreas
arterial blood pressure the animals’ toleran
to this drug was greatly enhanced after endri

Figure 1 and Table LA jhows yea
Perameters, Bradycardia, followed by a retu
toweede or above sutrel value, was “

experiment. Mean systemic arterial
pressure always decreased initially, but £
creased the control level in two
ments. Increased rectal temperature,
centration, decreased venous blood
increased leukocyte concentration also occurre:

always resulted from increase
eer evident with the neuropil i
were wit!
was in eee post-endrin hematocr
sample. Akohal infusions had no cardi
vascular effects and did not cause hemolysis,

4



TABLE !
TABLE 1-A
POST-ENDRIN

CONTROL 30-60 60-120 420-180
TYPE LEUKOCYTE (+S.E.) MIN MIN MIN

Neutrophils 53+28 60496 71+90 66+26

Eosinophils 12*50 9438 6426 9+06

Basophils 1406 +07 1£06 0

Lymphocytes 21452 21452 16+50 10+65

Monocytes 1B+586 816 7+26 8+50

No, of Experiments 3 3 3 2

TABLE 1-3 +

ie POST-ENDRIN

CONTROL 30-60 60-120 190-180
TYPE LEUKOCYTE  (+S.E.) MIN MIN MIN

A EY
Neutrophils W218 M4247 BlHS6 HIS
Eosinophils S222 1208 8409 1207

Basophils 1406 1£06 O£01 0#0
Lymphocytes 724 19239 139429 8223
Monocytes, B+13 7209 8207 8215
No. of Experiments 8 4 4 8
' .

ri

’ “TABLE 1.0

. } sxe. POST-ANECTINE

ns CONTROL 30460 00-190 = 190-180
TYPE LEUKOCYTE (+S.E.) MIN MIN MIN

Neutrophils GOL SFL? 8Se82 O97
Eosinophils , SELL 93210 8228 Bele
Basophils O+04 o+x02 0+0 0202

+ Lymphocytes O48 W248 S218 6226
Monocytes Athi 612 9200 7215
_ No of Experiments 8 6 8 4

TAME 1 A Men differential cuuats (¢ S.) from enndetn
Nee eee antl ost Faby iter ah eae Ravin
Ehime berating differentia (CEL) fom control anbnals teretving no

-H. 8 8 COVERORT PRorTIe FTIR: 1000+ Nee



HEART RATE
(beets / min.)

ARTERIAL
@LO00 PRESSURE
(ma He)

HEMATOCRIT
> (% ROC)



ini.

pressure can produce bradycardia and hyper-
tension (26, 27), this relationshig was appar-
ently not observed in the present stedy. Acutely
lowering the elevated CSF pressure to control
level by fluid withdrawal or preventing CSF
pressure from increasing: did not alter the de-
gree of bradycardia or hypertension, Cerebral
venous blood pressure alterations may have
been associated with the cardiovascular re-
sponses after endrin, Maintaining CSF pres-
sure at near control level did not prevent ele-
vation of sagital venous sinus (SVS) pressure.
Increased cerebral venous blood pressure may
decrease the arteriovenous pressure difference
across the cerebral vasculature and produce
cerebral hypoxia if of sufficient magnitude.
Hypoxia of the medulla could contribute to
bots bradycardia and

Extracerebral arterial blood
increase followed the rise in SVS pressure and
central blond pressure did not increase

dogs. However, convulsions are apparently not
prominently involved because the animals
which did not exhibit convulsions (succinyl
choline treated) showed a greater leucocytosis
than the convulsing dogs. Both mobilization
of stored leukocytes and increased bone marrow
production, indicated by the appearance of im-
mature neutrophils in the plasma, appear to
have contributed to the increased plasma
leukocyte concentration.

The hemoconcentration observed in most ani-
mals could result from (a) release of erythro-
arom the spleen ea (b) increased
capi permeability, or (d) stimulatory ac-
tion of endrin on erythropoetic bone masrow
ti ,

The trend toward acidosis during endrin in-
toxication did not appear to be of respiratory
origin since increasing ventilatory rate did not
prevent the decreased pH, Decreased

i
i

A schema of the possible mechanisms of
fection of endrin insecticide is presented in
gure



we a

NO a Me MRR RE TON OM OE

quently fell to hypotensive levels in ai Dut one
study. Blood pH also decreased more and
hemoconcentration was more Pronounced in
these animals than in the previous group. Car.
diovascular alterations exhibited here were pre-
sumably not related to succinylcholine muscle
relaxant as demonstrated by control experi-
ments and reports in the literature (23-25).
In some of these animals bradycardia was re-
placed by tachycardia in a manner resembling
vagal escape, Following this phenomenon the
heart rate would often oscillate between brady.
cardia and tachycardia.

C. Control experiments, Figure 3 shows data
from six control animals recelving no endrin,
No changes comparable to those seen in the
dogs which received endrin were demonstrated,
Mean values for leukocyte differentials are pre-
sented in Table 1-C.

Group 3 — Effect of endrin on heart rate

Figure 4 shows mean values of control and
post-endrin heart rates, Atropine, injected
when the post-endrin bradycardia was pro-
Bounced, was followed within 30 seconds by an
increased heart rate to near control levels,

Figure 5 shows portions of photogra
onda from two shelice demonstrating arial
reversal

of bradycardia following intravenous
Injection of Atropine,

Group 3 — Effect of endrin oh cerebrospinal
» full proesure

Figures 6 and 7 (graphed data and photo
graphed record respectively) show the develop.
ment of increased ‘cerebrospinal fluid (CSF)

as well as arterial | a

Cerebrospinal flujd pressure

vation precedes arterial hypertension, but may
follow the appearance of bradycardia, Figure 8
shows photographed portions of two’ tegords
tn which the elevated CSF pressure was lows
ered by fluid withdrawal to approximately zero
mm Hy for several minutes and subsequently
returned to the elevated level, No significant
effect on arterial blood pressure or heart rate
was demonstrated, In the lower record, intra-
cranial fluid pressure is also shown, Lowering
CSF pressure by fluid withdrawal at the cis.

terna magna level resulted in an equivalent
decrease in intracranial fluid pressure measured
in the subarachnoid space.

In three experiments in which sagital venous
sinus (SVS) pressure was monitored, it was
seen to increase rapidly with CSF pressure
elevation while peripheral internal jugular vein
pressure did not change. It was not possible
to determine which pressure rise occurred first.
Transmitted pulse pressure in the SVS and CSF
Increased significantly following endrin, the
greater increase being in the SVS tracing, Low.
ering CSF pressure no appreciable effect
on SVS pressure, Sagital venous sinus pressure
could be lowered onl a few mm Hg hy with-
drawing blood from the SVS; however, pressure
changes in the sinus were followed closely by
CSF pressure changes. H: or brady-
cardia was never significantly affected hy ra
idly decreasing CSF pressure via fluid wit
drawal, nor were phenomena prevented
by preventing CSF pressure from increasing.
Maintaining CSF pressure at control level did
hot prevent the rise in SVS pressure,

DISCUSSION

engntiovescular sherations s produced t by acute
in poisoning in ¢ hyper-
tion aed voy brdycarda "Tho fact tat
ypotension ma
multancously (Croup I-A), or that bradyecrdla
May precede nypegtension (Croup 1B) indt
tl

“increased vagal activity and/or a tation
of acety! . Increased acety! ac
tivity could be related to the fall in pH since
choli activity decreases with decreas.
Ing pH. This has also been ob-
served in ani soutely stressed with dieldrin

(18) and aldrin (17). Bradycardia, coplous
mucoid salivation, » Convulsions
and other manifestations following endrin sug.
gest that both sympathetic and parasympathetic
nervous systems are hyperactive after endrin,
Although elevated cerebrospinal fluid (CSF)

-3.


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MECHANISMS OF ACTION OF
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REFERENCES

-l. E, Danopoulos, K. Melissinos, and G.
Katsas, Arch. Ind. Hyg. Occupational Med.
8, 582 (1953).

A Bell. Med, J. Australia, 2, 698 (1960).

M, BR. Zavon, and R. E. Hamman, Amer.
J. Public Health, 51, 1026 (1961),

4. J. E. Chapman, and C, E, Lewis. J. Kansas
Med. Soc. 63, 228 (1962).

5. A. A, Buck, and L, Pfannemuller, Arch
Toxicol, 18, 328 (1957).

p

16.

17.

C. W. Gowdey, A. R. Graham, J. J. Seguin,
and G, W. Stavraky. Can, J. Biochem.
Physiol. 32, 498 (1954).

C, W. Gowdey, A. R, Graham, J. J. Seguin,
G, W. Stravraky, and R, A. Waud. Can. J.
Med. Sei, 30, 520 (1952).

. E. P. Laug, F. M. Kunze, and C, S. Prickett.

Arch Ind. Hyg. Occupational Med, 3, 245
(1951).

. S. T. Read, and W, P, McKinley. Arch

Environ, Health, 3, 209 (1961)

6. J..M. Arena, N. Carolina Med, J. 21, 470% W. J. wes Jr. W_ FE, Durham, and C.
(1900), Cueto, Je J Am. 3 | Assoc, 162,
7. O. Stur, and E, Zweymueller, Deut, med. 91. EP, |. Pharmacol. Exp. Therap, 93,
Wochschr. 88, 1474 (1961). : a (oe Esp. Therap, 89,
8. L, Friberg, and J, Martensson. Arch, Ind. 22. J. 8, Busvine, Practitioner, 188, 267 (1962),
Hyg, Occupational Med, 8 166 (1953). 23 J. G, Boume, H. O, J, Collier, and G, F.
® W. J. Hayes, Jr. Ann, Rev, Entomol, 5,379 Somers. Lancet, 2, 1225 (1952).
(1980). 24. PC, Lund. Am. J. Surgery, 86, 312 (1953),
25. O, Von Dardel, and S, Thesleff. Acta Chir.
10, W Reyes Bol Chileno Parasitology, 15, 57 oe cia (sh -
UL J. Blazques, and C, Blanchini, Bol. ofic. and M. BY Visscher, Am. 7}. Ph Adar,
sanit, panam, 43, 504 (1957), 96 (1949). Am. J. Physiol. 158,
12 BE . (Secretary, Committee on 97, H. Cushing. Bull, Johns Hopkins Hosp, 2
Tosca) J. Am Med, Apoe, 172, 207 20 (1801 en 1,
bod i ‘ 28. W. E, Garvey, and W. R. Bryan, Physiol.
13. J. F. Treon, F.:P, Cleveland, and J. J. Rov. 15, 587 (1935).
Cappel. Agri. Food Chem, 3, 843 (1855). 99 gy. and M, Kunnas, Acta
14. F, DeMatteis, B, E, Prior, and C, Rimin Physiol. Scand, 29, 290 (1953),
ton,’ Nature (London), 192, 363 (1961). 30, J, Barcroft, Am. J. Med, Sct, 179, 1 (1990),
18. R, K. Ockner, and R. Nature 31. W. G*Guntheroth, and G, L, Mullins, Am.
(Londun), 189, 499 (1961 )/ + J. Physiol, 204, 35 (1983),



o

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TRE Se PRIA LE SITS OCT SNORE EY RON TIM oct wa Rene we

eee

ton

MECHANISMS OF ACTION OF
THE INSECTICIDE ENDRIN

Thomas E. Emenon, Jr. Chastes M. Brake, and Lerner 8. Hivshew

Acute lethal and stub-lethal potsoning by
chlorinated hydrocarbon insecticides rink acd
reported In man (1-12) and animals (11-17),
Signs and symptoms foliowing absorption of
large amounts of chlorinated hydrocarbon in-
secticide, include hyperescitability, tremors,
ataxia, tonic-clonic convulsions, dyspnea, come
and not infrequently death (1, 5, 13). Fever
(1, 5, 6 8) and gastrointestinal disturbances
(1, 12) have also been noted clinically, Head-
ache, blurred vision, ataxia, tremors and mental
confusion often acompany absorption of smaller
amounts of these Insecticides, Hematological
alterations are not well defined, Clinical test

expos
erythrocyte (1, 6, 8) and leukocyte (1, 2, 5-8)
concentration, |

Chlorinated hh: Insecticides In-
clude endrin, die! akirin, chlordane, lin.
dane, and DDT, ginong others, They accum-
in body fat. (12, 18-20) fatty tissue
the liver, kidrley and brain (21). Endrin,*

ef

received little attention and was chosen
the present study. It is insoluble in water,
but soluble to varying degrees in oil; absorp-
tion is by ingestion, inhalation or through the
unbroken skin (13). Little is known concem-
ing the cardiovascular changes following-acute
exposure to lethal amounts of endrin insectt-

(2, 3, 4, 20, 10 t. , 4 da, SO 2,
ny Phomt Maribpeirngien Noirs A ovinbet Sa
pel ° me

PEF

most potent member of this group (22), -

METHODS
be ager fr oe
to
fotre anest] with sodium pento-

Group 1 —~ Conorel systemic effects of endrin
A. Initiel Lethal amounts of

endrin, 953 ethanol
Jr iar abl gohinatr at



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MECHANISMS OF ACTION OF
THE INSECTICIDE. ENDRIN

THOMAS £. EMERSON, JR.
CHARLES M. BRAKE
LERNER B. HINSHAW

Environmental Physiology Bronch
CWwil Aeromedical Research Inctitute



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