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This is to certify that the i

thesis entitled .

Comparative Effects of Thyroi-
dectomy and Thiouracil Administration I
on the Growth and Development of Dogs t

presented by
Ebbert G. Schirmer

has been accepted towards fulfillment
of the requirements for

Me So degree in PzflSiOlogy

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s. P. flg'flgb.

Major professor

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COMPARATIVE EFFECTS OF THYROIDECTOME AND THIOURACIL.ADMINISTRATION
ON THE GROWTH AND DEVELOPMENT OF DOGS

By
ROBERT G. §2§IRMER

A THESIS
Submitted to the School of Graduate Studies of Michigan
State College of Agriculture and Applied Science
in partial fulfillment of the requirements
for the degree of
MASTER OF SCIENCE

Department of Physiology and Pharmacology
1952 '

ACKNOWLEDGMENTS

The author would like to offer his sincere thanks and
appreciation to Dr. E. P. Reineke for his patience, under-
standing and assistance during the course of this work, withp
out which completion could not have been accomplished. Thanks
are also due to the other members of the Department of
Physiology and Pharmacology for their consultation, and
eSpecially to Dr. L. F. Wolterink who gave helpful suggestions
from time to time. I

Thanks are due to the late Dr. C. S. Bryan through.whose
efforts this work was started, and who gave considerable aid
and advice in setting up a course of study.

Gratitude is extended to Mr. George R. Lynch who so ably
cared for the animals, and whose assistance in carrying out
the mechanical tasks associated with the experiments was
invaluable.

The assistance of Miss Louise Feng in completing the
technical aspects of the studies with radioactive iodine is
greatly appreciated.

To Dr. W. D. Baten for his aid in the statistical treat-
ment of the data, and to Mrs. M. Anderson for her translation
of the German literature, sincere thanks are extended.

The author would like to express his sincere thanks for
the assistance and understanding afforded particularly during
the preparation of this manuscript to his wife, Lillian.

The expenses in connection with this work were defrayed
by funds from the Michigan State College Agricultural
Experiment Station.

The thiouracil used was supplied.by the Lederle Labor-

atories, Pearl River, New York.

TABLE OF CONTENTS

 

 

 

 

 

 

 

 

INTRODUCTION. . . . . . . . . . . . . . 1
REVIEW OF LITERATURE. . . . . . . . . . . . 3
Effects of Thyroidectomy . . . . . . . . . . . . 3
Effects 33 Body Weight. . . . . . . . . . . 4

Effects 2g Body Stature and Skeletal Growth 5

Effects pg Dentition. . . . . . . . . . . . 7

Effects 33 Body Temperature . . . . . . . 7

Effects 23 Pulse Rate . . . . . . . . . . . 8

Effects 23 HemOpoietic System . . . . . . . 8

Effects 2g Food Intake. . . . . . . . . . 9

Effects 22 General Appearance and Vitality. 9

 

Effects of Thiouracil Administration . . . . . . lO

 

 

 

 

 

Effects 22 Body Weight. . . . . . . . . . . 11
Effects g3 Body Stature and Skeletal Growth 1%
Effects 23 Body Temperature . . . . . . . . 15
Effects 9g Pulse Rate . . . . . . . . . . . 16
Effects 23 Food Intake. . . . . . . . . . . 16
Effects 23 the Hemopoietic System . . . . . 17

 

General Effects . . . . . . . . . . . . . . 18

1131 Uptake in Experimental Hypothyroidism . . . 19

Cell Plasma Ratios of Radioactive Iodine . . . . 22
MATERIALS AND METHODS . . . . . . . . . . . . . . . . 23

 

General. . . . . . . . . . . . . . . . . . . . . 23

Thyroidectomy. . . . . . . . . . . . . . . . . . 25

Thiouracil Administration.

Body Weights . .

Tibial Measurements.

Dentition. . . .

Body Temperatures.

Pulse Rates. .

Food Intake. .

Blood.Examination.

1131 Uptake. . .

Cell Plasma 1131 Ratios.

RESULTS 0 O O O C O 0

Body Weights . .

Tibial Measurements.

Dentition. . . .

Body Temperatures.

Pulse Rates. .
Food Intake. . .

Blood Examination.

1131 Uptake. . . .

‘Qpll Plasma 1131 Ratios.

DISCUSSION. . . . .
SUMMARY . . . . .
CONCLUSIONS . . . . .
.LITERATURE CITED. . .
APPENDIX. . . . . . .

26
27
2s
28

29

. 29
. 29

30
3o
31
32
32

39

he
44

INTRODUCTION

Since the late 1800's, when physiologists first became
interested in the thyroid gland and its function, there has _
been more interest and research in this phase of endocrinology
than any other.

Thyroid function has been studied quite thoroughly in
most species of experimental animals and in man. If one is
to review the literature on this subject he will find differ-
ences in reaction of the various species to experimentally
induced hyperthyroid and hypothyroid states. The study of
thyroid function resolves itself into more or less of a
separate problem in each species. There are similarities
of course, but there are also differences among the various
species which should be brought out.

The experimental animal employed in this paper, the
dog, has been used very little in research along these lines,
the probable reason being that this species is inherently
quite nervous and does not lend itself well to experiments
of a metabolic nature. The dog is not as simple an animal
to keep and work with as some of the smaller species.

As a result, literature available on experimental hypo-
thyroidism in dogs is quite meager. From the literature,
one might gain the impression that the thyroid is not as
essential for normal body function in this species as in

others. Dye and.Maugham (1929) reported cretinism in the

dog following surgical thyroidectomy, but their tables lead
one to suspect a smaller change than is represented in the
written portion of their work. Mayer (1947) and Glock (1949)
are very much in agreement that goitrogen administration
produces no change in growth or development of dogs, although
both report gross and microscopic evidence of thyroid hyper-
trOphy and hyperplasia;

Clinically, the writer has observed a condition of older
dogs which in some respects resembles human myxedema. The
animals become overweight and blocky in appearance. The skin
is thickened, particularly over the lumbar and gluteal regions,
and the hair in these areas becomes sparse and wiry. No edema
has been seen. The cases have, for the most part, responded
well to thyroid administration.

When the thyroid gland was first noted it was theorized
that its purpose was to fill out and lend a smoother appear-
ance to the neck region. Schiff (ISSG) in his research on
thyroid function stated that it seemed quite improbable that
an organ with the highly specialized structure of the thyroid
would be placed in the body for the sake of appearance.

It seems as though this thought might easily be applied
to the thyroid of the dog, in view of the more recent research.
With the before mentioned statements in mind, it was decided
that clarification of the functional status of the thyroid of
the dog might be attained through concurrent study of chemically
and surgically induced hypothyroidism. '

REVIEW OF THE LITERATURE

Effects of Thyroidectomy

Early studies on the effects of thyroidectomy are some-
what clouded in that the full significance of the parathyroid
was not understood at that time, and the results reported in
these earlier papers reflect the effects of thyroparathyroid—
ectomy rather than of thyroidectomy alone.

Schiff (1884) was the first to investigate this field.

He stated that the removal of the thyroid of the dog almost
invariably resulted in death, while in rodents no severe
symptoms were noted. These results were confirmed.by Hersley
(1891) who described nervous symptoms, severe tetany, con-
vulsions, and early fatal termination following thyroidectomy
in dogs and other carnivore. This worker was apparently the
first to describe the effects of thyroidectomy in ungulata

by unwittingly leaving the external parathyroid when operating.
These results in dogs have been duplicated.by Vincent and
Jolly (1905), and Carlson and Woelfel (1910).

Considerable light was shed on this subject by the work
of Gley (1891) who first designated the importance of leaving
the parathyroid glands intact when removing the thyroid. He
found that this procedure resulted in a marked reduction in
symptomatology and considered the parathyroid a Ihelper organ”
which could replace the function of the thyroid. With the
advent of these findings more attention was given the individual

study of these glands.

Effects pg Body Weight

The effect of thyroidectomy on the body weight of dogs
is described by Dye and Maugham (1929). In dogs which were
thyroidectomized at five to six weeks of age a noticeable
decrease of weight gain was seen at the end of two weeks
following the operation. It was found that frequently the
retardation of growth was masked by the excessive deposition
of adipose tissue, but that the retardation invariably exceeded
the fatty deposition and the weight gain remained adversely
affected. Binswanger (1936) presented data which confirms
this work. His body weight charts showed somewhat more
definite differences.

These findings have been duplicated in other species.
Larson (1919: 1920) found significant retardation in weight
gain together with unthriftiness in young rats after thyroid-
ectomy. Similar results were observed in this species by
Hammett (1922). Salmon (1938) found severe retardation of
weight gain in newborn rats which had been thyroparathyroid-
ectomized. She observed that a growth plateau was established
at three weeks after the operation, and that while injections
of thyroid substance stimulated further growth and weight gain,
injections of parathyroid substance gave little reaponse. In
sheep and goats, Simpson (1924) reported a distinct retardat-
ion of weight gain in animals thyroidectomized at three to
four weeks of age. Landauer (1929) reported a general arrest

of growth in domestic fowl in three naturally occurring cases

of thyrogenous dwarfism. In monkeys, Flieschman, Shumaker
and Straus (1943) reported one case in which growth was
completely arrested. Considerable drop in weight gain
following thyroidectomy in immature guinea pigs has been
reported by Silberberg and Silberberg (1940).

The above results were obtained on immature animals.
Thyroidectomy in older animals has not shown any demonstrable ,
effect on the body weight as indicated by the work of Simpson
(1913) except possibly in the manner of decreased basal metap
bolic rate and consequent fattening. An initial loss followed
by an increase of weight in thyroidectomized mature dogs was
reported by Bergman (1949).

Effects pp EEQX Stature Egg Skeletal Growth

A definite change in body stature and relative growth
and deve10pment of the osseous skeleton is seen in most cases
in which thyroidectomy is performed in the young experimental
animal. Dye and Maugham (1929) reported broadening of the
head, shortening and broadening of the muzzle, thickening of
the neck, and feet, and relatively broader and thicker limbs
in young dogs after thyroidectomy. The animals appeared
stunted and hump-backed, and showed typical cretinism. Edema
was not present in the various parts of the body as observed
in human patients suffering from hypothyroidism (Cecil 1946).
The effects on dogs were confirmed.by Binswanger (1936). In
the domestic fowl with thyrogenous dwarfism, Landauer (1929)

reported bulging of the eyes and edema of the surrounding

tissue accompanied by arrested skeletal development. Simpson
(1913) described sheep which had been thyroidectomized at two
months of age as having a squat, stunted appearance. Reineke
and Turner (1941) reported that goats appeared dull and
sleepy, and exhibited a relaxed stance after thyroidectomy

at four weeks of age.

The skeletal system seems from all accounts to be severely
affected by surgically induced hypothyroidism. The average
length: of the long bones was less in dogs which were thyroid-
ectomized at four to six weeks of age. There was very little
change in the width of the diaphysis of the long bones, but
the lengthpbreadth index was considerably greater in thynhid-
ectomized as compared to control animals (Dye and Maugham 1929).
Binswanger (1936) also reported this striking difference,
particularly in the length of the long bones. He stated that
while the normal controls had gained full length of the long
bones by nine months of age, the thyroidectomized animals
gained as much as 3 cm after this age.

In rats, Hammett (1927) observed the same degree of
retardation in both bone growth and body weight. In this
work it was found that bone weight remained the same, but that
the long bones were considerably shorter in thyroidectomized
animals than in controls.

Very little disturbance of the diaphysis of the long bones,
but definite delay in the replacement of hypertrophic cartilage

cells by bone was reported in immature guinea pigs after

thyroidectomy. Proliferation of the cartilage cells was
maintained and temporarily increased in some cases (Silberberg
and Silberberg, 1940).

In sheep thyroidectomized at two months of age, Liddell
(1925) reported the appearance of prognathism at six months
of age. He also noted that the skulls were shorter and dis-
proportionately wide in these animals. Reineke and Turner (1941)
observed a growth lag in the jaw bones of goats after early
thyroidectomy.

It has been found that hypothyroidism may be the cause
of some of the deforming bone diseases of children such as
Perth'es disease and OsgoodpSchlatters disease (Schaefer and
Purcell, 1941).

Effects pp Dentition

 

It would be reasonable to assume, in view of the effects
of thyroidectomy on the develoPment of bone, that teething
might also be affected. Binswanger (1936) stated that secondary
dentition in thyroidectomized dogs occurs from one to two
weeks later than in normal control animals. With the exception
of one case in which the secondary molars did not appear, Dye
and.Maugham (1929) saw no effect on dentition. Delayed
eruption of secondary teeth.has been observed in sheep (Liddell,
1925).

Effects pp 9393: Temperature

In dogs, Binswanger (1936) reported an average temper-
ature drop of .300 following thyroidectomy. The body temper—

ature of adult thyroidectomized dogs averaged only slightly

less (.50 F) than prior to the Operation (Bergman 1949).
Simpson (l913)reported a distinct fall in body temperature
after thyroidectomy at two months of age. In his work with
cats, Smith (1894) stated that thyroidectomy results in in-
efficient function of the heat regulatory mechanisms of the
animal body.

Effects pp Pulse_Rate

 

Binswanger (1936) observed a decrease in pulse rate in
thyroidectomized dogs. Bergman (1949) reported a 16% drop
in the pulse rate following thyroidectomy of adult dogs. The
pulse rate of rats was slowed to fifty to one hundred beats
'per minute after thyroidectomy compared to a normal of three
hundred beats per minute in control animals (Fishbeurne and
Cunningham, 1938). In thyroidectomized sheep two years of
age and over, Simpson (1913) observed only a slight slowing
of the pulse. The same worker reported a distinct fall in
pulse rate in young, thyroidectomized lambs within two weeks
after the operation. Jailer, Sperry, Engle, and Smelser
(1944) reported circulation time decreased by approximately
30% in adult monkeys following thyroidectomy. Studies in
human beings have revealed correlation of metabolism and
pulse rate in children, but the relationship is lost as aging
takes place. (Sutliff and Holt 1925).

Effects pp Hemopoietic System

The effect of thyroidectomy on the blood of animals is
not well established. In dogs, Goldberg and Chaikoff (1952)

reported that in two of six dogs thyroidectomized by the use
of 1131 a drop in red cell count of 20% to 30% was seen. The
cells in this case appeared hypochromic.

Landauer (1929) in his studies on naturally - occurring
thyrogenous dwarfism in fowl found a decrease in the number
of bone marrow cells, and in some cases complete replacement
of the bone marrow by connective tissue. Maerocytic anemia,
with decreased cell volume and hemoglobin was seen in rabbits
after thyroidectomy by Kunde, et a1 (1932).

Effects pp Food Intake

 

Little attention has been given specifically to food
intake following thyroidectomy, although it is generally
assumed to be less. This is reported specifically in dogs
by Bergman (1949).

Effects pp General Appearance and Vitality

A distinct lassitude, particularly after seven months
of age, and a coarse dry hair coat is described by Binswanger
(1936) in thyroidectomized dogs. In his work with the collie,
he stated that the ears did not stand in the normal upright
manner after thyroidectomy. Goldberg and Chaikeff (1952)
reported sluggishness, thickening of the skin and coarse,
wiry hair in dogs thyroidectomized with radioactive iodine.
Thyroidectomy in sheep resulted in listlessness and a stupid
appearance. Falling wool was observed in some cases and in
all cases there was a diminution of fleece weight when shorn.

Horn growth in sheep and goats was found to be markedly

lO

retarded (Simpson 1924). In thyroidectomized rats, Larson
(1920) reported unthriftiness and laziness. Landauer (1929)
showed this in the domestic fowl.

Thyroidectomy at four to twenty days of age delayed
the appearance of mature feathers in the brown leghorn fowl.
When mature feathers did appear they showed a decrease in
melanin, decrease in barbules and had a tendancy to become
long and tapered. (Blivaiss and Domm 1942).

The effects on activity are probably due to a decrease
in metabolic rate. The decrease in basal metabolic rats
following thyroidectomy has been shown to be quite constant
among the species. In the dog a 30% drop in BMR was reported
by Bergman (1949). In the rat, a 20% to 30% drop was observed
(Mayer and Ransom 1945), while in the pigeon the drop was
27% (larvin and Smith 1943). Workers on other species have
produced similar results.
ngects of Thiouracil Administration

Following the discovery that several naturally eccuring
materials such as cabbage and rape seed would produce a
condition resembling goiter when fed ever a period of time,
much attention has been given to the inhibition of thyroidal
activity by chemical compounds. Astwood (1943 a) compared a
number of chemicals by biological methods and concluded that
those containing the thieureylene radical produced the great-
est effect with the least toxicity. The compound 2- thieuracil
was found to be one of the most effective in inhibiting thyroid

_functien.

11

The effect of these compounds on the thyroid gland is
hypertrophy and hyperplasia, with decreased colloid content
of the follicles and increased height of acinar epithelium
(Mackenzie and.Mackenzie 1943).

In studies on the effect of thieurea and sulfenamides
on the thyroid of rats, Astwoed, et a1 (1943) determined
that the administration of thyroxine inhibited the effects
on the gland, and that likewise these effects did not occur
in hypophysectomized animals. This work indicated that
possibly an overproduction of thyrotrophin was responsible
for the gross and microscopic changes in the thyroid of
animals treated with goitrogens.

'The administration of thieuracil to human patients
causes a more rapid uptake of iodine by the thyroid gland
and also a very rapid loss (Stanley and Astwood 1947).
Franklin, et a1 (1944) demonstrated that there was less
thyroxine and diiodotyrosine in the thyroid of rats after
the administration of thieuracil. Thyroglobulin storage
was inhibited completely by the administration of thieurea
to rabbits (Bauman, et a1 1944). These studies show that
thieuracil administration results in a definite inhibition
of thyroxine formation at the diiodotyrosine level.

Effect 3;; _B_q_dy Weight

Danowski, et a1 (1946) reported no change from normal
of weight gain in dogs fed thieuracil. In his experiments
with.beag1e puppies, Mayer (1947) reported no differences

12

from control animals in body weight gain between pups fed
thiouracil twice daily for the first sixty days of the
experiment, then once daily for four months, at the rate
of 25 - 30 mg per kilogram of body weight. No obvious
difference in growth as measured by body weight was noted
in puppies by Glock (1949). The adult dogs which.were given
thiouracil maintained their body weight as well as the controls.
Williams, et al (1944) demonstrated that thiouracil
definitely inhibited the growth of young rats, and that the
administration of growth hormone did not reverse this effect.
After the administration of thiouracil to rats, Hughes (1944)
found growth to be very much inhibited after the first ten
days. His control animals ultimately weighed twice as much
as those treated. In adult rats fed 1% thiouracil in their
diet an average weight loss of 42 gm in twenty to twenty-
two days of treatment was recorded by Leathem (1945).
Astwood, et al (1945) found a very definite retardation of
body weight gain in rats on goitrogenic drugs and used this
as a means of estimating the effectiveness of several of
these compounds. A.loss of weight was reported in adult rats
fed .5% thiouracil in the ration (Leathem, 1946). A marked
depression of growth was reported by Boatman and Moses (1951)
in young rats receiving .5% thiouracil in the diet. Bauman
and.Marine (1945) reported that rats fed 40 mg of thiouracil
daily gained weight at nearly the same rate as normally
handled littermates, but that increased dosage caused stunting.

13

In the chick, Mixner et a1 (1944) found that .l%
thiouracil in the ration for twelve days produced the maximal
effect on the thyroid. Lighter, perhaps more hyperthyroid
breeds, gave the greater response. Kempster and Turner (1945)
noted that .2% thiouracil in the ration of broilers for
sixteen days did not influence body weight, food consumption,
or economy of gain, but that there was an improvement of
finish. In a second trial covering a period of five weeks,
it was found that this level of thiouracil produced lower
gains, greater food consumption per pound gain and consistently
lower grade when slaughtered. In New Hampshire cockerels fed
on rations containing .025, .05 and .1 percent thiouracil
respectively, Mixner,et a1 (1946) found a progressive decrease
in weight gain as thiouracil was increased. Glazener and.Jud1
(1946) found a depressed growth when .2% thiouracil was given
to young chicks in the mash. This is confirmed by Andrews
and Schnetzler (1946) who stated that in addition to growth
depression there was a greater efficiency of food consumption,
and a significant improvement of flashing and fat deposition
in broilers.

The use of .l% thiouracil in the ration of swine has
been reported to cause an increase in body weight gain and
reduced total food requirement per pound of gain (McMillan,
et a1 1947). When the administration of thiouracil is started
before maturity less weight gain is seen. (Beeson, et a1
1947). Swine given .25% thiouracil in the feed gain rapidly

14

at first and then stop gaining, although they consume less
feed.per pound gain than controls (VanderNoot, et a1, 1948). p
In these studies it was found that the normally active breeds
responded more vigorously to this therapy than the breeds
which are more docile.

Andrews, et a1, (1947) reported a depression of weight
gain of .064 to .071 lb per day in lambs, with no difference
in feed consumption per pound of gain when feeding .33 gm of
thiouracil daily in the ration.

Weight gain in steers was not altered by 4 to 6 gm of
thiouracil daily, but there was a slight increase in weight
gain and slightly better gain per pound of feed when 2 to 4
gm were administered daily. There was a tendency to improve
the dressing percentage and degree of finish at both dosage
levels (Beeson, et a1, 1947).

McQuillan and Trikojus (1946) found that guinea pigs
given 80 mg of thiourea twice daily did not gain weight as
fast as controls.

Effects 23 Eggy Stature and Skeletal Growth

Studies on the skeletal growth of animals made hypo-
thyroid.by the administration of anti-thyroid compounds have
not been emphasized in the literature. In most cases it has
been simpler to use the body weight as an index of drug
activity.

No changes in growth rate or body stature were reported

in dogs by Glock (1949) or by Mayer (1947) after administration

15

of thiouracil. Epiphysial fusion was unaltered macroscopically
and microscopically in the latter case.

A distinct retardation of skeletal growth in rats was
noted.by Williams, et a1 (1944). Likewise, Hughes (1944)
showed that the administration of 1% thiouracil in the drink-
ing water of rats caused inhibition of growth and caused
persistence of infantile skull proportions. Intermittent
(once-weekly) doses showed no effect.

Mixner, et.al (1946) showed that 1% thiouracil produced
a distinct decrease in length gains in New Hampshire cockerels.
Depression of growth in the body skeleton of the chick was
seen after the administration of .2% thiouracil in the feed
(Glazener and Jull 1946).

In their work on swine, McMillen, et a1 (1947) showed
that there was possibly a slight decrease in skeletal growth
in animals fed .1% thiouracil in the ration for a period of
forty-one days. A concentration_of .25% thiouracil caused a
more rapid gain for the first ten days, but almost a cessation
of skeletal growth after that time (VanderNoot, et al 1948). '
Very definite retardation of growth, causing a short, I'chuffy"
appearance in swine fed for six weeks on .1% thiouracil was
seen by Beeson, et a1 (1947). .

Effects gg'gggy Temperature

Although specific study of the body temperature as
influenced by thiouracil administration has not been attempted,

it is assumed that the effect would be depression as reported

16

following surgical ablation of the thyroid gland (Salmon
1938). .A lower body temperature was noted by Hughes (1944)
in rats fed.1% thiouracil in their drinking water.

Effects _o_n_ 133133 BEL?

Leblond and Hoff (1944) fed thiourea to rats over a
four month.period and produced a reduction of heart rate from
313 to 218 per minute.

Effects 23 Food.;ntake

 

Leathem (1945) found that the daily food consumption
of rats fed .1% thiouracil remained normal for ten days and
then was slightly below normal. In rats given .1% thiouracil
in drinking water no change in quantity of food consumed
was noted (Rawson, et a1 1944).

Much more research has been done on meat-producing
animals in which case the ratio of weight gain to food
consumption is an important factor. In broilers fed .2%
thiouracil in the ration for sixteen days no influence on
food consumption or economy of gain was noted by Kempster
and Turner (1945). They found, however, that over a longer
period of time (five weeks) food consumption per unit gain
increased. Mixner, et a1 (1946) reported an increased gain,
while food consumption decreased in cockerels fed .025, .05
and .l% thiouracil in their mash. These findings are born
out by Andrews and Schnetzler (1946) who noted greater
efficiency of food consumption in broilers fed on the same

percentages of thiouracil for a period of eight weeks.

17

In swine, McMillen, et a1 (1947) showed that feeding a
ration containing .1% thiouracil reduced total feed require-
ment per unit gain. This is substantiated.by the work of
VanderNoot, et al (1948). ‘

Andrews, et a1 (1947) reported no change in feed consump-
tion per unit gain in lambs fed .25 to 2 gm of thiouracil
daily. Steers fed 4 to 6 gm of this compound daily for
fifty-four days showed a slightly increased gain per pound
of feed (Beeson, et a1 1947).

Effects 9n the Hemopoietic System

In dogs fed thiouracil, Mayer (1947) found no significant
change in the blood picture except in two experimental
animals which showed high relative lymphocyte counts (6o%+).

A mild anemia, averaging three million less red blood cells,
has been reported in rats fed .1% thiouracil in their diet
for a period of one hundred and fifty days. Leucopenia was
observed in some cases, but this finding was not constant
(Leathem 1945). The administration of .2% thiouracil in
the feed resulted in granulocytopenia, lymphocytosis and
reduced red blood cells and hemoglobin (Gordon, et al 1945).

Warren (1945) studied the effects of thiouracil in vitro
and found that when 100 mg % thiouracil was added to autogenous
neutral serum the respiration of bone marrow placed in the
serum was reduced. He notes that the compound has an affinity
for the myeloid cells, particularly the more immature, but
that the erythroid elements are disturbed very little.

18

Many more reports of maleffects of thiouracil on the
blood have been reported in the human being due to its use
in treatment of clinical thyrotoxicosis. Kahn and Stock
(1944) reported a case of fatal agranulocytosis which developed
after the administration of 30.8 gm of thiouracil over a
fifty-four day period. In one patient showing anemia, leuco-
penia and complete agranulocytosis the effect on the bone
marrow was apparently irreparable (Gargill and.Lesses 1945).
Williams, et a1 (1944) found no ante-mortem or post-mortem
abnormalities in six patients fed 6 gm of thiouracil daily
for twenty-eight days. A marked lowering of the granulo-
cytic cells was noted in 20% of human patients on thiouracil
and 2% showed complete agranulocytosis (Fishberg and Vorzimer
1945). In clinical patients being treated for thyrotoxicosis,
toxic reactions to thiouracil were noted in 14.5%, and 1.2%
showed agranulocytosis (Williams et a1 1946). Other untoward
reactions are seen such as fever, skin rash and adenopathy,
but the agranulocytosis is the dangerous symptom, usually
indicating a fatal termination (Bierwaltes and Sturgis 1946).

General Effects

The effect of thiouracil on the integumentary system
seems to be much the same as that of thyroidectomy. Hughes
(1944) reported a delay in the development of the adult coat
in rate. No effect on pigmentation or hair growth was noted
by Dieke (1947) after thiourea administration, although phenyl-
thiourea and alpha-napthyl thiourea caused inhibition of both.

19

Beeson, et a1 (1947) reported thickened skin and dull, coarse
hair in swine fed .1% thiouracil in the ration for six weeks.
Comb growth in cockerels was adversely affected by thiouracil
administration (Mixner, et a1 1946), as was feather pigment-

ation (Juhn, 1944). ’

Sluggish reflexes and awkward muscular movements were
noted in rats which were given thiouracil (Hughes 1944).
McMillen, et a1 (1947) noted this effect in swine.

Thiouracil reduced the basal metabolic rate of rats
23% when given at the rate of .1% in the drinking water
(Reineke, et a1 1945). McCartney and Shaffer (1949) found
that chicks given .1% thiouracil in the ration required
16% less oxygen. In human patients, Astwood (1943 b) showed
that the administration of .2 to 1 gm of thiourea twice daily
gave relief from the symptoms of thyrotoxicosis and caused
the basal metabolic rate to return to normal. Dosage of
.8 gm daily to a patient suffering with thyrotoxicosis lowered
the basal metabolic rate from + 64 to + 10 in four days.

When an attempt was made to withdraw the drug, the rate
again increased (Kahn and Stock, 1944).

Attention is drawn to the marked similarity between the
effect of thiouracil administration and that of thyroidectomy.
;}31 Uptake in Experimental Hypothyroidism

The work of Hertz, et a1 (1938) opened the way for
further intensive study of thyroid physiology. The normal

thyroid was found to collect more radioactive Iodine-than

20

do other tissues. The administration of thiocyahate or the
feeding of cabbage to rabbits was found to cause an increased
affinity of the hyperplastic gland for iodine (Hertz, et a1,
1940).

Horton, et a1 (1943) reported that the completely
thyroidectomized rat was still able to convert iodide to
diiodotyrosine and thyroxine. By chemical analysis they
determined that ninety-six hours after the injection of
radio-active iodine into thyroidectomized animals 30% of
this material present in the liver and small intestine was
protein-bound; 20% being found in the diiodotyrosine fraction
and 8% in the thyroxine-like fraction.

There has been considerable study of iodine metabolism
in the thyroid as influenced by the various anti-thyroid
compounds. Franklin, et a1 (1944) found that thyroids removed
one day after the feeding of thiouracil for one week, contained
only 12% as much thyroxine as controls, and that this condition
persisted to a progressively smaller degree for about two
weeks at which time the amounts of labeled thyroxine and
diiodotyrosine in the gland had returned to normal. An
average of only 10% of a tracer dose of radioactive iodine was
concentrated by the thyroid gland of rats given .1% thiouracil
daily in their drinking water after twenty-eight days while
controls took up an average 56%. LRawson, et a1,(1944),
indicated that apparently the thiouracil blocked the uptake
of radioactive iodine by the gland. In an attempt to gain

21

confirmatory evidence on the efficiency of the thiourea
group of goitrogens, Stanley and Astwood (1947) injected
radioactive iodine into human patients being treated with
thiourea and found that while the controls took the iodine
up more slowly, gaining a plateau at twenty-four to forty-
eight hours and then remaining constant for some time, the
thiourea-treated patients showed a very rapid uptake of
radioiodine by the thyroid, but did not retain a plateau

for over thirty-six hours. McGinty, et a1, (1948) found
that eight hours after a single injection of thiouracil rats
showed partial escape from the drug, as indicated by the use
of radioactive iodine as a tracer. In chicks, on the other
hand, it was twenty-four hours before this partial escape
was noted. Rawson, et a1 (1948) noted that rats which had
been fed .2% thiouracil in the ration for a period of time
took up only about 1/10 to 1/5 as much 1131 as control
animals. The thyroids in this case were examined four hours
after the 1131 injection. Only a slight difference in the
amount of 1131 concentrated in the thyroid gland of rats given
thiouracil and controls is noted at a short period (three
hours) after injection (Boatman and.Moses 1951). In rats
which received a tracer dose of 1131 forty-eight hours prior
to the administration of 1% thiouracil in the drinking water,
Albert and Tenney (1951) report 50% excretion of radioactive
iodine daily, while the normal rate is 8-9% daily.

22

Cell Plasma Ratios of Radioactive Iodine

In research on the permeability of cell membranes of
human red blood cells, Hall, et a1 (1950) concluded that
ionic chlorine, bromine and iodine pass rapidly across the
cell membrane in vitro and that equilibrium is rapidly
established. They observed that in the case of iodine the
distribution in cells and plasma is about equal. Salter.
(1940) had previously reported the erythrocyte to contain
approximately 50% of the blood iodine. Utilizing I131 as
a tracer, Scott, et a1 (1951) studied the effect of various
levels of thyroid function on the relative amounts of iodine
present in the cells and plasma. They found that the initial
cell plasma ratio was the same in hypothyroid, euthyroid,
and hyperthyroid patients, but that the ratio dropped as the
inorganic 1131 was bound to protein in the thyroid. The A
drop in the cell plasma ratio was caused.by the impermeability
of the cells to the larger protein-combined.molecules. The
rate of drop of the cell plasma ratio is interpreted as an
expression of thyroid activity.

Boatman and.Moses (1951 a) determined only a slight
rise of 1131 in the plasma twenty-four hours after an intra-
peritoneal injection, the cell plasma ratio being quite

constant over a twenty-four hour period.

23

MATERIALS AND METHODS

General

Twelve pups were procured at the age of six and one-half
weeks. There were two litters of six pups each, one litter
being a collie-farm shepherd cross, and the other a shepherd-
setter cross, in so far as the owners were able to acertain.
One pup in the shepherdssetter litter was a male, the remainder
of this litter and all of the other litter were females. The
pups were divided at random into four groups, two pups from
each litter being placed in a group. Identification, was
achieved by tatooing the assigned numbers on the inner surface
of the ear flap. The male pup was number 4 in the thiouracil
group. The animals were of fairly uniform size and stature
at the onset of the experiment (see Figures I and II).

The animals were housed in the central portion of Animal
Disease barn No. 2 in individual kennels built especially for
this experiment. These kennels were of 2x4 frame construction
with chicken wire sides, tops and doors. Shavings were used
as bedding material and were changed daily. The room temper-
ature fluctuated between 58° and 68° F. Humidity and odor
was controlled by an exhaust fan system. These animals were
not allowed out of doors, but were allowed to exercise inside
while the kennels were being cleaned.

From the beginning of the experiment until the animals
were three months of age they were fed three times daily. The

24

first feeding, at 7 a.m., consisted of canned Ken-L-Ration
dog food and fresh skim milk. At noon they were fed skim
milk and about 6 p.m. they were given skim milk, canned Ken-
L-Ration and KenfiL-Biskit.

From three months of age until the termination of the
experiment the dogs were fed a combination of fresh skim
milk and Ken-L-Biskit dog food morning and night. The amount
of food given each dog was governed by the feeder's experience
as to how much the individual would eat. The animals were
full-fed as nearly as possible.

Water was placed before the dogs twice daily for a period
of about ten minutes. It was found that the quantity consumed
when given in this manner was quite small.

As soon as the dogs were procured they were given lcc.
per pound of body weight of anti-canine distemper serum sub-
cutaneously in the cervical region. This was repeated two
weeks later.

At three months of age each animal was given lcc. of
Ashe-Lockhart distemper vaccine intradermally in the flank
fold. This procedure was repeated ten days later.

The dogs were heavily infested with toxacara caninum
at the onset. They were given Vermiplex (Pitman-Moore) in
prescribed dosage to relieve this condition. Two weeks
later another dose of this compound was given, and there-
after no evidence of intestinal parasites could be found

upon microscopic examination of the feces.

25

A heavy infestation of ctenocephalides caninum neces—
sitated the use of pyrone powder (Jen—Sal) containing 10%
D.D.T. This powder was applied four times at five day inter-
vals, and following that only when it was thought necessary.

Thyroidectomy

Thyroidectomy was performed on four of the puppies
seven days after the initial data were taken. The animals
were anesthetized with Halatol (Jen-Sal) given intravenously
in the cephalic vein. They were clipped over the ventral
portion of the anterior cervical region, and this area scrubbed
with liquid germicidal detergent.

An incision was made through the skin on the mid-line
extending from the level of the cricoid cartilage distally
for a distance of 4 cm. The sterno-hyoid muscles were separated
for the same length and this region of the trachea was bared.
The thyroid glands were disected free of fatty tissue. The
external parathyroid, lying on the antero-lateral surface of
the thyroid was located in all but one case. This was dissected
away from the surface of the thyroid gland taking care to
preserve the small branches of the anterior thyroid vessels
supplying it. The anterior thyroid vessels were then ligated
distal to the point where the parathyroid branches left it.

The lobe of the thyroid which was disected free first
was left in position until that of the opposite side was free.
They were then removed simultaneously taking the thin isthmus

26

of facia which crosses the ventral surface of the trachea
with them.

The muscle separation was then closed with interrupted
sutures of cotton. The skin incision was closed in the same
manner.

Recovery from the operation was uneventful and the
sutures were removed five days later with good healing
evident. I

Seven days following the operation one of the dogs
showed symptoms of tetany when being handled. Symptoms were
relieved with the intravenous injection of 5 cc of a 10%
solution of calcium gluconate twice daily. The animal died
two days later. This dog was the one in which we had difficulty
locating the parathyroids. None of the other individuals of

the group showed any deviation from normal.

Thiouracil Administration

The administration of powdered 2-thiouracil' was started
in four of the remaining eight animals on the day following
thyroidectomy of the four dogs previously mentioned. It
was given by individual dosage by means of gelatin capsules.
The dogs were given the drug at approximately 7 a.m. and
6 p.m. daily, at least ten minutes before they were fed. The
dosage given was approximate but an effort was made to admin-
ister 25 to 40 mg per kg twice daily. This was accomplished
by weighing an empty capsule first, then filling it in a
standard manner and reweighing it. By subtracting the two

27

values we were able to acertain the amount of 2-thiouracil

each capsule size would hold. Rather than weighing individual
capsules, the one weighed initially was used as a standard by
which to pack the capsules used in the experiment. The

animals were started on a dosage of 140 mg of 2-thiouracil
twice daily and as the body weight of the individuals increased
so that the level given reached the lower range it was again
adjusted to the point where the animal was receiving close

to 40 mg/kg twice daily.

Body_fleights

The dogs were weighed before the evening feeding at
seven day intervals during the experiment on a spring type
dairy scale. It was found that the animals were too active
to be weighed in the basket with which this scale was equipped,
so a rope sling was fashioned. A rope loop, approximately
three feet in diameter was placed on the floor between the
front and rear legs with the dog in standing position. The
anterior part of this loop was drawn between the forelimbs
and the loop thus formed drawn over the head so that it rested
just anterior to the shoulders. The edges of the original
loop were then picked up on either side of the dog and brought
together over the back. It was found that the dog could be
elevated to the scale hook in a harness of this type with
very little discomfort and a minimum of struggling. As a
result, the weight could be easily read to the nearest quarter-

pound with some degree of accuracy.

28

Tibial Measurements
Radiographs were taken of the left tibia in lateral
position at four to sixeweek intervals during the experiment.
The machine used was a 10 milliampere General Electric
portable. The cassettes were screen-type bakelite without
grid inserts. Kodak Blue Brand medical x-ray film was used.
The animal was placed in lateral recumbency with the
left leg in contact with the x—ray cassette. The right
leg was held forward and outward to avoid interference. The
tibia was aligned to be directly in the path of the x-rays.
Relaxation was attained by holding the animal in this position
for a few moments before the radiograph was taken. Exposures
were standardized at 10 milliamperes and 50 kilovolt potential
for .25 second at a distance of 26 inches in all cases. The
films were processed in the conventional method.
Measurements were made from the original radiographs
of the overall length of the tibia, width of the tibial
diaphysis at midshaft, width at the distal epiphyseal fusion
point, and the proximal and distal fusion points of the tibial
tubercle. A transparent mm scale was used in these measurements.
In order to facilitate printing, the films were increased
slightly from their original size in a uniform manner so that
differences would still be apparent.

Dentition
Examination of the mouth of each animal was performed

weekly, noting primarily the appearance time of the secondary

teeth.

Body Temperatures

Rectal temperatures were taken weekly with the animals
in a post-absorptive state. A standardized Fahrenheit
rectal thermometer was used. The thermometer was left in
place for two minutes before being read.

Since the animals were easily excited when anyone was
in the room, it was decided to start with a different dog
each time the temperatures were taken. It was thought that
this might compensate to some degree for the temperature rise

associated with excitement.

Pulse Rates

Pulse rates were taken weekly on the animals from the
fifth to the thirteenth week of the experiment. The pulse
was taken directly over the heart by palpation. Counts
were taken for a full minute and recorded in this manner.
Pulse rates were taken in the same order as the body temper-

atures.

Food Intake

A rough estimate of the food intake was made by measur-
ing the amount of food fed in a pint measure and subtracting
the amount which was left. The value thus derived was

recorded in pounds.

30

Blood Examination

During the last week of the experiment 5 cc of blood
was drawn from the cephalic vein of each animal. This was
placed immediately in a vial containing sodium oxalate. Data
were recorded for the following:

1) The red blood cell count, using the standard haemo-
cytometer method.

2) The hemoglobin was estimated with the use of the
Sahli hemometer. Results were read in grams.

3) The white blood cell counts, using the standard
haemocytometer methods.

4) Cell volume was estimated by the method of Wintrobe.

5) Sedimentation time was determined by Westergren's
method.

6) Differential Counts. Blood smears were stained
with Wright's stain and 100 white cells counted and class-
ified in each case.

The methods used in this part of the work were described

by Todd and Sanford (1948).

;}31 Uptake
Five-tenths cc of a stock solution containing 1500 micro-

131 as sodium iodide was diluted with 40 cc

curies per cc of I
of distilled water to give a solution strength of approximately
20 microcuries per cc.

Each dog was given .1 cc per pound of body weight of

this solution intravenously via the cephalic vein. A separate

31

needle was used to withdraw the radioactive material from

the storage vial. After the material was injected into the
vein, blood was drawn into the syringe two or three times

and reinjected into the vein to avoid deposition of the radio-
active material around the site of puncture.

The animal was then removed to an adjacent room where
background counts were taken. Counts were then taken over
the thyroid and over the medial aspect of the tibial region.
The total time elapsed between the time of injection and the
first series of counts was five minutes.

Subsequent counts were taken in this manner at 12, 2M,
48, 72 and 170 hours after the injection.

A Tracerlab portable laboratory monitor was used for

making the counts.

Cell Plasma Ratios of I131

Blood samples were drawn from the jugular vein 5 minutes,
12, 2k, 48 and 72 hours after the injection of 1131 described
above. Care was taken to avoid the region of the thyroid.
The venipuncture was made as far caudally as possible. A
sample of lOcc of blood from each animal was placed in tubes
containing .5 cc of 30% sodium citrate solution and mixed
gently.

Separation of the cells and plasma and subsequent count-

ing was performed by the method described by Scott, et al (1951).

32

RESULTS

Bogy_Weight

Appendix tables I, IA and IB show the overall tabulation
of body weights during the experiment. Note that in appendix
table II in which body weight averages are given that the
thiouracil group averaged consistently less than the other
two groups, and that the thyroidectomized and control groups
were quite consistently alike, within experimental error.

Figure I on the following page points out that the
differences in weight gain between the thiouracil group and
the two remaining groups increase as the experimental period
increases. At the onset of the experiment there was approxi-
mately one pound difference in the groups and at the end of
the experiment the thiouracil group averaged about eight pounds
less than the others.

These differences did not prove to be statistically
significant when checked by means of analysis of covariance,
because of the failure of dog number 5 to gain weight in

relation to the other members of the group.

33

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Tibial Measurements

The tibias of the control group of dogs grew more
rapidly and attained greater final length during the course
of the experiment than the thiouracil-treated or thyroidp
ectomized group as shown by figure II. The thyroidectomized
animals grew faster than the thiouracil group as measured
by growth in length of the tibia. Complete data on tibial
length measurements and group averages are given in appendix
tables III and IV. These differences were highly significant
when subjected to an analysis of covariance.

Measurements of the distal epiphysis of the tibia show
what is apparently a lag in the development of this bone in
the thiouracil group. The dogs of the control group showed
the greatest mean width of tibial epiphysis at the second
month, and the thyroidectomized group at the third and fourth
months, whereas the thiouracil-treated group had apparently
not reached its greatest mean width at the time of the last
radiograph. This is shown by figure III. The specific
measurements and averages are shown in tables V and VI in
the appendix. The differences are not statistically sign-
ificant.

The tibial diaphysis ultimately grew wider in the control
group than in the other groups as can be seen in tables VII
and VIII of the appendix. These differences were slight
but approached significance when subjected to analysis of

covariance.

35

In measuring the proximal and distal unfused areas of
the tibial tubercle it was noted that proximal fusion which
seems to take place first was complete about two months
earlier in the control group than in either the thiouracil
or thyroidectomized groups. Distal fusion was also advanced
in the control group. This slowing of fusion was more
noticeable in the thiouracil group than in the thyroidect-
omized group. See table A. page 38, and figures IX to XIX
in the appendix.

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TABLE A

FUSION OF TIBIAL TUBERCLE

MEASUREMENT OF PROXIMAL AND DISTAL GAPS (ME)

 

Dog NO' 12/12 lg2o dat3/20 3/20 4/10
P* D* P D P D P D P D
I. Thiouracil
2 5 3 5 5 1 6 1 6 PF* 6
3 5 3 2 6 l 6 .5 7 PF 6
u 6 5 l 6 .5 5 .5 A F* u
5 7 n 2 2 2 2 .5 u .5 3
II. Control
6 6 u .5 6 F 6 F 5 F 3.5
7 61+ .56 F7 F6 F
s 71; 15 F1!- FM» Fl!-
9 6 6 l 6 F n F 3 F 2
III. Thyroidectomized
lo 6 6 2 12 l 12 5 12 F
ll 7 5 2 6 .5 6 .5 5 F
12' 77 57 27 57 F5

*PF Partial Fusion

*F Ossification complete

*P Proximal - unossified area
*D Distal - unossified area

39

Dentition
In all but one case eruption of secondary teeth started
earlier in the control group than in the thyroidectomized
and thiouracil-treated groups. The time at which secondary
dentition was complete was essentially the same in all groups.
It should.be mentioned that retained primary canine
teeth were noted in two cases in the thiouracil group, but
in none of the control or thyroidectomized pups.
A tabulation of the eruption times of the secondary
teeth is given in tables IX, X and XI of the appendix.

#0

ngy_Temperatures

After the first three temperature recordings were
taken, in which cases the body temperatures averaged about
the same in all three groups, the controls invariably had
a higher mean body temperature than the other two groups,
(Table B). These differences approached significance in
several instances, but the F value exceeded significance
on only three occasions. This was on 1/23, 2/27 and 3/6.

In no instance was the difference highly significant.

41

TABLE B
BODY TEMPERATURES - GROUP AVERAGES

 

standard error

Date Thiouracil Control Thyroidectomized
12/12 101.7i.2 101.si.2 101.si.2
12/19 101.9i.1 101.8i.l 102.1i.2
1/2 102.1:.2 101.9i.2 101.7t.2
1/9 102.11.2 102.3i.2 101.93.2
1/16 102.3i.2 102.3i.2 101.9i.2
1/23 102.1i.2 103.2i.2 102.01.}
1/30 102.ui.2 103.0i.2 102.2i.2
2/6 102.33.} 103.31.} 102.21.}
2/13 102.43.} 103.0i.3 101.9i.3
2/20 102.43.2 103.13.2 102.1:.3
2/27 102.n1.3 103.43.} 101.93.}
3/6 102.5i.2 103.1:.2 102.oi.2
3/13 102.9:.5 103.5:.5 102.53.6
3/20 102.53.2 102.si.2 101.9i.3
3/27 102.71.: 103.73.} 102.51.u
u/3 102.8i.3 103.31.3 102.31.}
u/lo 102.5i.3 103.31.} 102.2:.3

42

Pulse Rates

The average pulse rates are presented in table XIV
of the appendix. Complete data appear in table XIII. The
results are inconsistent and in no case are the differences
significant. It is of interest to note that the pulse rate
of the control group was in most instances higher than the
thiouracil-treated or thyroidectomized groups, much in the

manner of the body temperature. Figure IV on the next page

shows this relationship.

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Food Intake

Complete data on food intake are shown in table XV in
the appendix. The thyroidectomized and control groups
consumed food at about the same rate throughout the experiment.
The thiouracil-treated group as a whole consumed considerably
less food and their appetites were very erratic. Even when
the food consumption in this group approached that of the
other two groups, it was noted that these animals seemed to
relish food to a lesser extent and frequently ate all the
food.given if it was left in the kennel overnight. The
relationship of these approximate figures can be seen in
figure V on the next page.

It should.be noted that the control group were much
more active than the thyroidectomized or thiouracil groups.
The latter two groups were quite listless and showed a
tendency to react more slowly to handling than did the

controls.

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Blood Examination

The red blood cell counts of the thiouracil-treated
group of dogs averaged significantly less than those of
either the control or thyroidectomized groups. The thyroids
ectomized group had significantly lower red blood cell counts
than the control group of dogs.

In hemoglobin, cell volume, and sedimentation time
determinations the thiouracil-treated group consistently
averaged significantly less than the other groups. There
were no significant differences in these determinations
between the control and thyroidectomized groups.

The total and differential white blood cell counts
showed no significant differences.

These data are presented in their entirety in appendix

table XVII, and their averages in table C on the following

page.

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;}31 Uptake

In considering the uptake of radioactive I131 as recorded
by counting over the thyroid region, it was found that the
thiouracil-treated animals took up the material very rapidly,
but returned approximately to the level of the controls at
#8 hours post-injection. The initial level exhibited by the
thyroidectomized group, taken at 5 minutes post-injection
was approximately the same as the controls, but the uptake by
the thyroids of the controls increased steadily until the peak
was reached at 72 hours. A considerably slower uptake occurred
than in the case of the thiouracil-treated animals.

The graphic representation is shown in figure VI.

The amount of radioactivity as recorded over the medial
aspect of the tibial region shows a reciprocal of the thyroid
uptake on a lesser scale. The control group showed an initial
higher level which gradually decreased until only a very small
amount remained at 170 hours. The thiouracil-treated group
showed.lower levels until 48 hours at which time it became
essentially the same as the control group. The thyroidect-
omized group showed constantly lower levels over the extremities
until about 140 hours at which time it became the same as the
control group.

These results are shown in figure VII.

Complete data and averages on thyroid and extremity
counts are given in appendix tables XVII and XVIII.

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51

Cell Plasma Ratios, 1131

Initial and 12 hour cell plasma ratios were quite
variable, the thiouracil-treated group showing higher and
the thyroidectomized group showing significantly lower
levels than the controls. There were no significant differ-
ences in the ratios exhibited by the groups at 24 or #8 hours
post-injection, but at 72 hours there was a lower ratio
exhibited by the control group than the other groups. This
value was significantly lower than that of the thiouracil-
treated group, and approached significance when compared to
the thyroidectomized group.

The results are shown in figure VIII on the following
page and complete data in table XIX and XX in the appendix.

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53

DISCUSSION

From the previous experiments by Danowski et a1 (19h6),
Mayer (1947), and Glock (1949) one would assume that the
administration of thiouracil to dogs does not produce effects
similar to those of thyroidectomy as previously described by
Dye and Maugham (1929), and Binswanger (1936). In this
experiment similar effects were noted in thyroidectomized
and thiouracil groups on the body weight, skeletal growth,
dental eruption, blood picture, and cell plasma ratios of
1131.

It seems desirable to discuss body weight and skeletal
measurements together as they are closely associated in the
growth of the animal.

Dye and Maugham (1929) described distinct inhibition
of weight gain and skeletal length in young dogs following
thyroidectomy. Binswanger (1936) reported similar results.
Thiouracil-treated dogs did not respond in this manner as was
reported by Mayer (l9h7) and Glock (1949).

No significant weight differences were noted among the
groups in the present experiment, but, although the weight
gains were fairly consistent in all groups, there was definite
inhibition of tibial growth in the animals made hypothyroid
by thiouracil administration or thyroidectomy.

One must theorize to some extent to derive a reason
for the differences between the results reported herein,
and the results of previous work on the influence of

thiouracil administration on growing dogs. There has been

no published data on the amount of thiouracil and the frequency
of administration necessary to maintain stasis of thyroXine
production in the dog. Williams (1955) reported rapid absorp-
tion after oral administration of thiouracil to man, maximal
blood levels being reached thirty minutes to two hours after
administration. Paschkis, et a1 (19u5) reported very rapid
excretion in the urine, with excretion almost completed eight-
een hours after the administration. Ely, et al (l9h8) reported
that peak levels are not reached in the blood of ruminants
until four to eight hours after a single dose of thiouracil,
and that elimination is complete at twenty-four hours. They
concluded that in order to gain maximal effects thiouracil
should be given at least every twelve hours. It would seem
that this dosage schedule might have to be lowered in the

case of non-ruminants as indicated by the previous work in
human beings.

Mayer (1957) administered thiouracil to his dogs twice
daily, at 8 a.m. and 3 p.m., on weekdays, once on Saturday
and the animals received none at all on Sunday. In another
group of dogs on a thiouracil trial, Clock (1949), admin-
istered thiouracil every twelve hours for the first three
weeks and thence only once daily for the remainder of the
experiment. It would seem that these dosage schedules would
have left adequate gaps in the thiouracil block which could
have allowed the thyroid to resume function and to some

extent satisfy the demands of the animal.

With the deletion of dog number 5 in the thiouracil group
which did not conform to his group mates in growth or weight
gain, there is little or no difference between the thiouracil-
treated and thyroidectomized groups in the experiment described
here. Both groups show essentially the same relation to the
control group having gained about as much in weight, but lagging
significantly in skeletal growth.

The tibial diaphysis width of the thiouracil-treated and
thyroidectomized groups averaged only slightly less than in
the controls. The tibial length differences were much greater.
This confirms the data reported by Dye and.Maugham (1929) who
found that length, but not width of bones was adversely affected
by thyroidectomy.

The slower fusion of the tibial tubercle in the thiouracil-
treated and thyroidectomized groups resembles the radiographic
findings reported in hypothyroidism of children by Schaefer
and Purcell (1941).

Dental eruption dates in these animals conform well with
the findings in dogs by Binswanger (1936) who stated that in
thyroidectomized individuals secondary dentition occurred from
one to two weeks later than in controls. The thiouracil-treated
and the thyroidectomized animals in this experiment followed a
similar course. Liddell (1925) reported a like condition in
thyroidectomized sheep. No effect on dentition was noted in
young dogs following thyroidectomy by Dye and Maugham (1929).

56

The reason why dentition was complete in all groups of this
experiment at the same time despite the retarded eruption in
the hypothyroid groups is not understood.

Although the body temperature was not significantly
affected by thiouracil administration or thyroidectomy it
was found that the control dogs almost invariably showed
a higher mean body temperature. Only slight influence on
body temperature following thyroidectomy in dogs has been
reported in previous experiments by Binswanger (1936) and
Borgman (1949). It may be possible in this experiment to
attribute the slightly higher temperatures in the control
animals to the fact that they were more easily excited
and reacted with.much more vigor to handling than did the
hypothyroid individuals.

Binswanger (1936) observed a decrease in the pulse
rate of thyroidectomized dogs. A 16% drop in pulse rate
was reported by Borgman (1949) after thyroidectomy of adult
dogs. Leblond and Hoff (1944) reported a reduction of pulse
rate of about 30% in rats fed thiourea over a four'months
period.

The differences noted in this experiment were not as
striking as those previously reported and were not statist-
ically significant. However, the control animals almost
invariably showed a higher rate than the hypothyroid animals.
It is noteworthy that the thiouracil-treated group and the
thyroidectomized group had very similar pulse rates during the

course of the experiment.

57

The food consumption was not influenced in this case
by thyroidectomy. Borgman (l9u9) noted a decrease in food
intake following thyroidectomy in adult dogs.

The food intake was distinctly lowered in the thiouracil-
treated group. All dogs in the group showed this effect, some
to a greater degree than others. Mayer (l9fl7) and Glock (1959)
did not report lowered food intake as a result of thiouracil
administration. This effect is quite well established in the
meat-producing animals (Mixner et a1 19%6) Andrews et a1 1957).
In these cases the lower food consumption was associated with
increased weight gain, whereas weight gains were not signifi-
cantly effected in the present experiment.

Although the thiouracil-treated and thyroidectomized
animals in this study showed distinct listlessness and lack
of vigor, abnormalities of the skin and hair coat and edema
of the neck and eternal regions as observed by Goldberg and
Chaikoff (1952) in adult dogs was not seen. This might be
explained by the fact that these animals were on experiment
for a comparatively short period of time.

Following thyroidectomy of dogs by the use of 1131,
Goldberg and Chaikoff (1952) reported a 20 to 30% drop in the
‘red blood cell counts. Kunde, et al (1932) reported macro-
cytic anemia and decreased hemoglobin and cell volume in
thyroidectomized rabbits. A mild anemia was reported by
Leathem (1945) in rats following thiouracil administration.

58

The dogs of both the thiouracil-treated and thyroid-
ectomized groups showed a significant decrease in red.blood
cell count as compared to the control group in this case.
This is in contrast to the results reported by Mayer (1949)
who found no changes from normal in the blood picture of
thiouracil-treated dogs. I

The hemoglobin and cell volume were significantly lower
in the thiouracil-treated group than in the control group.
The thyroidectomized animals showed lower values of hemo-
globin and cell volume than the controls, but these results
only approached significance.

There were no apparent effects on the leucocytic
elements of the blood due to thiouracil administration or
thyroidectomy in this experiment. This is in contrast to
reports by Kahn and Stock (1954), and Gargill and.Lesses
(1945) of cases in human beings in which agranulocytosis was
observed following thiouracil therapy of thyrotoxicosis.
Williams, et'al (19th) in a compilation of cases treated with
thiouracil stated that only 1.2% showed agranulocytosis.
This figure is much less than the 20% reported by Fishberg
and Vorzimer (1945).

The sedimentation rate of the blood of the thiouracil-
treated group was significantly increased in relation to
the thyroidectomized and control groups. This.effect has
not been previously reported.

It was found by Franklin, et a1 (19kt) that the admin-

istration of thiouracil did not prevent the uptake of iodine

59

by the thyroid gland. Stanley and Astwood (1947) showed that
the thyroid of thiourea-treated patients took up radioiodine

very rapidly but did not retain a plateau for over 36 hours,

while the controls gained a plateau somewhat more slowly

but retained it for a much longer period of time.

The determination of the uptake of radioiodine was per-
formed primarily to give some indication as to the complete-
ness of thyroidectomy. The results were as eXpected and
conform quite well with the previously cited work. The
thyroidectomized animals took up very little of the injected
dose. The thyroids of the thiouracil-treated group took up
the radioiodine very rapidly and the level was apparently
beginning to drop at the time the 5 minute counts were taken.
The level became approximately the same as that of the thyroid-
ectomized group between 24 and 48 hours after the injection.
The control animals took up the radioiodine more slowly, the
plateau being reached between 48 and 72 hours post-injection
and showed only a slight depression of this level at 170 hours.

The extremity levels were the approximate reciprocal of
the thyroid levels. As the thyroid took up the radioiodine,
the extremity levels decreased, and as release took place the
extremity levels increased relatively.

As stated by Scott et al (1951) the cell plasma ratio
after an intravenous injection of 1131 may be used as an
index of thyroid activity. They found that the initial cell

plasma ratio was the same in hypothyroid,euthyroid and hyper-

6o

thyroid patients, but that the ratio dropped as the inorganic
1131 was bound to protein by the thyroid.
‘The results in this part of the experiment showed much
variability among the groups during the first 24 hours. At
24 hours post-injection the cell plasma ratio had become
essentially the same in all groups. The reason for this
initial variability is not clearly understood and has not
been reported previously. There was a significant decrease
in the cell plasma ratio of the control group between 48
and 72 hours after the injection of radioiodine. It may be
worthy of note that this change did not occur until about the
same time as the plateau was reached in the thyroid uptake of
1131.

Boatman and.Moses (1951) noted only a slight decrease
in the cell plasma ratio of rats 24 hours after an intra-
peritoneal injection of I131. In view of these findings,
one might assume that a longer waiting period might be
advisable after the injection of radioiodine if the cell

plasma ratio is to be used as an index of thyroid activity.

SUMMARY

The comparative effects of thiouracil administration
and thyroidectomy were studied in young, growing dogs.

Thyroidectomy or thiouracil administration did not
significantly affect weight gain of the animals as compared
to controls, but skeletal growth was significantly inhibited
by both means of inducing hypothyroidism.

The width of the tibial diaphysis was only slightly
decreased in thyroidectomized and thiouracil treated animals.

The fusion of the tibial tubercle occurred more than a
month earlier in the controls than in the hypothyroid animals.

Control animals were one to four weeks earlier in dental
eruption time than thyroidectomized and thiouracil—treated
animals of the same age, but dentition was complete in all
groups at approximately the same time.

Body temperature and pulse rate were not significantly
affected by thyroidectomy or thiouracil administration. The
control group averaged slightly higher in both cases, probably
due to decreased reaction to handling on the part of the hypo-
thyroid individuals.

Thiouracil administration adversely affected food intake,
while thyroidectomy did not.

The erythropoietic system was affected adversely by both
thyroidectomy and thiouracil administration. The thiouracil-

treated group exhibited this effect to a greater degree.

62

Neither thyroidectomy nor thiouracil administration
caused any alteration from normal of the white cell com-
ponents of the blood.

Thiouracil administration caused a significant increase
in the sedimentation time of the blood. This effect was not
seen in the thyroidectomized animals.

In 1131 uptake trials the thyroids of the control animals
took up the radioiodine over a period of about 48 hours, then
maintained quite constant counts, with a very small loss up
to 170 hours after the injection. The thyroids of thiouracil-
treated animals picked up 1131 very rapidly, a plateau
probably reached before the 5 minute counts were taken, but
returning to the level of the thyroidectomized animals at I
48 hours.

Initial and 12 hour cell plasma 1131 ratios were quite
varied among the groups. These ratios were approximately
the same at 24 to 48 hours.

The cell plasma 1131 ratios of the control group fell
significantly between 48 and 72 hours after the injection.

The pronounced deviation from the normal of both the
iodine turnover and the cell plasma 1131 ratio of both groups

of experimental dogs is considered to be satisfactory evidence

that a true condition of hypothyroidism had been established.

63

CONCLUSIONS

The administration of 25 to 40 mg per kg of 2- thiour-
acil twice daily to the growing dogs used in this experiment
produced effects which were very similar to those of thyroid-
ectomy.

The like effects produced were:

1) No significant effect on body weight gain.

2) Significant inhibition in increase of tibial
length while the diaphysis width was only slightly depressed.

3) Inhibition of the fusion of the tibial tubercle.

4) An average two—week delay in the eruption of
secondary teeth.

5) No significant alterations of body temperature or
pulse rate from normal controls.

6) Anemia of significant proportions.

Thiouracil administration produced some effects which
were more pronounced than those of thyroidectomy.

l) The food intake was adversely affected by thiouracil
administration, but not by thyroidectomy.

2) The anemia produced was more severe in the thiouracil-
treated group.

3) Hemoglobin, cell volume and sedimentation time were
significantly lowered by this level of thiouracil administra-

tion, but were only slightly affected by thyroidectomy.

64

The degree of inhibition of the thyroid was as great
in thiouracil-treated as in thyroidectomized animals as
indicated by the thyroid uptake of 1131 and the cell plasma

I131

ratios.
The cell plasma I131 ratios were significantly lowered
in the control group of animals, but not until at least 48

hours after the intravenous injection of I131.

65

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67

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Cockerels. Poultry Sci. 25:536-538.

Morton, M. E., Chaikoff, I. L., Reinhardt, W. 0., and
Anderson, E. 1943. Radioactive Iodine as an Indicator of

the Metabolism of Iodine. VI. The Formation of Thyroxine and
Diiodotyrosine by the Completely Thyroidectomized Animal.
Jour. Biol. Chem. 147:757-769.

Paschkis, K. E., Cantarow, A., Rakoff, A. E., and Tillson, E.
1945. Thiouracil Levels in Serum and Urine. Juur. Pharmacol.
and Exper. Therap. 83:270-274.

70

Ball, J. E., Power, M. H., and.Albert, A. 1950. Distribution
of Radioiodine in the Erythrocytes and Plasma of Man. Proc.
Soc. Exper. Biol. Med. 74:460-461.

Rawson, R. W., McGinty, D. A., Peacock, W., Merrill, P.,
Wilson, M., and.Lockhart, H. 1948. The Effect of Certain
Goitrogenic Drugs on the Absorption of Radioactive Iodine

by the Thyroid Gland of Rats and Chicks. I. Collection of
Radioiodine by Thyroids made Goitrouss Following the Chronic
Administration of these Agents. Jour. Pharmacol. and Exper.
Therap. 93:240-245.

Rawson, R. W., Tannhiemer, J. F., and Peacock, W. 1944. The
Uptake of Radioactive Iodine by the Thyroids of Rats made
Goitrcuss by Potassium Thiocyanate and by Thiouracil.
Endocrinology. 34:245-253.

Reineke, E. P., Mixner, J. P., and Turner, C. W. 1945.

Effect of Graded Doses of Thyroxine on Metabolism and Thyroid
ng it: of Rats Treated with Thiouracil. Endocrinology.

3: 7.

Reineke, E. P., and Turner, C. W. 1941. Growth Response cf
Thyroidectomized Goats to Artificially Formed Thyroprotein.
Endocrinology. 29:667-673.

Salmon, T. N. 1938. 'The Effect on the Growth Rate after
Thyro-parathyroidectomy in Newborn Rats and the Subsequent
Administration of Thyroid, Parathyroid and Anterior Hypophysis
Endocrinology 23:446-457.

Salter, W. T. 1940. The Endocrine Function 9; Iodine. Harvard
University Press. Cambridge, Mass.

Schaefer, R. L., and Purcell, F. H. 1941. Juvenile Osteo-
chondral (Chondro-epiphysites) Hypothyroidism. Am. Jour.
Surg. 54:589-604.

Schiff.1884. As cited by Simpson, S. 1913. Age as a Factor
in the Effects which Follow Thyroidectomy and Thyroparathyroid-
ectomy in Sheep. Quart. Jour. Exper. Physiol. 6:119-145.

Scott, K. G., ngyis, J. 0., Saunders, W. W., and White, W. E.
1941. Use of I Red Cell Plasma Ratio as a Measure of Thyroid
Function. Proc. Soc. Exper. Biol. Med. 76:592-595.

Silberberg, M. and Silberberg, R. 1940. The Effect of Thyroid-
ectomy and.Administration of Anterior Pitiutary Extract of
Cattle on Growth of Cartilage and Bone in Immature Guinea

Pigs. Am. Jour. Path. 16:505-524.

71

Simpson, 8. 1913. Age as a Factor in the Effects which
Follow Thyroidectomy and Thyroparathyroidectomy in Sheep.
Quart.iJour. Exper. Physiol. 6:119-145.

Simpson, S. 1924. The Effect of Thyroidectomy on Growth in
the Sheep and Goat as Indicated by Body Weight. Quart. Jour.
Exper. Physiol. 14:161-183.

Smith, J. L. 1894. On some Effects of Thyroidectomy on
Animals. Jour. Physiol. 16:378-409.

Stanley, M. M., and Astwood, E. B. 1947. Determination of
the Relative Activities of Antithyroid Compounds in Man
Using Radioactive Iodine. Endocrinology. 41:66-84.

Sutliff, W. D., and Holt, E. 1925. The Age Curve of Pulse
Under Basal Conditions. Arch. Int. Med. 35:224-241.

VanderNoot, G. W., Reece, R. P., and Skelley, W. C. 1948.
Effects of Thyroprotein and Thiouracil alone and in Sequence
in the Ration of Swine. Jour. An. Sci. 7:84-91.

Vincent, 8. and Jolly, W. A. 1905. Some Observations upon
the Functions of the Thyroid and Parathyroid Glands. Jour.
Physiol. 32:65-86.

Warren, 0. O. 1945. The Effect of Thiouracil on the Resp-
iration of Bone Marrow and.Leucocytes in Vitro. Am. Jour.
Physiol. 145:71-76.

Williams, R; H. 1944. Further Studies of the Absorption,
Distribution, and Elimination of Thiouracil. Jour. Clin.
Endocrinol. 4:385-393.

Williams R. H., Clute, H. M., Anglem, T. J., and Kenney,
F. R. 1946. Thiouracil Treatment of Thyrotoxicosis. II
Toxic Reactions. Jour. Clin. Endocrinol. 6:23-51.

Williams, R. H., Weinglass, A. R., Bissill, G. W., and
Peters, J. B. 1944. Anatomical Effects of Thiouracil.
Endocrinology. 34:317-318.

72

APPENDIX

 

mm.~a o.ma mm.ma ms.ma m.ma m.HH m.oH mm.oa ma
mm.om mm.ma o.-H m~.ma m~.sa mm.s- m-.-H m.aa . Ha
mm.ma m.-H m.o- mm.sa mm.m- m.ma mm.ma mm.ma oa
oonasocoooaonana. .HHH
o.wH m.wa o.ma m.ma mm.HH mm.m o.m 0.8 m
m~.ma mm.~a o.~H o.ma mm.ma mm.mH m.HH o.HH m
m~.w- m-.~H m~.ma mm.ma hm.ea mm.ma m.mH m.oa N
m~.ma m.- m.ma magsu o.ma m.-H o.HH m.m m
Hosscoo .HH
o.mH m-.HH m.ma o.mH nm.aa o.oH m.m o.w m
mm.am m.mH mm.ma m~.ma m-.ma o.ma m.ma o.m- :
mm.m- .o.mH m.mH m.:- m.aa m.oa o.ou m.m m
m.ma o.mH m~.o- mN.w mm.o mm.m mm.~ o.~ m
. . HaemaSonB .H
omxa mm\- wa\a m\- m\a mmmm- maxm- ma\ma

puma
mumbom .mameMB Nmom
H H.493.

.oz moo

TABLE IA

BODY WEIGHTS, POUNDS

1312]

3/13 03/20

,
O

./

Date
2120 2/27 __3

2/13

2/6

Dog No.

 

Thiouracil

I.

25

14.5 15.0 16.0 17.0 17.5 18.0 .
30.5

13.75
21.5

Q
/

[fl

‘LO
Cd

27.5

l:\

\0
d1

{.0
CU

(U
l"\

(U

U]

C‘\
OJ

\0
LU

(D

m
LU

.75
11.75

25.0

12.5

12.5

12.0

25

12.

a
J

12.

Control

II

29.5

28.0

23.5

22.25

[.0

N

Lf‘\

L.(\

f’\
(U

OJ
OJ

20.5

\o

m

27.0

23.75 24.25

23.0

21.75

20.25

1’20

\
1

‘(20
C ‘J

24.5

LG

(‘J

20.0

yroidectomized

Th

111.

Cu
P‘\

\Cf
(U

23.5

21.5

10

2.25

'7)
/

CU

P“:

LC‘\
(\1

(\i

\O
C ‘J

2.25

(3
(_

11

LP».

.4

(\J

(I)

01'

22.75

1.25

m
d

I
1

CU

7
-

O\

12

5/1

4/25

JDS

s
‘

Date

IB
/17

1

I

.J

I

'1

11

q

1T8, POU‘

TABL
HEIG-

1

BODY

4/10

4/3
19.75

Thiouracil

Dog Mo.

 

I.

37.0

l.(\

35.0

I“

1.2".

\f)
N‘\

(\I

15.0

d
J

14.7:

14

Control

II.

37.0

rm

2:
)5.

P“
r*’\

\3

\O
rm

LC\
7\_

LF\
P’\

35

.75

—-
‘\
I

L0

.2
31.25

Thyroidectomized

O\
(U

to

37.75

37.25

LO

.2

\o
F\

34. 75

5

III.

7\-
N\

56.

35-5

li‘\

34.0

33.5

10

41.0 41. 5

40.25

.a.

.1

LC‘ I
OJ

1

0‘\
OJ

28.25

r—l

TABLE II

 

BODY WEIGHTS - GROUP AVERAGES, POUNDS

Group Thiouracil Control Thyroidectomized
12/12 9.11.7 10.0i.7 11.3i.8
12/19 9.71.8 11.0i.8 11.5i1 0
12/26 10. i.8 11.61.8 12.4: a
1/2 11.4i.7 12.91.7 13.? .9
1/9 13.011.1 14.6i1.1 ”14.6i1..
1/16 14.8i1.2 15.6i1.2 18.311.4
1/23 15 2i1.4 17 3t1.4 17.211 6
1/30 16.3i1.5 13 6i1.5 18.9i1 7
2/6 17 8:1.7 20 3:1.7 21.0i2 0
2/13 18 8i2.o 21 9i2 o 2" 012 7
2/20 19 Li2.0 23.413.0 24.8i2 3
2/27 20.01:.1 24.4i2 1 :5 712.4
3/6 20 9:2.3 25.71: 3 27 oi2.7
3/13 21.3i:.6 27 1i: 5 28 513 0
3/20 "2 ‘i2.c 27.6“:C 6 :9.Li3.0
3/27 23.1i2 6 28 9:2 ’ 30.5i3 0
4/3 24.3i3.0 30.4i3.0 31 of L
4/10 25 4i3.0 31 9i3.0 32 9i3.5
4/17 27.113.4 34.2i3 4 34.5i3.9
4/25 27.6i3.6 35 8i3 o 35 3+4 1
5/1 27 9:3 5 36 Bil 5 33 “+4 2
5/8 2: 613.6 36 :i3.6 35 3i4.1

+
- standard error

TABLE III

TIBIAL LENGTH, CENTIMETERS

4/20

2120 2

1/20

2

rs
J
b

lg/l

.'

E No.

 

D0

Thiouracil

I.

0
OJ

9.1

C \J

\C O
\O \(D
H r!
P’\ .11"
\C' If:
H H
OJ [\-
1'.- \ :1"
H H
LC\ 0
:J’ l“\
H H
\O m
Ix) C" l
f*‘\ .21“

11.3

10.7

10

10.2

[CW

Control

II.

f.
d.

lfi

N\
‘CO

17.}

C)
C\

\O

f‘\

‘03
r‘.

17.4

‘6.)

If\

‘60
‘60

[\.

.“

10

4.-

1’4
"1),

17.4

\0
f“:

F’\

O
/

1:0

I“ \
‘00

Thyroidectomized

III.

C‘\

k”,

0
/

C)
[.4

17.5

0 l

l r“.

to
O\

H
r"!

Li".

I l\.

15

.—.

10.2

(\I
r-i

aoano casuawpm

 

H
m.«m.hH m.nm.ma w.«m.ma N.um.sa -.Hm.m sonasopocoaonsna
m.Hm.wH m.Hm.wH ~.HM.NH m.H~.mH m.Hm.m Homecoo
w.Hw.:H w.HH.:H ~.Hm.ma m.H:.mH m.HH.m Haemasodms

oaw: omwm om\m om\w .11: m-\ma nacho

m szmq iHmHB magma->4

>H mama-B

TABLE V

WIDTH, DISTAL EPIPHXSIS, TIBIA, CENTIMETERS

 

Dog No. Date
12/12 1120 2/20 3/20 4/10
I. Thiouracil
2 1.7 1.7 1.9 2.0 1.8
3 1.3 2.2 2.4 2.4 2.3
4 1. 2.0 2.2 2.2 2.2
5 1. 1.6 1.5 1.6 1.9
II. Control
6 1.4 2.4 2.2 2.2 2.3
7 1.5 2.4 2.2 2.1 2.2
8 1.5 2.0 2.2 2.0 2.0
9 1.6 2.2 2.3 2.3 2.0
III. Thyroidectomized
10 1.9 2.0 2.3 2.4 2.3
11 1.8 2.2 2.4 2.4 2.2
12 1.9 2.1 2.1 2.0 1.9

HOLE—”0 .0thde H.

 

ma.ua.m ma.um.m ma.«m.m oH.HH.m mo.nm.a oosasopoooaonasa
o-.aa.m ma.Hm.m ma.wm.m mo.um.m mo.um.a Hos-coo
oH.Ha.m ma.aa.m ma.ao.m wo.nm.a wo.um.a ascensodse

o-\: om\m, ONNM om\a mH\mH
opca msoaw

AmmmBHSHBzmov ¢HmHB b0

mHmwmmHmm udemHo .meoHa moemm>¢

H> mqmda

TABLE VII

WIDTH OF TIBIAL DIAPHYSIS, CENTIMETERS

Dog No. Date
12/12 1120 2120 3/20 4/10

I. Thiouracil

2 0.8 0.9 0.9 1.0 1.0
3 0.7 1.1 g 1.2 1.2 1.2
4 1.0 1.2 1.2 1.2 1.4
5 0.8 0.8 0.8 0.8 0.8

II. Control

6 0.8 1.2 1.3 1.3 1.3
7 0.7 1.1 1.2 1.2 .3
8 0.7 1.2 1.2 1.2 .
9 0.8 1.2 1.2 1.2 1.4
III. Thyroidectomized
10 0.8 1.1 1.2 1.2 1.3
11 0.8 1.0 1.2 1.3 1.3
12 0.8 1.0 1.0 1.1 1.2

moans canoes-m

 

u

mo.uem.a wo.um.a mo.ua.a wo.no.a mo.Hom. oonasopooe-onane

wo.umm.- mo.nm.- No.Hm.- mo.um.a so.nma. Honpeoo

wo.ua.- .mo.na.a ~o.no.a mo.uo.a so.nmw. ascensoasa
SN: omxm om\m on.) mim-

0 Ron 95.3

mmmemsHazmo .mHmwmmeao qumHa .meoHa modmmsd

HHH> H.493.

 

 

 

 

.pcoaaaomwo no
codpwcaahop Pm
ma non mocacoo

opoaasoo whom-02H

.H nosed .hoo
¢.H hogan .Aoo
.H some: .ch
.H aoeoq .ch
e.H some: .pcoo
.H aozoq .pcoo

ope-mace mom-:00

.pom
mos-:80 nosoq

cpoaqsoo whom-ocH
.H poem: .an

t.H Meson .pmmo
.H hoBoq .ucH

*.H momma .pcoo
.H aoaoq .pcoo

ope-msoo mocacso

ocacwo Momma .pom
mom-nae aosoq

opoamaoo whom-ocH
.H some: .pCH

.H momma .pcoo

.H ameoq .ch

¢.H momma .pcmo
.H aosoq .pcoo
¢.H amaoq .pnoo

mpoamaoonH

opoamaoo mocdcmo

mos-cco aokoq

opoamsoo whomdocH
.H nosoq .ch

t.H song: .pcoo
.H nosed .9200

mm
11m

mm
mm
Hm
om
m.-
m.-
N.-
m-
m-

m

 

:

m

62 won

m

Abomw AHodeOHmB I ZOHBHBZMQ demzoomm : HEHB ZOHBmDmm

NH mqmda

execs :- omw

opoamsoo mocacmo

amen-coo
amaoq .nomns

opoamaoo mocanso

emocdcso pogo; .nomdb

opoadsoo maomaocH
e.H momma .ch

.H nosog .noo

.H amzoq .ch

t.H momma .pnoo
$.H hogan .pcoo
.H 9630A .9200

epoamaoo maomaocH
.H aoaoq .aoo

e.H some: .psH

.H nosed .ch
.H pong: .pcoo
.H nmsoq .pcoo

opoamsoo mozdcmo
sums-can notoq

emocacso some:

opoadsoo whom-02H

.H Roam: .ch
.H nozoq .an

.H momma .pcoo

.H nozoq .pcoo

opoamsoc mocdcco
*EOGHGGU
hoe-cg fiend:

opoamaoo whomHOCH
.H 9030A .anH
.H some: .pcoo

.H nosoq .pcoo

poamsooaH *

N
mm

Am

 

m

.02 won

m

mbomw Aomszoo I ZOHBHBZHQ Hmddzoomm I MHHB ZOHBmDmH

N mqm<e

mace: ca ow<

opoHQsoo mendedo

opt-QBOOCH *

 

opoadsoo mom-coo ope-msoo mocacwo m
anon-can nozoq mos-can aoaoq mm
mm
opoHQsoo maomdocH Hm

e.H nods: .»:H
.H arson .ch om
opoadsoo maomaocH ope-maoo maomaocH .H some: .pcoo ma

e.H .aoo nosed .H nozoq .ch .H cocoa .pcoo
.H momma .pcoo ma

.H cocoa .ch
.H moan: .ch .H amsoq .0200 NH
.H some: .pnoo ma
.H nosoq .pcoo ma
ma
H
NH HH 0H
.oz won exec: ca omd

abomw QMNHEOBOHQHOmMmB I ZOHBHBZHQ HMszoomm I HEHB ZOHBmDmH

H% qu49

O.NOH

 

m.Ho- w.-oa m.aoa o.mo- m.aoa A.mo- m.-oa ma
a.mo- o.mo- m.moa w.-oH m.moa :.-o- o.moa o.moa H-
:.mo- m.moa o.mo- o.moa :.Hoa o.moa m.HoH m.aoa o-
oonasopooo-onana .HHH
m.moa A.moa m.mo- a.moa o.mo- a.moa o.mo- :.Hoa m
o.soa A.mo- a.moa m.moa A.mo- o.moa o.moa m.-o- m
m.moa m.moa m.moa a.moa o.moH m.-oa m.-oa m.mo- N
m.moa w.mo- a.mo- o.moa m.moa m.-oa m.ao- o.mo- m
Honpcoo .HH
a.moa m.moa m.HoH o.mo- a.moa a.mo- w.-oa w.ao- m
m.moa A.moa m.HoH h.Ho- o.moH a.moa w.aoa o.moa :
m.moa o.moa w.moa o.moa w.aoa o.woa o.moa m.aoa m
m.ao- o.moa o.moa a.mo- o.moH m.aoa o.moa m.aoa m
ascensoana .-
m\m omww mmwa m-\H open m\H m\w mawwa m-\ma .oz mom

.a mammomn .mmmsedmmmama moon

HHN Hamil-a

 

m.aoa m.aoa. o.mo- w.Hoa o.moa m.-oa m.-oa m.aoa m.-o- NH
a.mofl m.mo- a.mo- o.moa m.mo- o.mo- m.ao- m.moa o.moa Ha
m.moa w.moa o.moa o.moa m.moa m.mo- a.moa w.moa m.moa oa
sonasopoooaonana .HHH
o.moa w.moa m.moa m.moa o.mo- a.moa a.moa m.moa a.moa m
m.moa w.moa o.moa m.moa m.eoa A.moa o.:oH o.moH «.moa w
«.moa o.mo- m.moa m.mo- m.m0H m.mOH m.m0H m.mo- a.moa A
m.moa a.mo- m.moa m.moa a.moa o.moa a.moa w.mo- a.moa h
Hospnoo .HH
m.-oH a.moa «.moa m.mo- o.moa a.moa m.moa m.-oa m.moa m
a.moH m.mo- o.mo- m.mo- m.soa a.moa a.mo- m.mo- o.moa :
o.moa m.moa w.moa m.moa w.moa o.moH m.moa m.m0a m.moa m
a.moa m.mo- m.moH w.aoa :.Hoa o.moa w.aoa o.moa :.Ho- m
HHOMHSOEB . H
oa\¢ M\: ~m\m om\m, mwmm m\m ~m\m om\w ma\m .02 won

.a mammomn .mmmaadmmmame anon

4H Hum @493.

 

was mm- :m- omH om- ooa mma om- maa ma
w-H mma :m- wma oma NH- wm- emu NH- Ha
oma wma me- mma 64H mm- med 04H oma o-
oonasopoooaonena .HHH
mad mm- mma mm- hma mm- mma one sod m
mm- NH- mma mma hm- oea mm- osa NHH m
ms- med 0:- wsa osa s:- osa mm- ONH N
m? me- oi 13H oi: oi: mma 9: cos m
Honcnoo .HH
med mad m-H m-H soa ooa mma oma mma m
mm- oma wm- :ma one oea wma mud woe A
owe hma sea 00- osa mea one oma mm m
mmH wma and mm- 64- NHH mma owe om m
Ascensoana .H
om\m max» m\m mm\m mmmma maxm mum mm\w om\mr. .oz won

memZHa mam mezmoo .nmedm mmuam

HHHN mama-B

TABLE XIV

PULSE RATES - AVERAGE WEEKLY

 

Date Group

Thiouracil Control Thyroidectomized
1/20 103i7 10917 1168
1/29 132:7 13637 128i8
2/5 13516 139:6 135:?
2/12 12519 138:9 113110
2/19 126:6 13816 127:7
2/26 13338 13914: 13319
3/6 130% 13416 13216
3/13 121439 13339 1383511
3/20 1295 1341’ 5 117175
1'

standard error

 

o.Hm o.am o.Hm o.-m o.Hm o.-m m.NH 0.0- 0.4H m.ea o.ms ma
o.am o.-m o.am o.am o.-m o.Hm o.-m m.~ m.~a o.Hm 0.4- He
o.am o.-m o.-m o.-m o.Hm o.am o.am o.~e m.~a o.am 0.:H o-
o.-m m.~H m.~a m.na o.-m. o.am o.am o.m* 0.:H o.am m.oa m
04m 04m 0: T:- oém 9: m;- mée T: 0.3 m; m
o.am o.am o.~s m.~a o.-m m.~a m.ea o.ms o.am o.am o.~s A
m.sa m.aa m.:a m.ea m.:a m.:a m.:- o.m* o.ea 0.:H 0.:H m
m.oH m.oH m.oH m.oa m.oH m.oa em.oa m.m m.oa m.oa m.m* m
m.oH m.oa m.oa m.oH m.oa m.oa m.oH o.~ m.oH m.oH o.m A
m.oH m.oH m.o- m.oa m.oH m.oa m.oa m.oa ma.o- mH.oH. mH.oH m
m.oa m.oH m.oa m.oH m.oa m.oa m.o- m.m m.w m.w m.m m
NH dmNHEWMOOGHOHb-WM m w Hahn-SOON. m m fidOdhfiOfl-MB 4M4 M003

Ame<2onmdm<v mozsom 2H .amme mam madezH doom

an mflmde

haze moaswwa GQESmcoo t

 

o.am o.am o.Hm o.Hm o.Hm o.Hm o.Hm m.oa m.~a 0.:H m.ma Hm
o.am o.Hm o.Hm o.am o.Hm o.Hm o.Hm m.ma 0.:H m.NH 0.:H om
o.Hm o.am o.Hm o.Hm o.am o.Hm o.am m.ma 0.:H m.~a 0.:H ma
o.Hm o.am o.Hm o.am o,Hm o.am o.am m.oa m.~a m.ma a.ma ma
o.Hm o.Hm o.Hm o.Hm o.am o.Hm o.am o.oa. o.am m.~a m.:a NH
o.Hm o.am o.Hm o.am o.Hm o.Hm o.am m.~ o.Hm 0.:H o.ma wa
o.am o.Hm o.am o.Hm o.am o.am m.~a m.~ m.~a .o.:H 0.:a ma
o.am o.Hm o.am o.Hm o.Hm o.Hm m.ma m.m: o.am o.Hm m.:a :H
o.Hm o.Hm o.am o.am o.Hm o.am m.~a o.m o.Hm m.mH 0.:H ma

.mH donaEOMMmoaonman m w HahpzooN .o m “domuuomns N Mama

Admnndpcoov >x Hdmda

 

m.o mm.o o.wm m.oa oom.m ooo.om:.m NH
m.H m.o o.~m m.~H 0mm.aa ooo.oma.m Ha
m.o mm.o m.m: m.~a oom.ma ooo.o~w.m oa
ooNHEOpoouaouaga .HH”
o.H mm.o o.m: m.~a 0mm.aa ooo.oom.o m
o.H m.o m.m: m.NH oom.oa ooo.oom.m m
m.o o 0.0m a.ma ooa.:a ooo.omm.~ N
m.o mm. o.m: m.~a omm.oa ooo.o~m.m o
Hoppnoo .HH
ma H m.mm o.m oom.w ooo.omw.m m
oa m o.~m m.HH 0mm.ma ooo.omN.: :
HH : m.mm m.MH oom.mH ooo.om~.m m
m H m.mm a.ma ooo.ma ooo.o:o.m - m
Haownsodna .H
.cdsoo qwdsom, masao> A.awv.nm .o.m.a .o.m.m macaw
HHmo

cede :oapwpcoaduom

ZOH BSA dam @0015

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m m 0 mm mm H: NH

m . m 0 mm . mm mm HH

0 m m mm mm Hm 0H
coNHa0poooHoamga .HHH

o m m on Hm mm m

o o m om m: mm m

o o H wH mm mm H

o o m in Nm Nm . m

Honpcoo .HH

 

H m m mm mm H: m

m o 0 mm om mm H

o m H w: mH mm m

H H H mm m pm m
HHownsoHaa .H

omwm chom one: £9854 .Mmmlcoz qum

madnmonpsoz macaw
pcoonom I mpczoc Hprcmnmman
Adodndpcoov H>N mqm4a

NpHaoprm *pxm
odghne .138

dcsonwxvmn mom Umpomnuoo muczoo **

 

mH mH om omN 00H om: OMH om: mmm om: own om: NH
0H 0: mo om: 00H mNm co: 0mm ,oom mNm omm ow: HH
0 0 mm mm mm ONM OON mNm om: 0mm one on: 0H
umuaaopoocaonhsa .HHH
mH omHH mH mNMN mN QHHN 0mm omHN ONN ONHH om: owm m
0N mmHH o OHNN o: OOHN om QMHN OHM ommH co: oom m
o ommH 0H ONHN mm OHHN oNH mNmN OON oomH co: omm N
o omHH o: ONNN om OONN mOH mmNN OON ommH 0mm on: o
Hoppcoo .HH
0 o om omH om mmN omH om: mNN 0mm mmm omw m
0H 0H m: mmH ow 0mm omH OHHH omN omm owm ONON :
ON ON on OHM oNH mN: omH omw om: ome mmm mmmH m
0H mm ow 0mm OHH mam 0H» OHNH owm momH OHN OHNH N
HHoma=OHga .H
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TABLE XVIII
AVERAGE 1131 UPTAKE”

 

* Corrected for background and decay.

t Standard error

Thiouracil Control Thyroidectomized
165n1169 noilég 447i195
315:42 the 513350

12201176 1818:178 68120
nooiéa 2u2i62 246i715
1080:68 2621168 680$78
zuaing 2 61kg 268-57
ulsiéu 26 $64 57ui74
107i1n fiézlu 105116
071102 2721102 3233118
367:11 3 21:11 65:13
1:104 2 803104 4:121
igilo 317i10 isill

 

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mH. ON. Nm. HN. mm. HH
ON. ON. NO. NO. NO. OH
douHEOpoocHonhnE .HHH
Nmo. Nm. Hm. O». NH. O
mHOO. mm. Hm. Om. OH.H w
NH. HN. Om. HO.H NH. N
ON. NN . mm. HO.H NO.H O
Houpcoo .HH
mH. mH. NH. mH.m mN.N m
mH. mm. mH. mH.H mH.H H
uuu mN. Hm. HO.H om.H m
mH. mm. mm. mm. m~.H N
HHOONOOHHN .H
.NH NM. .9: NHOOHpooHeHhMmomN.maHe .nz NH .aHa m. .02 won

KHK mqm4a

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nogno chwdcwpm I

 

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Hwn NN .ns NH .93 HN .ng NH .OHa m1
:oHpooncHlpmom mafia macaw

HMHH «HOHHN HHNO .OOHBHN NO<mm>H
xx NHmHa

 

N .02 won .xH mmOOHO

 

n .02 m8 .x $32

 

H .02 moo .Hx EOE

 

 

m .02 man HQ 553...—

FIGURE XIII, Dog No. 6

 

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FIGURE XVII, Dog No. 10

 

FIGURE XVIII, Dog No. 11

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FIGURE XIX, Dog No. 12

 

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