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Two-Generation Reproduction
Toxicity of Propylthiouracil When
Administered to Sprague-Dawley Rats
in the Drinking Water.
J Bishop1, L Nehrebeckyj2,Y Wang2,
J Quance3, J Kariya4, and G Wolfe2
1NIEHS/NTP, RTP, NC 2TherImmune Research Corporation,
Gaithersburg, MD;3PAI, Frederick, MD;4USEPA, Washington DC;
Propylthiouracil
H2 H
H 3C C N S
C
H2
NH
O
a thyroid hormone-synthesis inhibitor
decreases T3 and T4; increases TSH
weight reduction
thyroid weight and pathology
Study Design
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35
F0: Exposure F0: Necropsy
F0: F0:
Vag. Cohabi
Cytol. tation
F0: Gestation
F0: Lactation F1: Exposure
F1: Pup Obs F1: F1:
Cohabi Vag
F1: AGD
tation
Cytol.
F1: Pinna F1: Gestation
detachment
F1: Lactation
and eye
opening F2: Pup Obs
F1: Ret.
F2:
Nipples
AGD
F1: Testicular F2: Pinna
Descent detachment
F1: Vaginal and eye
Opening opening
F1: F1: Preputial F2: Ret.
PND 16 Separation Nipples
Select. F2: PND
F1: 16
PND 21 Select.
Sep.
F2: PND
F1: PND 21
21
Necrop.
necrop.
F0 Body Weight
540
520
Group 1M - 0.0000% M
500 Group 2M - 0.0001% M
480 Group 3M - 0.0004% M
Group 4M - 0.0015% M
460
Group 1F - 0.0000% F
440 Group 2F - 0.0001% F
420 Group 3F - 0.0004% F
Group 4F - 0.0015% F
400
Grams
380
360
340
320
300
280
260
240
220
200
180
1 2 3 4 5 6 7 8 9 10
Study Weeks
F0 Food Consumption
F0 Water Consumption
38
37
36
35
34
33
32
31
Gram
30
29 Group 1M Group 2M
28 Group 3M Group 4M
Group 1F Group 2F
27
Group 3F Group 4F
26
25
24
23
22
21
20
1 2 3 4 5 6 7 8
Study Week
F1 Pups/litter
Dose Group 0.000 0.0001 0.0004 0.0015
% W/V
Male 6.2 5.6 5.4 5.5
Female 8.6 7.0 7.6 4.9*
4.9*
Combined 14.8 12.6 13.8 10.3*
10.3*
* p < 0.001
F1 and F2 AGD and
AGD/Pup Weight Ratio
F1 F2
Dose F F M M F F M M
Groups AGD AGD/ AGD AGD / AGD AGD/ AGD AGD /
mm gWt mm gWt mm gWt mm gWt
0.0000 1.14 0.18 2.58 0.39 1.20 0.19 2.72 0.40
0.0001 1.14 0.18 2.58 0.38 1.20 0.19 2.51*
2.51* 0.37
0.0004 1.15 0.18 2.59 0.38 1.22 0.19 2.52* 0.37*
0.37*
2.52*
0.0015 1.12 0.18 2.61 0.40 - - - -
* p < 0.05 Dunnett’s
F1 and F2 Sexual
Developmental Parameters
Dose Groups 0.0000% 0.0001% 0.0004% 0.0015%
F1 Eye Opening 15.7 15.6 16.2 17.6*
F1 Day of PPS 42.7 43.3 49.7* -
F1 Day of VO 32.4 32.9 33.8* -
F2 Eye Opening 16.3 16.1 16.9 -
F0 Thyroid Hormone Levels
DOSE T3 T4 TSH
GROUPS
F M F M F M
0.0000 105.3 96.1 1.2 2.1 3.8 3.6
0.0001 113.8 96.2 1.4 3.0 4.6 3.8
0.0004 111.5 95.1 0.6 1.1 7.2*
7.2* 8.2
0.0015 90.9 88.3 0.6 0.5*
0.5* 21.6* 22.1*
21.6* 22.1*
Ref. 50-100 3-7 .57-3.41
*p>0.05 (Dunnett's)
F1 Thyroid Hormone Levels
DOSE T3 T4 TSH
GROUPS
F M F M F M
0.0000 111.0 94.3 2.3 3.5 3.7 5.1
0.0001 109.4 92.9 2.6 4.6 4.8 5.5
0.0004 111.8 87.1 0.9* 1.4*
0.9* 1.4* 9.1* 13.9*
9.1* 13.9*
Ref. 50-100 3-7 .57-3.41
*p<0.05 (Dunnett's)
F0 and F1 Organ Weight Changes
F0 Generation F1 Generation
0.0001% 0.0004% 0.0015% 0.0001% 0.0004%
Body Weight M F
Abs Thyroid F M F M F M F
Rel Thyroid M F M F M M F
Abs Adrenals F
Abs Brain F
Abs Kidney F
Abs Liver F
Abs Ovaries F
Abs Spleen F
Rel Brain M
Rel Pituitary M M
Rel Right Testis M
Rel Seminal Vesicles M
Rel Adrenals F
F0 Thyroid Weight
Male Abs olute Male Re lative
0.14 * 0.3
*
0.12 0.25
0.1
0.2
% BW
grams
0.08
* 0.15
0.06
*
0.1
0.04
0.02 0.05
0 0
0.0000% 0.0001% 0.0004% 0.0015% 0.0000% 0.0001% 0.0004% 0.0015%
Dos e Le ve l Dos e Le ve l
Fem ale Absolute Female Relative
0.14 0.45
* *
0.12 0.4
0.35
0.1
0.3
% BW
grams
0.08 0.25
0.06 0.2
* 0.15
0.04 * *
0.1
0.02 0.05
0 0
0.0000% 0.0001% 0.0004% 0.0015% 0.0000% 0.0001% 0.0004% 0.0015%
Dose Level Dose Level
F1 Thyroid Weight
Male Absolute Male Relative
0.06 * 0.09
*
0.08
0.05
0.07
*
0.04 0.06
% BW
grams
0.05
0.03
0.04
0.02 0.03
0.02
0.01
0.01
0 0
0.0001% 0.0004% 0.0015% 0.0001% 0.0004% 0.0015%
Dos e l Le ve l Dos e Le ve l
Female Absolute Female Relative
0.045 * 0.14
0.04 *
0.12
0.035
0.1
0.03
% BW
0.08
grams
0.025
0.02 0.06
0.015 0.04
0.01
0.02
0.005
0 0
0.0001% 0.0004% 0.0015% 0.0001% 0.0004% 0.0015%
Dose Level Dose Level
F0 and F1 Histopathological
Changes
Dose Group 0.0000% 0.0001% 0.0004% 0.0015%
Thyroid Follicular Hyperplasia
F0 M 0/10 0/10 7/10
7/10 10/10
10/10
F0 F 0/10 0/10 1/10 10/10
1/10 10/10
F1 M 0/10 0/10 1/10
1/10 -
F1 F 0/10 0/10 0/10 -
Degeneration of germinal epithelium
F0 0/10 3/10
3/10 3/10
3/10 2/10
2/10
F1 0/10 1/10
1/10 1/10
1/10 -
Summary
PTU at 0.0015% in drinking water is a
reproductive toxicant based upon reduction
in F1 litter size
Thyroid hormones (T4 and TSH) were altered
at both 0.0004% and 0.0015% PTU
Thyroid hyperplasia and degeneration of
testicular germinal epithelium were noted at
all dose levels
Degeneration of the testicular germinal
epithelium was the only observable effects
of PTU at 0.0001%
