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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.

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slide1

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, NC2TherImmune Research Corporation, Gaithersburg, MD;3PAI, Frederick, MD;4USEPA, Washington DC;

propylthiouracil

H2

C

H

N

S

H3C

C

H2

NH

O

Propylthiouracil
  • a thyroid hormone-synthesis inhibitor
  • decreases T3 and T4; increases TSH
  • weight reduction
  • thyroid weight and pathology
study design
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:

Cohabi

Vag.

tation

Cytol.

F0: Gestation

F0: Lactation

F1: Exposure

F1:

F1: Pup Obs

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

and eye

F1: Vaginal

opening

Opening

F2: Ret.

F1:

F1: Preputial

Nipples

PND 16

Separation

Select.

F2: PND

F1:

16

PND 21

Select.

Sep.

F2: PND

F1: PND

21

21

Necrop.

necrop.

f 0 body weight
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

380

Grams

360

340

320

300

280

260

240

220

200

180

1

2

3

4

5

6

7

8

9

10

Study Weeks

f 0 water consumption
F0 Water Consumption

38

37

36

35

34

33

32

31

30

Gram

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

f 1 pups litter

4.9*

10.3*

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*

Combined 14.8 12.6 13.8 10.3*

* p < 0.001

f 1 and f 2 agd and agd pup weight ratio

2.51*

2.52*

0.37*

F1 and F2 AGD and AGD/Pup Weight Ratio

* p < 0.05 Dunnett’s

f 0 and f 1 histopathological changes

10/10

7/10

1/10

10/10

1/10

3/10

3/10

2/10

1/10

1/10

F0 and F1 Histopathological Changes
summary
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%