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A B S T R A C T

T

a n

y

a

M

o o r e

S

tu

d ie s

in

t

o t

l

i e

IVIe c

h

a n

is

m

s o

f P

o

ta s s

iu

m B

r o

m

a

t

e

I

n

d

u c e

d T l

i

y

r o

id C

a r c

i

n o

g

e n e s

is

.

(

U

n

d

e r

t h

e

d i

r e c

t i

o n o

f

L

o u

is e

B

a

ll

,

P

h

.

D

,

A

n

t h

o n

y D

e

A

n

g

e

lo

,

P h

.

D

.,

A

v r a

m

G

o

ld

,

P

h

.

D

)

B

r o

m

ate

(

B

r

O

g "

)

o c c u r s

i

n

fi

n

is

h

e

d d

r

in

k in

g w

a

t

e r a s a

b

y

-p

r o

d

u ct o

f

t

h

e o z o n a

t io n

d is

in

f

e c

t io n

p

r o c e s s .

P

o

t

a s s

iu

m b

r o

m

a

t

e,

t h

e e x

p

e r

i m

e n

ta

l m

o

d

e

l

c o

m p

o u n

d

,

h

a s

b

e e n

fo u n

d t

o

in

d

u c e t

h y

r o

id f

o

ll ic u

la r c e

l l t

u

m

o r s

i

n

t h

e r at a

ft

e r

1 0 0 w

e e

k

s .

L it

t le

i

n

fo r

m

at

io n

e x

is

t

s o n

t h

e

m

e c

h

a n

is

m

(

s

)

b y w h i

c

h p

o

t

a s s

i

u

m b

r o

m

a

te

in

d

u c e s

t h

y

r o

i d

c a n c e r

T h y

r o

id h

o r

m

o n e

le v e

ls

e x e r

t

a s

i

g

n

if ic a n

t

e

ff

e c

t

o n c e

l

lu

l

a r

m

e

t

a

b

o

l is

m

,

h

o

m

e o s

t

a s

is

,

a n

d

c e n

t

r a

l

n e r v o u s s

y

s

t

e

m d

e v e

lo

p m

e n

t

.

In o r

d

e r

t

o s

h

e

d l ig h t

o n

t h

e

p

o s s

i b le

m

e c

h

a n

i

s

m

(

s

)

o

f

c a r c

in o

g

e n e s

is

,

th

e e a r

ly

e

ff

e c

t

s o

f K B

r

O

g a

d m i

n

is

t

r at

io n

in

t h

e

d

r

in

k in

g

w

ate r o n t

h

e s e r u

m le v e

l

s o

f t h

y

r o

id

st

i m

u

l

a

t in

g h

o r

m

o n e

(

T

S

H

)

, tr

i io

d

ot

h y

r o n

in e

(

T 3

)

, a n

d

t h y

r o x

i

n

(

T 4

)

,

t h y

r o

i d h is

t

o

p

a

t h

o

lo

gy

,

f

o

ll ic u

l

a r c e

l l p

r o

l if

e r a

t io n

, a

p

o

p t

o s

is

, a n

d

O

H

^

g

u a n o s

i

n e

g

l

y

c o s

y l

a s e

(

0 G G

1

)

r e

p

a

i

r a c

t iv

it

y

w

e r e e x a

m

i

n e

d

.

A

n

i m

a

ls

e x

p

o s e

d t

o

K B

r

O

g

d is

p l

a

y

e

d in c r e a s e s

i

n

T 3

a n

d T 4 h

o r

m

o n e s at

3 0 d

a

y

s,

w it

h

n o c

h

a n

g

e

in

T S H le v e

l

s

C

o

llo

i d d

e

p l

et

io n

wa s o

b

s e r v e

d w ith i

n

fo

l li

c u

la r c e

l ls

i

n a

d

o s e a n

d

t

im

e

d

e

p

e n

d

e nt

m

a n n e r.

I

n c r e a s e

d

a

p

o

p t

o s

is

w

a s o

b

s e r v e

d in

t

h

e

h ig h d

o s e a n

im

a

ls

(4 0 0 m g / L K B

r

O

g

)

a t

3 0 d

a

y

s.

N

o e n

h

a n c e

d

0 G G

1

e x

p

r e s s

io n

wa s o

bs e r v e

d in

t h

e

t h y

r o

id

s

f

r o

m

r a

ts

tr e ate

d

w it

h K B

r

O

g

f

o r

7

d

a

y

s .

It

a

p p

e a r s

t

h

a

t

h

o r

m

o n a

l

e

f f

e c

t

s

m

a

y

p

la

y

a n a ct

iv e r o

le

in

t

h

e

(2)

A B S T R A C T

T

a n

y

a

M

o o r e

S

tu

d ie s

i

nto the

IVI

e c

h

a n

i

s

m

s o

f P

ota s s

iu

m B

r o

m

a

t

e

i

n

d

u c e

d T l

i

y

r o

i d C

a r c

i

n o

g

e n e s

is

.

(

U

n

d

e r

t h

e

d i

r e ct

i

o n o

f L

o u

is e

B

a

ll,

P h

.

D

,

A

n

t h

o n

y

D

e

A

n

g

e

lo

,

P h

.

D

.

,

A

v r a

m

G

o

ld

,

P h

.

D

)

B

r o

m

a

t

e

(

B

r

O

g "

)

o c c u r s

i

n

f i

n

is

h

e

d d

r

in

k i

n

g w

a

t

e r a s a

b y

-p

r o

d

u ct o

f

t

h

e o z o n at

io n

d is

i

n

f

e c

t io n

p

r o c e s s.

P

o

t

a s s

i

u

m b

r o

m

a

t

e,

t h

e e x

p

e r

i m

e n

ta

l m

o

d

e

l

c o

m

p

o u n

d

,

h

a s

b

e e n

fo u n

d t

o

in

d

u c e

t h

y

r o

id fo

l l ic u

la r c e

ll t

u

m

o r s

i

n

t h

e r a

t

a

ft

e r

1 0 0 w

e e

k

s .

L i tt le

i

n

fo r

m

a

t io n

e x

is

t

s o n

t h

e

m

e c

h

a n

is

m

(

s

)

b

y

w h ic

h

p

o

t

a s s

i

u

m b

r o

m

a

te

in

d

u c e s

t h y

r o

i d

c a n c e r.

T h

y

r o

id h

o r

m

o n e

le v e

ls

e x e r

t

a s

i

g

n

if ic a n

t

e

ff

e c

t

o n c e

l l

u

l

a r

m

e

t

a

b

o

li

s

m

,

h

o

m

e o s

t

a s

i

s,

a n

d

c e ntr a

l

n e r v o u s s

y

s

t

e

m d

e v e

lo

p m

e n

t

.

In o r

d

e r

t

o s

h

e

d l ig h t

o n

t h

e

p

o s s

ib l

e

m

e c

h

a n

is

m

(

s

)

o

f

c a r c

in o

g

e n e s

i

s,

t h

e e a r

l

y

e

f fe c

t

s o

f

K

B

r

O

g a

d

m in

is

t

r a

t io n

in

t h

e

d

r

in

k

i

n

g

w

a

t

e r o n

t

he s e r u

m le v e

ls

o

f t

hy

r o

i d

s

t im

u

l

a

t in

g h

o r

m

o n e

(

T

S H

)

,

t

r

iio

d

o

t h

y

r o n

i

n e

(

T 3

)

, a n

d

t h y

r o x

in

(

T 4

)

,

t h y

r o

id h is

t

o

p

a

t h

o

lo

g y

,

f

o

ll ic u

l

a r c e

l l p

r o

l ife r a

t io n

, a

p

o

p t

o s

i

s, a n

d O H

^

g

u a n o s

in e

g ly

c o s

y

l

a s e

(

0 G G

1

)

r e

p

a

ir a c

t iv

ity w

e r e e x a

m i

n e

d

.

A

n

i m

a

ls

e x

p

o s e

d

to

K B

r

O

g

d is

p l

a

y

e

d in c r e a s e s

i

n

T 3

a n

d T 4 h

o r

m

o n e s at

3 0 d

a

y

s,

w it

h

n o c

h

a n

g

e

in

T

S

H l

e v e

l

s.

C

o

llo

i d d

e

p

le

t

io n

w

a s o

b

s e r v e

d w it h in

f

o

l li

c u

la r c e

l ls

in a

d

o s e a n

d

t

i m

e

d

e

p

e n

d

e nt

m

a n n e r.

I

n c r e a s e

d

a

p

o

p

to s

is

w

a s o

b

s e r v e

d in

t

h

e

h i g h d

o s e a n

im

a

l

s

(

4 0 0 m

g/

L K B

r

O

g

)

at

3 0 d

a

y

s.

N

o e n

h

a n c e

d 0 G G 1

e x

p

r e s s

io n

w

a s o

b

s e r v e

d in

t

h

e t

h y

r o

id

s

f

r o

m

r ats tr e ate

d

w it

h K B

r

O

g

f

o r

7 d

a

y

s .

It

a

p p

e a r s t

h

a

t h

o r

m

o n a

l

e

ff

e cts

m

a

y p l

a

y

a n a ct

iv e

r o

le

in

t

h

e

m

e c

h

a n

is

m

o

f K B

r

O

g

i

n

d

u c e

d

t

h

y

r o

i d

c a r c

i

n o

g

e n e s

is

.

(3)

D

E D

I

C A T

I

O N

(4)

A

C K N

O

WL E D

G

M

E

N

T S

I

w

i

s

h

to e x

p

r e s s

m y

a

p p

r e c

i

at

i

o n to

M

r.

M

i

c

h

a e

l G

e o r

g

e a n

d

M

r .

S

te v e

K i l b

u

m

f

o r t

h

e

i

r

a s sista n c e w

i

th the stu

d y

.

M

y

tha n

k

s to

D

r . Ju

l

ia

C

a rte r a n

d B

e

m

e

d

et te

St

e

p h

e n s o n

f

o r the

i

r

a s s

i

sta n c e w

i

t

h

t

h

e c e

l l p

r o

l i f

e r at

i

o n a n

d

a

p

o

p

to s

i

s

d

ata.

M

y

t

h

a n

k

s to

D

r.

K

e vin

M

o r

g

a n ,

D

r

L

y

n n

C

r o s

b

y, Law r e n c e Yo o n , a n

d D

r.

M

ic

h

a e

l

Jo

k

in e n

f

o r a

l l

o

f

the

i

r s u

p p

o rt I w o u

l d

als o l

i k

e

to tha n

k

D r.

A

ntho n

y D

e

A

n

g

e

l

o a n

d D

r. Lo uis e

B

a

l

l fo r their

g

u

i d

a n c e a nd

p

at

i

e n c e

(5)

C

O

N

T

E N

T

S

P

A G

E

U

S T O F

T

A B L E

S

V H

L I

S

T

O

F

F

I

G U

R

E S

V

m

C ha

p

te r

I. B

R

O

M

A

T E:

A

B Y

-P R

O D U C

T

O F

T H

E O

Z O

N

A T I

O N D

I

S

I

N

F E C T I O

N

P R O C E S S 1

A

.

A

Br

ie

f H is

to r

y

o

f

t

h

e

U

.

S

.

D i

s

in

f

e ct

i

o n Po

Uc

y

3

B Ex

p

o s u r e to Ro

d

e nts a n

d H

u

m

a n s

5

C

. I

m

pa c t of Pota s s

iu

m

Br o

m

ate o n the

m

e cha nis

m

s of th yr oi

d

c a r c

in o

g

e n e s

i

s 6

1

.

T h

e o r

y

8

2

.

M

e a s u r e

m

e nt

9

D

.

S

tu

d

y

D

e s

i g

n 1 1

E.

M

ate ria

ls

&

M

et

h

o

d

s 1 0

n

S

T U D Y : R E

S U L

T

S & D

I

S C U

S S I

O N

A Re s u

lt

s 1

9

B .

D i

s c u s s

io n

3 2

(6)

m

. R E F E R E N

C

E

S

3

9

I V .

A P

P E

N D

I

X A

:

H

e

m

ato x

y l

in

& E

o s

in

St

a

i

n

i

ng 4

5

A P PE N D I X B

:

I

s o

l

at

io

n o

f R N A f

r o

m Sm

a

l l

Q

u an t

it

i

e s o

f T i

s s u e

(

1

- l

Om

g

)

4

7

A P P

E N D I X C

:

T h

yr o

i d St

i m

u

l

atin

g H

o r

m

o n e

R

a

d i

o

i m

m

u n o a ssay 4

9

A P

P E N

D

I

X D

: T

3 S

ti

m

u

l

a t

i

n

g

H o r

m

on e R a

d

io

i m m

u n o ass ay

5 1

A P P E N

D

I

X E

: T

4

Sti mulat

in

g H o r

m

o n e Ra

d

ioi

m m

u n o a s s a

y

5

2

A

PP E

N D I

X F:

I d

e nt

i f i

c ation o

f PC N

A

in

arc

h i

v a

l R

at a n

d

M

o u s e T

i

s s u e

5

4

A P P E N

D

IX G : T

U N

E L Pr ot oc ol 5 7

A PP E

N D

IX H : Re a

l T i

m

e Re v e r s e

T

r a n s c r

i p

ta s e P

C R

o

f O H 8 g

u a n o sin e g

l

yc o sy

l

a s e

m

R

N A

59

(7)

L I S T

O

F T A B L E

S

T

a

b l

e

1

D

o s

i

n

g R

e

g

im

e n s

2 5

T

a

b l

e

2

B

o

d y

a n

d

O

r

g

a n

W

e

i

g

h t

s

2 6

T

a

b l

e

3

F

o

l li

c u

l

a r a

p

o

p

t

o s

i

s a n

d

c e

ll p

r o

lif

e r a

t i

o n

i

n t

h

e

T h y

r o

id

s o

f F 3 4 4 / N m

a

l

e

r a

t

s r e c e

i

v

i

n

g

d

r

i

n

k i

n

g

w

a te r c o nta

i

n

i

n

g K B

r

O

g o r

d

e

i

o n

i

z e

d

w

a te r

2 7

(8)

L IS T O F F IG

U R E

S

F IG

U R E 1

T h y

r o

id

-

P it

u

it

a r

y

H

o r

m

o n a

l A

x

is

(

N

e

g

a

t iv e

F

e e

d b

a c

k P

at

h w

a

y

)

.. .. ... .

2 3

F IG

U R E 2

F

o

l l ic u

la r

C

e

l l

s

(

C

o n

t

r o

l

a n

d T

r e ate

d

)

2 4

F IG U R E 3

T 3

C

o n c e ntr a

t io n

(

n

g

/

d L

)

2 8

F IG U R E 4

T 4 C

o n c e ntr at

io n

(Mg / d L

)

2 9

F IG U R E 5

T S H

C

o n c e n

t

r a

t i

o n

(p l U

/

m L

)

3 0

F IG

U R E 6

O H

^

G

u a n o s

i

n e

G

ly

c o s

y l

a s e e x

p

r e s s

io n

in

t h

e

m

a

le

F 3 4 4 / N

r at

k id

n e

y

s

a n

d

t

h

y

r o

id

s

3 1

(9)

L IS T O

F A B B R

E V

IAT I

O N S

A E C

A m in o e

t

h y l

c a r

b

a z o

le

B

S

A

B

o v

in e

Se r u

m A lb

u

m in

c

A M P

C y

c

l ic

A d

e n o s

in e

M

o n o

p h

o s

p h

ate

D A B

D ia

m in o

b

e n z

id i

n e

D B P

D is

i

n

fe c

t io n

B y

-

P

r o

d

u c

t

s

D P C

D ia

g

n o s

t ic

P

r o

d

u cts

C

o r

p

o r at

io n

d U

d

e o x

y

u r

id in e

H A A

H

a

lo a c e

t

i

c a c

i d

M D D

M

e a n

D

a

i l

y

D

o s e

m R N A

M

e s s e n

g

e r

R i b

o n u c

le

ic

A

c

i d

N S B

N

o n s

p

e c

if i

c

B in

d in

g

0

G G

1

O

H

^

g

u a n o s

in e

g

ly

c o s

y

la s e

P B

S

P h

o s

p

h

a

t

e

b

u

ff

e r e

d

s a

lin e

P

C

N A

P

r o

lif

e r a

t in

g

c e

l l

n u c

le a r a n

t ig

e n

R N A

R ib

o n u c

le

ic a c

id

R T

-

P

C

R

R

e a

l T im

e

p

o

ly m

e r a s e c

h

a

i

n r e a ct

io n

S

O

St

a n

d

a r

d d

e v

ia

t

io n

T 3

T

ri io

d

ot

h y

r o n

in e

T 4

T h y

r o x

in e

T d T

T

e r

m in a

l d

e o x

y

n u c

ie o

t i d y l t

r a n s

f

e r a s e

T S H

T h

y

r o

id

st

im

u

la

t

i

n

g h

o r

m

o n e

T U N

E

L

T

d

T

-

m

(10)

C

H A P T E R I

B R O M A T E

:

A B Y

-

P R O D U C T O F T H E O Z O N A T IO N

D IS IN F E

C

T IO N P R O C E S S

I

n

19 7 4 t h

e

S

a

f

e

D

r

i

n

k in

g

W

ate r

A

ct

w

a s e n a cte

d in o r

d

e r to

p

r o

t

e c

t

p

u

b l ic

h

e a

lt h b

y

r e

g

u

l

a

t i

n

g

t h

e

U

.

S

.

d

r

i

n

k in

g

w

a

t

e r s u

p p l

y

C

o n

g

r e s s

is s u e

d

a

m

a n

d

a

te

t

o

t h

e

E

n v

ir o n

m

e n

t

a

l P

r o

t

e ct

io n

A

g

e n c

y t

o

i d

e n t

ify

a n

d

r e

g

u

la

t

e c o n

t

a

m i

n a n

t

s .

T h

e

la

w f

o c u s e

d

o n

tr e at

m

e nt to

g

u a r a nte e s a

f

e

d

r

i

n

k in

g w

ate r.

T h is

l

a

w w

a s e n a cte

d

in

o r

d

e r to r e

d

u c e t

h

e a

m

o u n

t

o

f d is

in

f

e ct

io n

b y

-p

r o

d

u cts

(

D B P

)

i

n

t h

e

U

.

S

.

w

a

t

e r s u

p p li

e s.

F

o r a

lm

o s

t 1 0 0 y

e a r s,

t h

e

U

.

S

.

h

a s

ut

i liz e

d

c

h l

o r

in a

t

io n

t

o

p

r e v e n

t t h

e tr a n s

m is s

i

o n o

f h

a r

m f

u

l

wa

te r

b

o r n e

d is e a s e s

.

C

h l

o r

in a

t

io n

h

a s r e

d

u c e

d

t

h

e n u

m b

e r o

f

c a s e s o

f

c

h lo r e a

,

d y

s e n

t

e r

y

, a n

d p

o

l io

.

A lt

h

o u

g h i

t

h

a s

d

e c r e a s e

d

t h

e n u

m b

e r o

f

e

p

i d

e

m ic s

, c

h lo r

in a

t

i

o n r e s u

lt

s

in

t

h

e

f

o r

m

at

io n o

f

D B F

s

w h ic

h h

a v e r a

is e

d h

e a

lt h

c o n c e r n s

(

3

,

6

,

4 0

)

.

I

n

t h

e

1 9 7 0

'

s , r e s e a r c

h

e r s

f

o u n

d t h

a

t

c

h l

o r

in e c o

m b i

n e

d

w

it

h

o r

g

a n

ic

m

at te r

i

n

t h

e

w

a

t

e r

t

o

f

o r

m b y

-p

r o

d

u c

t

s

w it

h p

o

t

e nt

ia

l

r

is

k

to

h

u

m

a n

h

e a

lt

h

(

3

)

.

S

e v e r a

l

o

f

t

h

e

D B F

s

w

e r e

f

o u n

d

to

b

e

c a r c

i

n o

g

e n

ic

w h

e n

te s

te

d

o n

l

a

b

o r ato r

y

a n

im

a

ls

.

R

e s e a r c

h

e r s

h

a v e

t

a

k

e n a

p

r o

g

r e s s

i

v e a

pp

r o a c

h

b

y

s e a r c

h i

n

g

f

o r o

t h

e r

w

a

y

s to

(11)

o z o n e tr e at

m

e nt,

w h i

c

h b y

c o

m p

a r

i

s o n,

h

a s s e vera

l p

o s

i

t

i

v e

f

e a tu r e s .

O

z o n at

i

o n

i

s

b

e

i

n

g

c o n s

id

e r e

d

a s a n a

l

te r n at

i

v e

b

e c a u s e

it

a c c o

m p l i

s

h

e s t

w

o

g

o a

l

s.

It k i ll

s

m i

c r o

b

e s

m

o r e e

f f i

c

i

e nt

ly

t

h

a n

c

h l

o r

i

n e a n

d it

r e

d

u c e s

t h

e

l

e v e

l

s o

f

t

r

ih

a

l

o

m

e

t h

a n e s

i

n t

h

e

d

r

i

n

k i

n

g

w

a

t

e r.

U

n

f

o r

t

u n ate

ly

, t

h

e r e

i

s a n e

g

at

i

v e s

id

e

t

o e

m b

r a c

i

n

g

o z o n a

t i

o n .

L i k

e c

h l

o r

i

n e

d i

s

i

n

f

e c

t i

o n, o z o n at

i

o n a

l

s o

f

o r

m

s

b y

¬

p

r o

d

u c

t

s.

T h

e

f

o r

m

at

i

o n o

f b

r o

m

a te a s a

b y p

r o

d

u ct o

f

o z o n at

i

o n

i

s

o

f

c o n s

id

e r a

b l

e c o n c e r n .

B

r o

m

ate

f

o r

m

a t

i

o n o c c u r s

i

n t

w

o

w

a

y

s.

F i

r s

t

,

h

y

p

o

b

r o

m

o u s a c

i d m

a

y

f

o r

m i

n s u r

f

a c e

w

ate r s

w i

t

h

a

h ig h

b

r o

m

id

e c o n

t

e nt.

B

r o

m id

e

i

s

f

o u n

d i

n e s

t

u a r

i

n e

(

b

r a c

k i

s

h

)

w

ate r s ,

b

ut

i

t

i

s a

l

s o

p

r e s e nt

i

n

d

o

w

n str e a

m w

a

t

e r s n e a r

f

a cto r

y

ut

il i

t

i

e s.

H y p

o

b

r o

m

o u s a c

id

r e a cts

w i

t

h b

r o

m i

n e to

f

o r

m b

r o

m

ate .

A l

s o , t

h

e

o x

id

a

t i

o n o

f b

r o

m id

e

(

B

r

)

, a n atu r a

l ly

o c c u r r

i

n

g i

o n

f

o u n

d i

n

m

o st

p

u

b li

c

w

ate r s,

f

o r

m

s

b

r o

m

a

t

e

(

3

,

5

)

.

T w

o

p

at

h w

a

y

s a r e r e c o

g

n

i

z e

d

.

M

o

l

e c u

l

a r o z o n e

p

at

h w

a

y

:

1

)

B

r

+

O

3 -

O B

r "

+

O

2

O B

r ■

+

2

0

3

- »

B

r

O

g

-+

2

O

2

T h

e

b

r o

m i d

e

i

s o x

i d i

z e

d b y

o z o n e

f

o r

m i

n

g

t

h

e

h y p

o

b

r o

m i

te

i

o n

(

O

B

r ■

)

.

It

r e a c

h

e s a n e

q

u

i

lib

r

i

u

m

s

t

a

t

e

w it h h

y p

o

b

r o

m

o u s a c

i

d

(

w

e a

k

a c

id

) (

H

O

B

r

)

.

T h i

s c r e a

t

e s a

b

r o

m

a

t

e

i

o n

w h i

c

h i

s

p H

(12)

H y d

r ox

y l

r a

d i

ca

l p

at h w a

y

2

)

B

r +

'

O

H

^

B

r

O

a

T h

e s e c o n

d p

a

th w

a

y i

s t

h

e

h y d

r o x

y l

r a

d i

c a

l p

a t

h w

a

y

B

r o

m i d

e

i

nte r a cts

w it

h h y d

r o x

y l i

o n s

(

f

o r

m

s a s a

p

r o

d

u ct o

f

o z o n e

)

to

f

o r

m

b

r o

m

ate

(

5

)

.

I

n r e c e nt s

t

u

d i

e s,

K

r a s n e r a n

d

o

t h

e r s

m

e a s u r e

d

t

h

e

c o n c e n

t

r a

t

i

o n o

f

b

r o

m

id

e

i

n

t h

e s u r

f

a c e

w

a

t

e r s .

R

e s u

lt

s

i

n

d i

c a

t

e

d

7 0

-

1 0 0

u

g

/

L

b

r o

m i d

e

i

n

t h

e

i

n

f l

u e n

t w

a

t

e r s o

f U

.

S

. u

t il it

i

e s

(

2 5

)

I

n

a n e a r

ly

r e

p

o rt,

K

r a s n e r

f

o u n

d

t

h

a

t 7 5

%

o

f

the

w

ate r s u

p p l i

e s

c o n

t

a

i

n

4 0

u

g/

L b

r o

m

a te .

A l

s o , t

h

e

W

o r

l d H

e a

lt

h O

r

g

a n

i

z at

i

o n

h

a s

s et t

h

e

l im it

o

f b

r o

m

a

t

e

i

n

d

r

i

n

k i

n

g w

a te r to

2 5 p g

/

L

.

T h

e

E P A h

a s

s e

t t h

e

l im it t

o

1 0 p

g/

L i

n

d

r

i

n

k i

n

g w

ate r

(

3

)

.

B

e c a u s e

7 5

%

o

f

t

h

e

w

a

t

e r s u

pp

l

y

w

o u

ld

c o n

t

a

i

n

4 0 p

g/

L b

r o

m

a

t

e , a r

i

s

k

a s s e s s

m

e nt

f

o r

o z o n at

i

o n a n

d

c

h l

o r

i

n e

d i

s

i

n

f

e ct

i

o n

m

u st

b

e c a r r

i

e

d

o ut.

A

c o

m

p

a r

i

s o n o

f t h

e

d

e

t

r

im

e nta

l

e

ff

e cts o

f t h

e to x

i

c

b y

-p

r o

d

u cts

m

u st

b

e a n a

ly

z e

d

a n

d w

e

i g h

te

d

.

I

n the

1 9 7 0

'

s , s e v e r a

l l

a

b

o r ato r

i

e s c o n

d

u c

t

e

d

stu

d i

e s o n

c

h l

o r o

f

o r

m

.

T h

e

b i

o c

h

e

m i

c a

l

to x

i

c o

l

o

g y

o

f

c

h l

o r o

f

o r

m w

a s

r e v

i

e

w

e

d i

n

1 9 7 9

(

3 6

)

.

T h i

s

D B P i

s o n e o

f

t

h

e

m

o s

t

c o

m m

o n

tr

i h

a

l

o

m

e t

h

a n e s

(

T H M

)

f

o u n

d

i

n

d

r

i

n

k i

n

g

w

a

t

e r.

T h

e r e v

i

e

w f

o u n

d

t h

a

t

c

h l

o r o

f

o r

m

c a u s e

d h

e

p

a

t

o

t

o x

i

c

it

y

a n

d

p

o s s

ib ly

r e n a

l

to x

i

c

it

y i

n

r o

d

e n

t

s

(

3 6

)

.

I

n a

d d it i

o n

t

o c

h l

o r o

f

o r

m

, o

t h

e r

D B F

s

i

n

th

e wa

t

e r

(13)

i

n

g

r e

d ie n

t

I

n the s e

p

r o

d

u cts

b

e c a u s e o

f it

s o x

id i

z

i

n

g p

r o

p

e rt

y

.

P

o

t

a s s

iu

m

b

r o

m

ate

w

a s

f

o u n

d t

o

b

e c a r c

in o

g

e n

ic

i

n t

in e

n n a

le a n

d f

e

m

a

le

r at

(

7

,

2 6

,

2 7

)

.

W

h il

e r o

d

e nt s u s c e

p

t

ib i l it

y

to t

h is

c o

m p

o u n

d

d

o e s n o

t i m p ly

a

d

e

f i

n

it

e

h

e a

lt h h

a z a rd to

h

u

m

a n s ,

m

o st

stu

d i

e s

i

n

d i

c a

t

e a r e a s o n

f

o r c o n c e r n

fo r

p

o

t

a s s

iu

m b

r o

m

ate

in

d

u c e

d

tu

m

o r s.

A lt

h

o u

g h it i

s n o

t l is

t

e

d

a s a

h

u

m

a n c a r c

in o

g

e n,

K B

r

O

g

is a

n e

p h

r o a n

d

n e u r oto x

ic a n

t i

n

h

u

m

a n s

(

7

,

2 6

,

2 7

)

.

D

u e to

i

t

s

q

u e st

io n a

b le e

f

f

e c

t

s o n

h

u

m

a n s,

p

o

ta s s

iu

m b

r o

m

ate

h

a s

b

e e n

r e

m

o v e

d f

r o

m

c o s

m

e

t ic s

a n

d h

o

m

e

w

a v e

p

e r

m

a n e nt

k it

s .

T h

e

E P A h

a s r e c e n

t l

y

in v e s

t i

g

ate

d

r o

d

e nt a n

d h

u

m

a n

d

ata

in v o

lv

in

g t h y

r o

id f

o

l lic u

la r c e

l l

tu

m

o r s .

T h

e

E

n v

i

r o n

m

e nta

l

P

r o

t

e ct

io n

A

g

e n c

y

a s s e s s

m

e n

t

g

u

id

e

l in e s

fo r

t h y

r o

id

c a n c e r w e r e

im p l

e

m

e nte

d i

n

1 9 8 8

.

T h

e

g

u

i d

e

l i

n e s o

p

e r ate u n

d

e r t

w

o

a s s u

m

p

t

io n s

.

T h

e

f ir s

t

g

u

id

e

l in e

m

a

k

e s

t h

e

fo

ll

o

w i

n

g

a s s u

m p t i

o n : :

1

)

"

C

h

e

m ic a

l l

y

in

d

u c e

d

c a n c e r

in

la

b

o r a to r

y

a n

im

a

ls

s

i

g

n a

l

s

p

o

t

e n

t ia

l h

a z a r

d

s

in

h

u

m

a n s

(

1 5

)

. "

2

)

F

o r

d

o s e -r e s

p

o n s e a n a

ly

s e s, u s e

t h

e

m

o st

b io

lo

g i

c a

l l

y

a

p p

r o

p

r

ia

t

e

m

e a n s

f

o r

d

o s e

e x

t

r a

p

o

la

t i

o n.

In

th

e a

b

s e n c e o

f

s u c

h k

n o

w l

e

d g

e, u s e

o

f d

e

i

fa u

lt

s c

ie n c e

p

o

lic

y p

o s

it io n s s

h

o u

ld b

e

f

o

l lo

w

e

d

, e

it

h

e r

lo

w

-

d

o s e

li

n e a r, n o n -

l i

n e a r, o r

b

ot

h

p

r o c e

d

u r e s

(

1 5

)

.

F

o r t

h

e r

i

s

k

a s s e s s

m

e n

t

o

f t h y

r o

i d

c a n c e r, t

h

e r e

q

u

ir e

d

d

ata

m

u st

in c

lu

d

e : t

h

e

m

o

d

e o

f

a c

t io n

in

f

o r

m

at

io n

o n

m

uta

g

e n

ic

ity

,

i

n c r e a s e s

in

f

o

l lic u

la r c e

ll g

r o

w

t

h

, t

h y

r o

id g l

a n

d w

e

ig h

t, t

h y

r o

id

-p it

u

it

a r

y

(14)

p

r o

d

uc

i

n

g

t h

y

r o

i d

e

f f

e cts

w h i

c

h

c a u s e c a nc er a nd reve r si b il it

y

of

e

ff

e cts

w h

e n

d

o s

i

n

g

sto

p

s

(

1 7

)

,

I

n t

h

e r

i

s

k

a s s e s s

m

e nt

d

e

f

a u

l t

s c

i

e n c e

p

o

l i

c

y

, t

h

e

A g

e n c

y

c o n c

l

u

d

e

d

t

h

a

t t h

y

r o

i d f

o

l li

c u

l

a r c e

l l

tu

m

o r s a n

d

t

h y

r o

i d

tu

m

o r s a r e

r e

l

e v a n

t

to

h

u

m

a n c a r c

i

n o

g

e n

i

c

it

y

(

2

,

1 4

,

1 5

,

1 7

)

.

A

c

h

a n

g

e to

o z o n at

i

o n

d i

s

i

n

f

e ct

i

o n

w

o u

l d

e x

p

o s e

h

u

m

a n

p

o

p

u

l

a t

i

o n s

t

o

4 0

-

1 0 0

p g

/

L p

o

t

a s s

i

u

m b

r o

m

a

t

e

i

n

w

a

t

e r c o n

t

a

i

n

i

n

g

2 m g

/

L b

r o

m i d

e

(

i

n

f l

u e nt

w

ate r s

) (

4 4

)

.

I

n o r

d

e r to a

p p

r e c

i

ate

t h

e r o

l

e

p

ota s s

i

u

m b

r o

m

a te

m

a

y p l

a

y

i

n t

h y

r o

id

c a r c

i

n o

g

e n e s

i

s ,

it

i

s n e c e s s a r

y

to u n

d

e r sta n

d

t

h

e n o r

m

a

l

f

u n ct

i

o n s o

f

the t

h y

r o

i d

-p i

tu

it

a r

y

a x

i

s .

T h

e t

h y

r o

i d

-p i

tu

it

a r

y

a x

i

s

c o n s

i

s

t

s o

f

t

h

r e e

m

a

i

n e n

d

o c r

i

n e

t i

s s u e s;

t h

e s e

i

n c

l

u

d

e, t

h

e

h y p

o

t h

a

l

a

m

u s,

p i

tu

it

a r

y

a n

d

t

h

y

r o

id g l

a n

d

(

4

,

9

)

.

T h

e n e u r o n s

w i

t

h i

n t

h

e

h y p

o

t h

a

l

a

m

u s

p

r o

d

u c e t

h

y

r otr o

p h i

n r e

l

e a s

i

n

g h

o r

m

o n e

(

T R H

)

w h i

c

h

a ct

i

v a

t

e c e

l l

s

w it

h i

n t

h

e a nte r

i

o r

p it

u

it

a r

y

to r e

l

e a s e

t h y

r o

i d

s

t i m

u

l

a

t i

n

g

h

o r

m

o n e

(

T

S

H

)

.

T

S

H w

o r

k

s t

h

r o u

g h

two

m

a

i

n

p

a

t h w

a

y

s.

T

S

H

a c

t i

v a

t

e s a

d

e n

y l

ate c

y

c

l

a s e

w h i

c

h I

n c r e a s e s t

h

e

l

e v e

l

s o

f

c

A M P

.

I

n

t

u r n,

th

e c

A M P

a c

t i

v a

t

e s

p

h

o s

p h it i d y l

-i

n o s

it

o

l/ C

a^* s

i

g

n a

l

c a s c a

d

e

w h i

c

h t

u r n s o n

p h

o s

p h

o

l ip

a s e

C

.

A t

t h i

s

p

o

i

n t,

t h

e

p

a

t h w

a

y d i

v e r

g

e s

i

n

t

o t

w

o

b

r a n c

h

e s .

T h

e

f i

r st

b

r a n c

h

i

n c

l

u

d

e s

t h

e a c

t

i

v a

t i

o n o

f

i

n o s

it

o

l

t

r

i

p

h

o s

p h

a

t

e

w h i

c

h

r e

l

e a s e s

C

a^"

f

r o

m

c e

l l

s

t

o r a

g

e.

T h i

s

p

a

t h w

a

y

e v e ntu a

l ly l

e a

d

s to

h y d

r o

g

e n

p

e r o x

id

e

g

e n e r a

t i

o n a n

d t h

y

r o

i d h

o r

m

o n e s

y

n

t h

e s

i

s.

T h

e s e c o n

d

(15)

p

a

t h w

a

y

u s e s

1

,

2 d ia c

y l

g

ly

c e r o

l

to a c

t iv a

te

p

r ote

in

k in a s e

C

.

T h i

s

s

i g

n a

l li

n

g

c a s c a

d

e a ct

iv a

te s n u c

le a r

t

r a n s c r

i p

t

io n

f

a cto r

g

e n e s

w h ic

h

c o ntr o

l

c e

ll p

r o

l ife r a

t

i

o n a n

d

io

d id

e u

p

ta

ke

a n

d m

eta

b

o

lis

m

(

1 4

)

.

U l

t

i

m

a

t

e

l

y

,

t h

e

T

S

H

a c

t iv a

t

e s

f

o

l l ic

l

e s

w it h in

t h

e t

h y

r o

id

to

r e

le a s e

t

h y

r o

i d h

o rmo n e s .

T h

e s e t

h

r e e o

p

e r ate

in a n e

g

at

iv

e

f

e e

d b

a c

k

s

y

s

t

e

m

to s u s

t

a

in

t h y

r o

i d h

o r

m

o n e

h

o

m

e o sta s

is

w i

t

h i

n

t

h

e

b

o

d y

(

4

,

1 9

,

2 0

)

.

T h

e

th y

r o

id g l

a n

d is

lo c a

te

d

o n t

h

e tr a c

h

e a .

I

t c o n s

is

ts o

f

t w

o

l

o

b

e s c o n n e c

t

e

d b y

a s

m

a

l l is

t h m

u s o

f t is s u e

.

B l

o o

d is

s u

p p l i

e

d b y th

e s u

p

e r

io r a n

d in

fe r

io r

t h y

r o

id

a rte r

y

.

5 0

%

o

f

t

h

e

b lo o

d is

s u

p p l i

e

d b y

c a

p il l

a r

i

e s

w h ic

h

a r e a

d

j

a c e nt to t

h

e t

h y

r o

id

.

T h

e

t h y

r o

i d g l

a n

d is c o

m p

o s e

d

o

f tw

o c e

l l

t

y p

e s , t

h

e

p

a r a

f

o

ll ic u

la r

c e

l ls a n

d

t

h

e

f

o

ll ic

le s

.

T h

e

f

o

l l ic

le s

a r e t

h

e

p

r

i m

a r

y

c e

l ls

w h ic

h

p

r o

d

u c e

t h

e

h

o r

m

o n e s.

T h

e

f

o

ll ic

le c o n s

is

ts o

f

a s

i

n

g l

e e

p i

t

h

e

l ia

l

la

y

e r o

f

c e

l ls s u r r o u n

d i

n

g

a

l

u

m

e n .

T h

e

l

u

m

e n c o nta

i

n s c o

l lo

id

, t

h

e

o r

g

a n

ic

s

t

o r a

g

e

m

a

t

e r

i

a

l w h ic

h

c o nta

in s

th

e t

y

r o s

in e s

w h ic

h m

a

k

e

u

p T 3

(

a ct

iv e

f

o r

m

)

a n

d T 4

(

le s s a c

t

iv e

)

.

T h

e c o

llo

id f i ll

s t

h

e

lu

m

e n

c o

m

p

le

t

e

ly i

n n o rma

l

c e

ll

s, u nt

i l

s

t im

u

la

te

d b y T S H

,

f

r o

m

t

h

e

p it

u

it

a r

y

,

t

o r e

l

e a s e

h

o r

m

o n e s.

T

h

e

f

o

l lic u

la r c e

l ls

a r e c u

b

o

i d

a

l

w h

e n a c

t iv e a n

d f la

tt

e n e

d w h

e n a

t

r e st.

T h

e

p

a r a

f

o

l l ic

l

e c e

l ls

(

c

c e

lls

)

,

l

o c ate

d i

n

th

e

in

te r

f

o

l li

c u

la r s

p

a c e s , c o nta

in r o u

g h

e n

d

o

pl

a s

m ic

r e

t ic u

l

u

m

n e a r

t h

e

b

a s e o

f t h

e c e

ll

.

T h is

o r

g

a n e

l l

e

(16)

tra n s

f

er r e d to t he

g

o l

g

i a

p p

a r atu s, fo l lo

w

ed b

y

tr a n sfe r to the

s u

rf

a c e o

f

t

h

e c e

l l b y

v e s

i

c

l

e .

T h

e s e v e s

i

c

l

e s e

m p

t

y

t

h y

r o

g l

o

b

u

li

n

i

nto t

h

e

f

o

l li

c u

l

a r

l

u

m

e n

(

4

,

1 4

,

1 5

,

1 9

,

2 0

)

.

I

n o r

d

e r to s

y

nt

h

e s

i

z e

T 3

a n

d T 4

,

i

o

d i

n at

i

o n o

f

t

h y

r o

g l

o

b

u

l i

n

m

u st o c c u r.

T h y

r o

p

e r o x

i d

a s e c ata

ly

z e s t

h

e

i

o

d i

n e

b i

n

d i

n

g

to

t

y

r o s

y

l

r e s

i d

u e s

w it h i

n

th

e t

h

y

r o

g

l

o

b

u

li

n.

T h

e t

w

o

i

o

d i

n ate

d

t

y

r o s

i

n e s a r e c o u

p l

e

d b y

t

h y

r o

p

e r o x

i d

a s e .

T h i

s r e a ct

i

o n

f

o r

m

s

m

o

l

e c u

l

e s o

f i

o

d it

h y

r o n

i

n e s ,

t h

e

p

r e c u r s o r

t

o t

h

e

h

o r

m

o n e s.

L

y

s o s o

m

e s a r e

p

r e s e n

t

a n

d

a r e r e s

p

o n s

i b l

e

f

o r t

h

e

d

e

g

r a

d

at

i

o n o

f

t h

e

t h

y

r o

g l

o

b

u

l i

n ,

w h i

c

h

a

ll

o

w

s

h

o r

m

o n e r e

l

e a s e

(

1 4

)

.

T h

e e xtr a

p

o

l

at

i

o n o

f

r o

d

e nt

d

ata

t

o

h

u

m

a n

d

ata a r e

d

u e to

the

f

o

ll

o

w i

n

g

s

i m i l

a r

it i

e s o

f

r o

d

e nt a n

d h

u

m

a n s

y

ste

m

s.

F i

r st, t

h

e

t

h y

r o

id

-p i

tu

it

a r

y

n e

g

a

t i

v e

f

e e

d b

a c

k

a x

i

s

i

s

p

r e s e nt

i

n

b

o th r o

d

e nts

a n

d

h

u

m

a n s.

A l

s o

,

t h

e r e s

p

o n s e

t

o

d i

s

t

u r

b

a n c e s

i

n

t h

y

r o

id f

u n ct

i

o n

f

r o

m

a n

t it h y

r o

id

s

t i m

u

li i

s s

i m i l

a r

i

n

b

ot

h

s

p

e c

i

e s .

I

n c o ntr a st, t

h

e

d i

f f

e r e n c e s

b

e

t w

e e n r o

d

e n

t

s a n

d h

u

m

a n s a r e c a u s e

f

o r c a ut

i

o n

w h

e n e x

t

r a

p

o

l

a

t i

n

g d

ata .

T h

e s

i

z e ,

l if

e s

p

a n , a n

d b

a s a

l m

e ta

b

o

l i

c

r ate s

b

et

w

e e n t

h

e r o

d

e n ts a n

d h

u

m

a n s

d iff

e r.

H

u

m

a n s r e

q

u

i

r e

l

ow

a n

d h

ig

h

a

f

f i

n

it

y p

r o

t

e

i

n c a r r

i

e r s

f

o r

t h

y

r o

i d h

o r

m

o n e s , a

lb

u

m i

n a n

d

t

h y

r o x

i

n e-

b i

n

d i

n

g g

l

o

b

u

l i

n.

R

o

d

e n ts a

l

s o u s e t

h

e a

lb

u

m i

n,

b

ut

l

a c

k

t

h y

r o x

i

n e-

b i

n

d i

n

g g

l

o

b

u

l i

n.

A

s a r e s u

lt

, t

h y

r o

i d h

o r

m

o n e s

h

a v e a

s

h

o rt e r

h

a

lf

-

l if

e

i

n r o

d

e nts.

H

u

m

a n s a r e n o

t

a s s e n s

it

i

v e to s o

m

e

s

t im

u

li

a s a r e r o

d

e n

t

s.

T h

e r e a r e n o s e x

d if f

e r e n c e s

i

n

h

u

m

a n s,

(17)

w h

e r e a s ,

t h

e r o

d

e nt, e x

h i b it

s e x

d

iff

e r e n c e s .

A d

u

lt

m

a

l

e r ats

h

a v e

h ig h

e r

T

S

H l

e v e

l

s t

h

a n

f

e n n a

l

e s .

M

a

l

e r ats a r e

m

o r e s e n s

it

i

v e to

t h y

r o

id

s

t im

u

l

a

t i

o n a n

d

c a r c

i

n o

g

e n e s

i

s.

M

o s

t i m p

o r

t

a n

t

o

f

a

l l

, n o

c

h

e

m i

c a

l h

a s

b

e e n

f

o u n

d

to

b

e c a r c

i

n o

g

e n

i

c to t

h

e

h

u

m

a n t

h y

r o

i d

N

e v e rt

h

e

l

e s s, t

h i

s

d

o e s n ot

d i m i

n

i

s

h

t

h

e

p

o s s

ib i lit

y

o

f

a c o

m m

o n

m

e c

h

a n

i

s

m

f

o r c a r c

i

n o

g

e n e s

i

s

i

n

t h

e

th y

r o

id g i

v e n t

h

e c o

m m

o n

t

h y

r o

i d

-p it

u

it

a r

y p

at

h w

a

y

.

P

o

t

a s s

i

u

m b

r o

m

a

t

e

i

s a c a r c

i

n o

g

e n

i

n

b

ot

h m

a

l

e a n

d f

e

m

a

l

e

r a

t

s

(

7

,

2 6

,

4 4

)

.

I

n

d

r

i

n

k i

n

g

w

a

t

e r

d

o s e s a r e a s

l

o

w

a s

2 0 p p m

(

2 0 m g

/

l

)

,

K B

r

O

g

w

a s c a r c

i

n o

g

e n

i

c.

R

e n a

l

c e

l l

tu

m

o r s

, t

h y

r o

id

f

o

l li

c u

l

a r tu

m

o r s , a n

d

a

b d

o

m i

n a

l m

e s othe

l i

o

m

a s

h

a v e

b

e e n

o

b

s e r v e

d b

y

s e v e r a

l l

a

b

o r ato r

i

e s

(

2 6

,

2 7

,

4 4

)

.

T h

e

m

e c

h

a n

i

s

m

o

f

c a r c

i

n o

g

e n e s

i

s

w it h i

n

t h

e r at

k id

n e

y h

a s

b

e e n stu

d i

e

d

t

h

o r o u

g h ly

(

1

,

1 1

,

2 3

,

2 6

,

2 7

,

3 7

,

3 8

)

.

P

o

t

a s s

i

u

m b

r o

m

a te

i

n

d

u c e s o x

id

a t

i

v e

d

a

m

a

g

e to t

h

e r e n a

l p

r o x

im

a

l

tu

b

u

l

e s , the ta r

g

et s

it

e

f

o r

c a r c

i

n o

g

e n e s

i

s

w it h i

n

t h

e r a

t k i d

n e

y

(

3 7

,

3 8

)

.

I

n c r e a s e

d l

e v e

l

s o

f

l ip i d p

e r o x

id

at

i

o n

m

a

y

b

e t

h

e r e s u

lt

o

f

o x

id

at

i

v e

d

a

m

a

g

e.

A l

s o

,

p

ota s s

i

u

m b

r o

m

ate

i

n

d

u c e

d

t

h

e

f

o r

m

at

i

o n o

f m

e s ot

h

e

l i

o

m

a s o n t

h

e

t

u n

i

c a v a

g i

n a

li

s

p

a r

l

e

t

a

l i

s

(

l

o c a

t

e

d

o n

th

e a

t t

a c

h m

e n

t

b

e

t w

e e n

t h

e

te st

i

s a n

d t h

e e

p id i d y m i

s

) (

4 4

)

.

R

e c e n

t

stu

d i

e s

i

n

d i

c a

t

e t

h y

r o

id

f

o

l l i

c u

l

a r c e

l

l

t

u

m

o r s

d

e v e

l

o

p

a s e a r

l

y

a s

2 6 w

e e

k

s a

ft

e r

t

r e a

t m

e nt

w it h 1 0

-

2 0

pp

m K B

r

O

g

(

7

,

4 4

)

.

(18)

c a r c

i

n o

g

e n e s

i

s

i

s n ot

k

n o

w

n .

S

tu

d i

e s

l

i a v e s

h

o

w

n t

l

i at a

d i

r e ct

i

n

t

e r

f

e r e n c e

w it h t h

e

t h

y

r o

i d h

o r

m

o n e s

m

a

y

c a u s e

d

e v e

l

o

p m

e nt o

f

t

u

m

o r s

(

1 6

,

1 8

,

3 0

,

3 2

,

3 3

,

3 4

)

.

S

p

e c

if i

c a

l ly

,

d

e c r e a s e

d

tr

i i

o

d

ot

h y

r o n

i

n e

(

T 3

)

a n

d

t

h y

r o x

i

n e

(

T 4

)

l

e v e

l

s

w i

t

h i

n c r e a s e

d

t h y

r o

id

s

t im

u

l

a

t i

n

g

h

o r

m

o n e

(

T

S

H

)

m

a

y i

n

d

u c e t

h

e

f

o r

m

at

i

o n o

f

n e o

p l

a s

m

s

(

3 3

,

3 4

)

.

N

e o

p l

a s

m

s a r e a

b

n o r

m

a

l

n ew

g

r o

w

t

h

s o r

t

u

m

o r s.

T h y

r o

id f

o

ll i

c u

l

a r c e

ll p

r o

lif

e r a

t i

o n

m

a

y

a

l

s o

p l

a

y

a r o

l

e

i

n

th

e

d

e v e

l

o

p

m

e n

t

o

f h y p

e r

p l

a s

i

a .

H y p

e r

p l

a s

i

a

i

s t

h

e n o ntu

m

o r o u s

i

n c r e a s e

i

n

t h

e n u

m b

e r o

f

c e

ll

s

i

n a n o r

g

a n o r t

i

s s u e

(

4

,

1 6

,

1 9

,

2 1

)

.

T h i

s stu

d y w

a s

d

e s

i

g

n e

d

to

i

n v e st

i g

a te

t h

e

m

e c

h

a n

i

s

m

s

b y w h i

c

h

p

o

t

a s s

i

u

m b

r o

m

ate

d i

s r u

p t

s

t h

e n o r

m

a

l f

u n c

t i

o n o

f

t

h

e r at t

h y

r o

i d

.

T h i

s stu

d y w

a s c o n

d

u c

t

e

d t

o e x a

m i

n e

t h

e e a r

ly

e

ff

e c

t

s o

f K B

r

O

g

a

d m i

n

i

s

t

e r e

d i

n t

h

e

d

r

i

n

k i

n

g w

a

t

e r o n t

h

e s e r u

m l

e v e

l

s o

f

t

h y

r o

id

st

im

u

l

at

i

n

g h

o r

m

o n e

(

T

S

H

)

, tr

ii

o

d

ot

h y

r o n

i

n e

(

T 3

)

, a n

d

t

h y

r o x

i

n

(

T 4

)

,

t

h y

r o

id h i

s

t

o

p

a

t h

o

l

o

g y

,

f

o

l l i

c u

l

a r c e

l l p

r o

lif

e r at

i

o n, a n

d

a

p

o

p

to s

i

s.

M A T E R IA L

S

& M E T H O D

S

C

H E M IC A L

S

P

o

t

a s s

i

u

m b

r o

m

a

t

e

(

9 9

%

P

u r

it

y

)

w

a s

p

u r c

h

a s e

d f

r o

m S i

g

m

a

C he

m i

c a

l

C

o

m

p

a n

y

(

S

t

.

L

o u

i

s ,

M

O

)

a n

d d i

s s o

l

v e

d i

n

t

o

d

e

i

o n

i

z e

d

w

a

t

e r

t

o a c

h

ie v e

t h

e

t

a r

g

e

t

c o n c e n

t

r a

t i

o n s o

f

0

.

1 0 0 m

g/

L

a n

d 0

.

4 0 0

m g

/

L

.

T h

e

p H w

a s a

d

j

u ste

d t

o

6

.

8

-

7

.

4 w it h h y d

r o c

h l

o r

i

c a c

id

.

T h

e

d

o s

i

n

g

r e

g i

m

e n c o n s

i

s

t

e

d

o

f 3 g

r o u

p

s :

(

1

) (

d

e

i

o n

i

z e

d w

ate r

)

,

(

2

)

(19)

(

0

.

1 0 0 m g / L K B

r

O

g

)

, a n

d

(

3

) (

0

.4

0 0 m g / L K B

rO g

)

.

A

n

i m

a

l

s

w

e r e

a

l lo

w

e

d

a

d li b i tu

m

a c c e s s

t

o a

m b

e r

g

la s s

b

ot

t le s

f i

t te

d w i

t

h T

e

f lo n

,

d

o u

b le

-

b

a

lle

d

s

i p p

e r

t

o

p

s.

T h

e

b

o t

t le s

w

e r e

f il l

e

d

o n c e a

w

e e

k

S

a

m

p

l

e s

f

r o

m

e a c

h

e x

p

o s u r e c o n c e ntr at

io n

w

e r e c o

ll

e cte

d i

n 7

m L

s c

in

t il la

t io n v

ia

l

s a n

d

s

t

o r e

d

a

t 5

°

C

.

A l l

s a

m

p

l

e s

w

e r e a n a

ly

z e

d b y

H P L

C

u

l

tr a v

io

le

t

d

ete ct

io n a

t

2 1 5

n

m

(

3 0 0 m m X 7

.

8 m m

an

io

n

e x c

lu s

io n c o

lu

m

n

)

.

A

c o n sta n

t f lo

w

r ate o

f 1 m l/ m in o

f 1

%

p h

o s

p h

o r

ic a c

id w

a s u s e

d t

o

d

e

t

e r

m in e

t h

e

p

o ta s s

i

u

m b

r o

m

a te

c o n c e ntr at

io n s

.

T h

e r e s u

l

ts o

f

t

h

e s e a n a

ly

s e s a r e s

h

o

w

n

i

n

T

a

b le

1

.

A N IM A L S

F 3 4 4 m

a

le r a

t

s

2 1 d

a

y

s o

l d

,

w

e r e

p

u r c

h

a s e

d f

r o

m C h

a r

le s

R iv e r

L

a

b

o r a

t

o r

i

e s

(

P

o rta

g

e ,

M l

)

a n

d

a c c

l im

a

t

e

d f

o r

7 d

a

y

s.

2 8 d

a

y

o

ld

r ats

w

e r e r a n

d

o

m ly d i

v

id

e

d i

nto t

h

r e e e x

p

o s u r e

g

r o u

p

s .

T h

e

r a

t

s

w

e r e

h

o u s e

d 2

o r

3

p

e r c a

g

e

in

p

o

ly

c a r

b

o n ate c a

g

e s .

T h

e

a n

im

a

l

s

h

a

d

a c c e s s

t

o

P

u r

in a

R

o

d

e nt c

h

ow a n

d w

a te r a

d l ib i

tu

m

.

A

n

i m

a

ls

w

e r e

w

e

ig h

e

d

o n c e a

w

e e

k

a n

d

at

t h

e t

i m

e o

f

e ut

h

a n a s

ia

.

T

h

e r o o

m

s

w

e r e

m

a

in

t

a

i

n e

d

o n a

l i

g

h t/

d

a r

k

c

y

c

le o

f 1 2

/

1 2 h

o u r s .

T h

e te

m p

e r atu r e a n

d h

u

m i d ity w i

t

h i

n

t h

e a n

im

a

l f

a c

i li

t

ie s

w

e r e

m

a

i

nta

in e

d

at

2 0

-

2 2

°

C

a n

d 4 0

-

6 0

%

, r e s

p

e c

t iv e

ly

.

N E

C

R

O

P

S

Y

F

o r n e c r o

p

s

y

, r a

t

s

w

e r e e u

t h

a n

i

z e

d b

y

c a r

b

o n

d i

o x

id

e

(20)

lu n

g

,

k id

n e

y

, t

h y

r o

id

, a n

d

te st

is

w

e r e r e

m

o v e

d

,

w

e

ig h

e

d

, a n

d f ix

e

d

in

1 0

%

n e utr a

l b

u

ff

e r e

d f

o r

m

a

l in

.

H I

S

T

O

T E

C

H N

O

L

O G

Y

T h

e

f ix e

d t is s u e s

w

e r e

p

r o c e s s e

d th

r o u

g h

a sta n

d

a r

d

s e r

ie s

o

f d

e

h y d

r at

io n

f

o r

p

a r a

ff i

n e

m b

e

d d in

g

a n

d

s e ct

io n e

d

a t

5 |

j

m

.

T h

e

s e ct

io n s

w

e r e sta

in e

d

w

i

t

h h

e

m

oto x

y l i

n a n

d

e o s

in

b y

sta n

d

a r

d

h is

to

lo

g i

c te c

h

n

iq

u e

f

o r e a s

y

o

b

s e r v at

i

o n s u n

d

e r a

l ig h

t

m ic r o s c o

p

e

[

A p p

e n

d i

x

A

]

.

C E L L P R O L IF E R A T IO N

T h

e

Z y m

e

d In c

.

b

r o

m

o

d

e o x

y

u r

id i

n e

(

B

rd U

)

s

t

a

in

in

g

k i

t

w

a s

u s e

d

to

d

e

t

e r

m i

n e

t h

e

B

r

d U l

a

b

e

l in

g

a s r e c o

m m

e n

d

e

d b y

G

a

lb i

o c

h

e

m In c

.

(

S

a n

D ie

g

o

,

C A

)

.

St

a

in

in

g

w

a s

p

r e c e

d

e

d b y

a n

t i g

e n r etr

ie v a

l w it h h

e a

t

(

9 5

°

C

)

fo r

2 0 m i

n ute s a n

d

r

i

n s

in

g

w

i

t

h

p h

o s

p h

a

t

e

b

u

f f

e r e

d

s a

l in e

.

I

n o r

d

e r to

m

e a s u r e t

h

e n u

m b

e r o

f

c e

l ls

a ct

iv e

l

y p

r o

lif

e r a

t in

g

,

p

r o

l if

e r a t

in

g

c e

l l

n u c

le a r a n

t ig

e n

(

P

C

N A

)

w

a s

m

e a s u r e

d

u s

i

n

g

th

e

P

C

1 0

a nt

ib

o

d

y

a s r e c o

m m

e n

d

e

d b y

G

a

lb i

o c

h

e

m In c

.

S

e c

t io n s o

f t

o n s

il w

e r e u s e

d

a s a

p

o s

i

t

iv e c o n

tr o

l

[

A

p

p

e n

d ix

F

]

.

A P

O

P T

O S

I

S

A p

o

p

t

o s

is

w

a s

d

e

t

e r

m i

n e

d b

y

t h

e

T

U

N E L p

r o c e

d

u r e a s

d

e s c r

i b

e

d

b y G

a v r

ie

l

i

, e

t

a

l

.

w

i

t h m

o

d

if i

c a

t io n

.

[

A p p

e n

d ix

G

] (

12

)

.

T h y

r o

id

s,

liv e r s

, a n

d k id

n e

y

s

w

e r e c ut

in

to 5

p m

s e ct

io n s a n

d

m

o u n

t

e

d

o n

P

r o

b

e

O

n

P l

u s s

l

id

e s

(

F is

h

e r

B io

t

e c

h In c

.

)

.

T h

e

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