1496.pdf

T

A B

L

E O

F

C O N T E N T S

C h

ap

t

e r

P

age

#

A bstract

Ackn ow led ge

m

e nts

L ist of F i gu r e s i i

List of Tab le s iv

1. Intr odu ctio n

1 1 V in_yl A c etate 1

1.2 H y pothe sis 2

1 3 Ov erview of Pr o

_j

e ct 3

2. Back ground

2 1 Ge n eral To xicit_{y D}ata 4

2 1 1 Ge n etic E f fe cts 6

2.1.2 Car cin ogenicit y 8

2 2 Cu rr ent

M

odels 1 0

2.3

M

etabol is

m

Info r

m

atio n 1 4

2.4 A bs o rptio n of Vapo r s

-A_{n a}t_o

m

y a nd P h ysic al Pr o_pe rtie s 1 6

2 5 P B P K 1 8

3.

M

aterials a nd

M

ethods

3 1 Ex_pos u r e Infor

m

atio n _{2 0}

3 2

M

odel Design an_{d D}e velo_p

m

e nt 2 3

3 3

M

o del Variab le s 26

3.4

M

odel Para

m

ete r s 2 8

3 5 PB P K

M

odel Rate E qu atio n s _{3 0}

3.6

M

A T L AB

™

M

odel a nd Progr a

m m

ing 3 1

4 Re s ults

4 1

M

A T L A B

™

Re s ults 3 6

4 2 D is c u s sio n _{4 4}

4 3 S

M

U S H T / G L O B A L 8 6 4 5

5 Co n clusio n

5.1 Conclu sio n s 4 7

6 Refer en ce s

A B S T

R A

C T

K

a r

i

n F . Ba r o n .

A C

an c e r

R i

s

k A

s s e s s

m

e nt o

f L

o

w L

e v e

l V i

ny

l A

c etate

E

x

p

o s u r e

U

ti l iz

i

n

_g

a

P h y

s

i

o

lo

_{g i}

c a

l l

_{y B}ase

d P h

a r

m

a c o

k i

n et

ic

(

PB P

K

_{) M}

o

d

e

l

V i

n _y

l

a c etate

(

V A

)

i

s

w i d

e

l

_y u s ed

i

n t

h

e che

m i

c al

i

n

d

u str_{y f}o r the

m

anu

f

a ctu r

in

_g

o

f

_po

l

_yv

in

_y

l

a c etate e

m

u

l

s

i

o n s, c opo

l

y

m

e r s

w i

th et h y

l

ene

f

o r a

d

he s

iv e s

, an

d

pa

p

e r

c o at

in

_gs. T he Inte r n at

i

o n a

l A

ge n cy

f

o r Re s e a r c

h

o n

C

a n c e r

(

L

\ R C

)

h

a s c

l

a s s

i fi

e

d

v

in

y

l

a c etate a s a _po s s

i b le

h

u

m

a n c a r c

i

no_ge n

(

l A

R C

, 1 9 9 5

)

. T he r e

is s u

f

fi cie nt e v

i d

e n c e in t

h

e

l i

te r atu r e to

in

d i

c ate t

h

e c a r c

i

n o_ge n

ic

_pote ntia

l

to r ats e x _po s ed

b

_y

i

n

h

alatio n to v

_in

_{y l}

a c etate _T

h

e r e

i

s

l i

m

it

e

d

e_p

i d

e

m

i

o

lo

_g

i

c a

l d

ata to s u

_p

_po r_t a

_p

o s s

ib l

e e x c e s s r

i

s

k f

o r c anc e r

o

f

t

h

e r e s_p

ir a

to r_y s_yste

m

w i

t

h l

o n

_g

-t_{e r}

m

_{e x}

p

o s u r e to

i

n

d

u str

i

a

l w

o r

k

e r s. In o r

d

e r to

e sti m ate

m

o r e c

lo s e

l y t

h

e ris

k

at c u r r e nt o c c u_pat

io n a

l l

e v e

l

s, a p

h

ys

i

olog

i

c al l y

b

a s e

d

p h

a r

m

a c o

k i

net

i

c

₍

P B

PK

₎

m

o

d

e

l w

as c o n str u cte

d

_to

_p

r e

d ic

t

h

u

m

a n ta r

_g

et t

i

s s u e

c o n c e ntr atio n s at

_{p l}

a u s

i b l

e

i

n

d

u str

ia

_l

e x

_p

o s u r e s. T

h

e s e c o n c e ntr at

io n s

w

e r e t

h

e n

c

h

a r a cte r

i

z e

d

a n

d

c o

m

_pa r e

d

to t

i

s s u e le v e

ls c o r r e s

_po n

d in

_{g t}o

d

o s e s

k

no

w

n to

b

e

tu

m

o u ri ge n

i

c

in

a n

i

m

als to a r r

i

v e at an e st

i m

at

i

o n o

f h

u

m

an c a n c e r r

i

s

k

.

T h

e

m

o

d

e

l

de

m

o n str ated t

h

at

d

a

i l

_{y l}o

w le v e

l e x_po s u r e s to vin_y

l

a c etate _po s e a

m

i

n

i m

a

l

thr e at o

f

A

c

k

n o

w l

e

d g

e

m

e n

t

s

I

w

o ul d l i ke to tha nk

D

r . Lo u

i

s e

M

. B al l

f

o r

h

e r pe r s onal

i

nte r e st,

p

at

i

e nce an

d

g

u

i d

anc e du r

i

n_g

m

_y stu

d y

o

f

Env

i

r on

m

e n ta

l S

c

i

e n c e s an

d

En

_{g i}

n e e r

i

n

_g

.

I

a

m

a

l

s o

gr ate

f

ul to Dr Pa r

k

e r

K

. Re

i

st a n

d

Dr . E

l

a

i

n a

M

.

K

e nyo n

f

o r t

h

e

i

r

p

o s

it

i

v e c r

i

t

i

c

i

s

m

an

d

s u_{p p}o rt

d

u r

i

n_{g t}

h

e _pr e_pa r at

i

o n o

f

th is te c

h

n

i

c al r e_po r_t

A

s_pe c

i

a

l

n ote o

f

t

h

a n

k

s to

M

i

c

h

a e

l

Ea ste r

l i

n_g

f

o r

h i

s a s s

i

stan c e

w i

t

h

M

A

T

L

A B

™

.

I e s_pe c

i

a

l

l y a

_p

_pr e c

i

ate

m

_y

f

a

m

i l

_y

f

o r t

h

e

i

r

l

o v

i

n

_g

su_{p p}o rt

d

u r

i

n_{g t}

h

e t_{y p}

in

_g

a n

d

r e-t y p

i

_n

g

a n

d

r e-_{r e}

-t y p

i

n_g o

f

t

h i

s te c

h

n

i

c al r e_po rt

I

w

o ul d l i

k

e to a ckno

w l

e

d

_ge Re

i

c

h h

o

l d

, hi c. fo r the o

p

po r tu n

i

t y t

h

ey pr o v

i d

e

d m

e

w h i

ch

m

ade th is _pr o

j

e ct a n d

m

_y edu c at

i

o n

i

n Env

i

r o n

m

e nta

l S

c

i

e n c e s a n

d

En _g

i

n e e r

i

n _g

11

L i

s

t

o

f F i g

u r e s

F i g

u r e s

_p

a

_g

e

#

F i gu r e 1:

M

o rri s et al

M

odel D e s cri b in_g the U ptake a nd

M

etabol is

m

of No n-_{r e a c}ti_{v e} V_a pors in

F 3 4 4 Rats 7

F i gur e 2:Plowchal k et al.

M

odel Des cri b ing the U ptake a nd

M

etabol is

m

of V A thr o ug h the Rat

N a s al Ca vit y 8

F i gur e 3:Frede rick eta l

M

odel De s cn be s_{U p}take a nd

M

etabol is

m

of Aci d ic Va_po r s in Rats a nd

Hu

m

an s 9

F_{i g}ure 4:B o_{g d}a nf f_y etal

M

odel De s cri b in_g the U ptake a nd

M

etabol is

m

of V A in the Rat and

Hu

m

a n Na s al Ca vitie s 1 0

F i gur e 5;Des c ri be sthe Hydro_{l y}sis Re a ctio n of V A that Re s ults in the For

m

atio n of A

A

l d h a nd

A A 1 1

F i gure 6:Exhalatio n of Ac etal deh y de in T wo Ex_peri

m

e nts 12

F i gu r e 7:T

h

e

A

r ch i te ctu r al D

i f

fe r e n c e s Bet

w

e e n t

h

e Rat a n

d H

u

m

a n

N

a s a

l C

a v

i

t

ie s a

n

d

A

n

O

v e r a

l

l P

ic

tu r e o

f

t

h

e

A

nato

m

_y o

f

t

h

e Hu

m

an

R

e s_p

i

r ato r _y

S

_yste

m

1 4

F i gur e 8:P B P

K

M

o

d

e

l

De s c

ri b i

n _{g t}

h

e V

A U

_{p t}a

k

e a n

d

M

eta

b

o

l i

s

m

in

H

u

m

a n s

2 2

F i gure 9:A

m

o u nt in T is s u e s v s T i

m

e

₍

1p p

m

Do s e a n_{d 1 0 p p}

m

Do s e

₎

3 3

F i gure 10: Co n centr atio n in T is s u e s v s T ime at _{1 p p}

m

Do s e 3 5

F i gu r e 11: Co nc entr ation in T iss ue s vs T i

m

e at 10 pp

m

3 5

I l l

F i

gu r e s p a ge

#

F i_gu r e 1 3: Co n c e ntr atio n s in T is s ues vs. T ime at 1pp

m

Do s e w ith L i g ht Activity 3 7

F i gu r e 1 4: Co n c e ntr atio n Exhaled v s. T i

m

e at 1

pp

m

Do s e 3 9

F i gu r e 1 5: Co n c e ntr atio n Exhaled v s T i

m

e at _{10 p p}

m

Do s e 3 9

F i gu r e 1 6: Co n c e ntr atio n Exhaled v s T i

m

e at _{1 p p}

m

Do s e w it_{h L i g h}t Activi_{t y} 3 9

F igur e 1 7:T otal A

m

o u nt

M

etabohz ed v s. T ime at 1 p p

m

Do s e 4 0

F _{i g}u r e 1 8: Total A

m

o u nt

M

etabo l ized vs. T ime at 10 pp

m

Do s e 4 0

F i gu r e 1 9:T otal A

m

o u nt

M

etabol iz ed v s. T i

m

e at 1 p p

m

Do s e w ith L i g ht Activit y

I V

L

i

st o

f

T

a

b l

es

T

a

b l

e s

_p

age

#

Tab le 1: Re s ults fro

m

Br e ath in_{g Z}o n e Sa

m

_{p l}e s for In_du strial

W

o rke rs in T hr e e

M

a n ufa ctu rin_g

S ite s _Usin_{g V A} 19

Tab le 2; A

m

ou n_t of V A in Ea ch T is su e Co

m

_pa rtme nt at _{1 p p}

m

Do s e 3 4

Tab le 3: A

m

o u nt of V A in Ea ch T is s u e Co

m

_pa rtme nt at 10 p p

m

Do s e 3 4

T ab le 4: Co n c e ntr atio n of V A in Ea ch T is s u e Co

m

_pa rtme nt at _{1 p p}

m

Do se 3 6

Tab le 5: Co n c e ntr atio n of V A in Ea ch T is s u e Co

m

_pa rtme nt at _{1 0 p p}

m

Do s e 3 6

Tab le 6: A mo u nt o f V A in Each T is su e Co

m

_partment at 1 p p

m

Do s e w ith L i g ht Activit_y

3 8

Tab le 7: Co n c e ntratio n of V A in Ea ch T is s u e Co

m

_partme nt at _{1 pp}

m

Do s e w it_{h L i g h}t Activi_{t y} 3 8

1

.

I

n

t

r o

d

u c

t

i

o n

1.1

V

iny l

A

c etate

T

h

e Inte

rn

atio n a

l A

_ge n c_y

f

o r Re s e a r c

h

o n

_C

a n c e r

₍

l

_{A R C}

₎

h

a s c

la s s

i fi

e

d

v

in

_y

l

a c etate

(

V A

)

a s a

_p

o s s

i b

le hu

m

an c a r c

i

n o

_g

e n

(

l

A R C

, 1 9 9 1

)

.

V i

n y

l

a c etate

i

s a c

le a r

, c o

lo r

le s s

l i

_qu

i d

,

w i

t

h

a s

w

e et

f h

i

i

t

l i k

e o

d

o r

V A i

s

w i d

e

l

y u s e

d i

n the c

h

e

m ic a

l i

n

d

u str

y

f

o r t

h

e

m

an u

f

a ctu r

in

_g o

f

_pol yv

i

n_y

l

a c etate e

m

u

ls

io n s

, c opo

l

y

m

e r s

w i

t

h

ethy

le n e

f

o r

a

dh

e s

iv e s

, a n

d

pape r c o at

i

n gs. T

h

e r e

is n o

e v

i d

e n c e t

h

at v

in

y l a c etate e x

is

ts

i

n n atu r e.

Sh

o rt-_{te r}

m h

_{i u n a n}

i

_n

h

_a

la

_t

io n

_{e x}

po s u r e

i

s

d

o c u

m

en te

d

a s _pr o

du c

i

n _g

m

i l d

to s e v e r e u_{p p}e r r e s_p

i

r ato r_y

ir r

i

tat

i

o n . V

i

ny

l

a c etate

i

s n ot

d

o c u

m

e nte

d

a s c a u s

i

n g a

d

v e r s e

h

u

m

a n

r e_pr o

d

u ct

i

v e o r

d

e v e

lo

_p

m

e nta

l

e

f f

e cts. T

h

e r e

i

s

l i m it

e

d

ep

i d

e

m i

o

lo

g

ic a

l d

ata t

h

at

i

n

d ic a

te s a _po s s

i b le e x c e s s r

i

s

k f

o r c an c e r o

f

t

h

e r e s_p

i

r ato r_y s_yste

m

w i

th lo n_g-_{te r}

_m

e x _po sur e to

i

n

d

u str

i

a

l w

o r

k

e r s. L o ng -_t

e r

m

in

h

a

l

at

i

o n stu

_{d i}

e s

i

n r ats

h

a v e s

h

o

w

n the

d

e v e

lo

_p

m

e nt o

f

n e o_p

l

a st

i

c a n

d

n o n-_{n e o}

p

l

a st

i

c

l

e s

io

n s, e spe c

i

a

l l

y

i

n the o

l f

a cto ry r eg

i

o n, at

d

o s e

l

e v e

l

s o

f 2 0

0 an

d 6 0 0

_{p p}

m

₍

B

o

_{g d}

a n

f f

_y et a

l

, 19 94a

)

.

T h

e r e

i

s s u

f f

i c

i

e nt e v

i d

e n c e

i

n t

h

e

l i

te r atu r e to

i

n

d i

c ate the c a r c

in o

_ge n

i

c _pote nt

i

a

l

to r ats e x

_p

o s e

d b

_y

in

h

a

l

at

i

o n to

v

i

n_y

l

a c etate.

V i

n _y

l

a c etate

i

s r e a

d i l

_y

h

_y

dr o

l

_yz e

d i

n the

b lo o

d

.

H

y

d

r o

l

ys

i

s o

f

v

i

n y

l

a c etate

y

i

e

l d

s a c et

ic a c

i d

(

A

A

)

a n

d

v

i

n_y

l

a

lc o

h

o

l

,

w h i

c

h

ta uto

m

e r

i

z e s to a c eta

l d

e

h

y

d

e

(

A A l d h

)

.

T h i

s

h

_y

d

r o

l

_ys

i

s

i

s r a_p

i d b

_y c ata

l

_ys

i

s

in

r at l

iv e r a n

d l

u n_g

m i

c r o s o

m

e s

b

_y e ste r a s e s,

e s_pe cial l

_y

c a rbo x_{y l} e ste r a s e a n

d

a c et_{y l}chol in e e ste r a s e

(

S i

m

o n et al, 1 9

8

5

)

.

A

c eta

l d

e

h

_y

d

e

h

a s

b

e en s u_{g g}e ste

_d

to

b

e t

h

e c a r c

i

no _ge n

ic

m

eta

b

o

l i

te o

f

v

i

n _y

l

a c etate

(

P lo

w

c

h

a

lk

et a

l,

1 9 9 7

)

.

A

c etal

d

eh y

d

e

h

a s

b

e e n s

h

o

w

n to

b

e a c

l

a stoge n

w h

e r e a s a c etic

a c

i d i

s

k

no

w

n to

b

e a c_{y t}otox

i

n ,

h

e n c e t

h

e s e

m

eta

b

o

l i

te s a r e t

h

o u

g h

t to a c c o u nt

f

o r t

h

e

c

la s

to_ge n

ic

an

d

c_ytoto x

ic e

f f

e cts r e s

_p

e ct

i

v e

l y

, a s s o c

i

ate

d w it

h

v

i

ny

l

a c etate.

A

c eta

l d

e

h

_y

d

e

is

t

h

e _pr

i m

a r

_{y m}

eta

b

o

l i

te

f

o r

m

a n _y ot

h

e r s u

b

sta n c e s,

i

n c

lu

d i

ng et

h

a n o

l

. T he r e

i

s a n a

b

u nda n c e o

f

hu

m

a n

d

ata

d

e

m

o n str at

in

_{g t}

h

e c a r c

_{in o}

_g

en

i

c _pote n_t

_i

a

l

o

f

etha n o

l

1.2

H

y pothe sis

Kn o

w i

n_{g t}

h

at v

i

n_y

l

a c etate

i

s r e a

d i l

_y

m

eta

b

o

l i

z e

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nto a c et

i

c a c

i d

a n

d

a c eta

l d

e

h

_y

_d

e_, a n

d

t

h

at a c eta

l d

e

h

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d

e

i

n

d

u c e s n a s a

l

tu

m

o r s

i

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h i

_g

h l

e v e

l

s o

f

e x _po s u r e-

7 5 0

p p

m

an

d

_gr e ate r

_(M

o r r

i

s et a

l

, 1

9

9 3

)

,

w

e

h

y pot

h

e s

i

z e

d

t hat

l

o

w

le v e

l

v

i

ny

l

a c etate e x _po s u r e

w i l l

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e

l d

a s u

f f

i c

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e nt a

m

o un t o

f

a c etal

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eh y de to c a u s e

i

n c r e a s e

d

c a n c e r r

i

sk to

h

u

m

a n u_{p p}e r r e s_{p i}r ato r_y s_yste

m

s.

W

e

w i l

l als o e x a

m

i

n e t

h

e s

i

te o

f

a ct

i

o n

f

o r V

A

a c c u

m

u

l

at

i

o n

i

n t

i

s s u e s. T

h

e

e_p

i d

e

m i

o

l

o_g

i

c al

d

ata te n

d

s to

i

n

d i

c ate t

w

o _pote nt

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al s

i

te s o

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o n, t

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lo o

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w

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i

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l

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m

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ata

i

n

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c ate a t

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te, t

h

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t y.

To te st t

h i

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h

_{y p}ot

h

e s

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s a _p

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l

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l l

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a s e

d

_p

h

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m

a c o

k i

n et

i

c

₍

P B P

K

₎

m

o

d

e

l

w i l l b

e

m

o

d i f

i e

d fr

o

m

e x

i

st

i

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l i

te r atu r e. T

h

e

m

o

d

e

l w i l l

e x a

m

i

n e a

l l

t

h

r e e pote nt

i

a

l

s

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te s

o

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z

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o r

m

at

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on

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n t

h

e

l i

te r atu r e a n

d

a ctu a

l d

ata

f

r o

m

e x _po s e

d w

o r

k

e r s.

T

h

e

m

o

d

e

l w i l l

a

l

s o e x a

m i

n e

d i f f

e r e nt

d

o s

i

n_g s c

h

e

m

e s a s

w

el l a s

b i

o

l

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i

c a

l

v a r

i

at

i

o n s

s u c

h

a s

b

r e at

h i

n _g r ate s. T

h

e r e s u

l

ts

fr

o

m

t

h

e

m

o

d

e

l w i l l b

e

i

nput to a s s e s s v

i

n y

l

a c etate

1.3

O

v e r vie

w

of Pr o

j

e c t

T

h

e e x

_p

o s u r e

d

ata

w

a s c o

l l

e cte

d fr

o

m 19 9

7 to 2 0 0 0 at t

hr e e

in

d

u str

i

a

l

m

anu

f

a ctu r

i

n _g s

i

te s, s

it

e s

A

, B , a n

d C

. T

h

o s e s

i

te s

w

e r e

i

n v o

lv e

d i

n

d i f f

e r e nt a spe cts o

f

a

d

he s

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a n

d

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in

_gs a_{p p}

l i

c at

i

o n s ut

il

i

z

i

n _g v

in

_y

l

a c etate. Ea ch s

it

e e

m

p

l

oye e

w

a s

m

o n

it

o r e

d f

o r a

_p

_pr o x

i

m

ate

l

_{y 6}-8

h

_{ou r s}

, pe r

f

o r

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n

g

a v e r age

d

a

i

l y ta s

k

s, u s

i

n

g

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in

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m

ono

m

e r a n

d

v

i

n_{y l} a c etate

_p

ol y

m

e r s.

B

o_g

d

a n

f f

_y et a

l

,

19

9 9,

M

o r r

i

s et a

l

,

19 9

3 a n

d Si m

o n et a

l

,

19 8

5,

h

a v e

do c u

m

e nte

d m

eta

b

ol

i

s

m

a nd tis s u e

d

o s e r e s_po n s e s fo r

V A

, a n

d

t

h i

s

in

fo r

m

at

io n

w i l l b

e

u s e

d

to e sta

b l i

sh a

w

hole

b

o

d

_y

m

o

d

e

l

s_yste

m

. Esta

b l i

s

h i

ng a

w

o r k

in

g

m

o

d

e

l

, s u c

h

a s a p h

y

siolo_g

i

c a

l l

_y

b

a s ed p ha r

_m

a c o

k i

n et

ic

m

odel

(

P B P

K

)

,

f

o r v

in

y

l

a c etate

w i l l l i

n

k

t

h

e

k

no

w

n hu

m

a n a n

d

an

i

m

al e x_po s

m

e

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ata

w i

t

h

the a v a

i l

a

b l

e _p

h

_ys

i

o

lo

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l

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m

ete r s to

e st

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ate the a ctu a

l

c a n c e r r

is

k

o

f i

n

h

a

l

e

d

v

in

_y

l

a c etate.

T

h

e

B

o _g

d

a n

f f

_y et a

_l

,

19 9 9

,

P

B P

K m

o

d

e

l d

e v e

l

o

p

e

d

u s

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n g e

l

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m

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fr

o

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pr e v

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h

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in

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at

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n

m

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d

r ats a n

d

m

o

d

e

l i

n _g

d

ata

fr

o

m

Fr e

d

e r

ic

k

et a

l

, 19 9 8, to a s s e s s v

in

_y

l

a c etate

in

d

u c e

d

n e o

_{p l}

a st

i

c a n

d

n o n-_{n e o}

p

l

a st

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m

o r s

i

n t

h

e o

l f

a cto r_y

r e_g

io n

o

f

r ats a n

d m

a n .

T h

e Bo g

d

a n

f f

y et a

l

,

19 9 9

,

m

o

d

e

l

e sti

m

ate s e x

p

o s u r e to v

i

n

y l

a c etate

i

n

h

u

m

a n n a s a

l

a n ato

m

_y

w h i l

e Fr e

d

e

ri

c

k

et al, 199 8,

m

o

d

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le

d fr

il l

b

o

d

y e xpo sur e to a c

i d i

c v a_po r s. E

l

e

m

e nts

fr

o

m

the

m

o

d

e

l

s

d

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l

ope

d b

y o

f

Bog

d

a n

f f

y et a

l

_, 1 9 9 9, a n

d

Fr e

d

e

ri

c

k

et a

l

, 19 9 8, a s

w

e

l l

a s P

l

o

w

c

h

a

l k

et a

l

, 1

99

7 a n

d

M

o r

ri

s et a

l

,

19 9 3

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w i l l b

e

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o

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e

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to

d

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le

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an

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z e

d w i

th a ctu a

l

e x_po s u r e

d

ata to

2

.

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a c

k g

r o u n

d

2. 1

G

e n e r al T o x ic

i

t y D ata

V i

n_{y l} a c etate

i

s

d

o c u

m

e n te

d

a s

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ir r

i

ta nt at

l

e v els a

b

o v e t

h

e

A m

e r

i

c a n

C

o n

f

e r e n c e o

f G

o v e r n

m

e nta

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In

d

u str

i

a

l

H y g

i

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ts

(

A C G

I

H

₎

r e c o

m

m

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r e s

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o

l d l i m i

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1 0

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i

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te

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p i

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i

r r

i

tat

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s r e

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d

to o c c u r at t

h

e 1

0

to

2 0 p p m l

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l f

o r

h

u

m

a n s

(

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d Jo

_yn e r,

19 6 9

₎

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h

e o

d

o r t

hr e s

h

o

l d f

o r

h

u

m

a n s

i

s 5

p p

m

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le s s

d

e

p

e n

d i

n

g

upo n t

h

e

in

d i

v

i d

u a

l

.

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a cto r_y

f

at

i

_gu e

is r e

_po rte

d

to o c c u r

in

a

m

at te r o

f

m

i

nute s at

2 0

_{p p}

m

.

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i

n_y

l

a c etate

i

s n ot c o n s

i d

e r e

d

to

b

e a s e r

i

o u s s

k in

i

r r

i

ta nt, n o r

i

s

i

t t

h

o ug

h

t to

i

ndu c e

d

e r

m

at

it

i

s.

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t

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g

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t

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m

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m

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d

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m

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in

w i

t

h b l i

ste r fo r

m

at

i

o n a nd

b

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i

n_g o

f

the c o r n e a

(

G

r a nt, 1 9 8 6

)

.

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i

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i

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u r

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e s t

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o u _g

h

, a r e tho ug h t to

b

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a

b l

e w

i

th pr o

m

pt

f l

u s

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f f

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x_po s u r e o

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o_gs

f

o r

6 h

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d

a_y

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11 w

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ls

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f 9

_{1 p p}

m

- _{1 8}

6

p p

m

(

A C G

I

H

, 1 9 9 1.

)

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i

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h i b it

s

m

o

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m i

c to x

i

c

i

t y.

"

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d

to 2

0

0 0

p p

m

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d

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r e s

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r ato r_y

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l

t y a n

d h

a

d

r e

du c e

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o

d

_y

w

e

i g h

t ga

i

n .

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t a uto

p

sy

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la r

ge n u

m b

e r s o

f

m

a c r op

h

a

g

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w

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i

n t

h

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l

u n

g

"

(

l

A R C

,

1 9 9 5

₎

Fo u r-

h

o u r e x_po s u r e s to a 4 0 0 0 p

_p

m

at

m

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r o

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%

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₍

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C

_{s o}

₎

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f

o r

m

ic e e x

po s ed fo r 4 ho u r s

i

s 1 5 5 0 p p

m

a n

d f

o r r a

b b i

ts e x_po s e

d f

o r

f

o u r

h

o u r s

i

s 2

5

0 0 p p

m

Re_pe ate

d i

n

h

a

la

t

io n

e x_po s u r e o

f

r ats to 1

0

0 p p

m

f

o r 6

h

r s

/ d

a_y, 5

d

ays

/

we e

k f

o r

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e e

k

s pr o

d

u c e

d

n o s

i

gn o

f

a

d

v e r s e e

f f

e cts

(

A C G

I

H

, 1 9 9 1

)

.

O

r a

l

to x

ic

i

t y stu

d i

e s

i

n

b

ot

h

r ats a n

d m i

c e s e e

m

to

in

d ic a

te a

l

o

w

to x

ic

e

f f

e ct.

Do s

i

n_g e x_pe r

i m

e nts u s

in

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h

at r e c e

iv e

d

v

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l

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i

n

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r

in

k i

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w

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c o n centr at

io n s r a n

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n _g

f

r o

m

2

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p

m

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n

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m

_pt

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h i gh

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d

o s e

₍

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d

a n

f f

_y et a

l

, 1

9

9 4

b

)

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te e n

w

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k

o

l d m ic e r e c e

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in

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10 0 0

-

2 0 0 0

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b

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f

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V A

in r ats

b

_{y g}a v a_ge

i

s a_{p p}r o x

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m

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l

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/k

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u

d

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, 1 9 8 9

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d i

n

m i

c e

i

s 1.

6

1 g / k g

(

A C G

I

H

, 1 9 9 1

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i m

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l d

ata

i

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e

m

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n o o

b

s e r v a

b l

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l

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l

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l

to x

i

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t_y

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d

rink in_g

w

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l

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s u_{p t}o 5 0 0 0 p p

m

,

b

ut

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n

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a

l

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o n o

f

1 0 0 0

p

p

m

d i d

a_{p p}e a r to r eta r

d

e

m

br_yo n

i

c _gr o

w

th a n

d i

n c r e a s e

m i

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k

eletal a

l

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i

o n s, s u c

h

a s

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l

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o n

(

H

u rt t et a

l

_, 1

9 9 5

₎

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M

u

l

t

i g

ene r at

i

o n a

l

stu

d i

e s

i

n r ats

f

a

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e

d

to

d

e

m

o n str ate a c o n s

i

ste nt ef

f

e ct o n r e_pr o

d

u ct

i

o n. V

i

ny

l

a c etate at

l

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l

s o

f

5 0

0

0 p

p m i

n

d

r

i

n

k i

n_g

w

ate r o

f

r ats,

d i d

a

l

te r s o

m

e r epr o

d

u ct

i

v e pa r a

m

ete r s, s u c

h

a s

f

e rt

i l i

ty a n

d

m

at

i

n _g,

b

ut t

h

e s e r e spo n s e s

w

e r e

i

n c o n s

i

ste nt a c r o s s a t

w

o ge n e r at

i

o n e x pe r

i

m

e nt

(M

e

b

u s

2

.

1

.1

G

e n et ic

E f f

e c ts

T

h

e e v

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e n c e c o

l l

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d b y l A R C

,

i

n

d i

c ate s t

h

at v

i

ny

l

a c etate c an

i

n

d

u c e D

N A

c r o s s-

_{l i}

n

k

s

i

n

i

s o

l

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u

m

an

l

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_p

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d i

n

i

s o

l

ate

d

r at n a s a

l

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h

e

h

a

l

c e

l l

s. T

h

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d

ie s in

d

ic atin_g the a

b

i l it_y o

f

v

i

n _{y l} a c etate to in

d

u c e siste r-_{chr o}

m

_at

i d

e x c

h

a n_ge

(

S C

E

)

at

l

e v e

l

s r an_g

i

n

_{g fr}

o

m

0.0 5

- _{2 4}

_m

_M

.

"

A

4

8 h

r tr e at

m

e nt

w i

t h v

i

n_y

l

a c etate

(

0.0 5

- l

m

M )

i

_n

d

_{u c e}

d

_a

d

_{r a s}t

i

c

i

n c r e a s e in siste r c

h

r o

m

at

i d

e x cha n

ge s and

₍

i

n

fi

r st

d i

v

i

s

i

o n c e

l l

s

)

str u ctu r al c

h

r o

m

o s o

m

e a

b

e r r at

i

o n s

i

n c u

l

tu r e

d

hu

m

a n l y

m

_p

h

o c_{y t}e s "

(

N

o r_{p p}a et a l, 1

9

8 5

)

.

N

o rp pa et a

l

a

l

s o o

b

s e r v e

d

s

i

m

i l

a r c

h

r o

m

o s o

m

e

d

a

m

age

w i

t

h

0

.

1

2 5

-2

m

M

tr e at

m

en t o

f

a c eta

l d

e_{h y}

d

e. V

i

n_y

l

a c etate

i

n

w h

o

l

e-

b l

_{o o}

d

_{c u}

l

tu r e s

pr o

d

u c e

d

a c

l

e a r

d

o s e

d

e_pe n

d

ent

i

n c r e a s e

i

n tota

l

c

h

r o

m

o s o

m

e a

b

e r r at

i

o n s.

T h

e s

i

ste r

-chr o

m

at

i d

e x c

h

a n _ge

fr

e_qu e n c_{y i}n c e

l l

s tr e ated

w i

t

h

v

i

n_y

l

a c eta_te

i

n c r e a s e

d l i

n e a r

l

_y

w i

th e x _po s u r e t

i m

e s u_{p t}o 2 4

h

o u r s. V

A i

s a

l

so

d

o c u

m

e nted a s

i

n

d

u c

i

n _g

S C

E, c

h

r o

m

o s o

m

al a

b

e r r at

i

o n s, a n

d m i

c r o n u c

l

e

i i

n

h

u

m

a n

w

hole b lo o

d

a n

d i

n

i

s o

l

ate

d l

_y

m p h

o c_{y t}e c u

l

tu r e s in vitr o

(M

a

k i

-_{Pa ak}

k

_{a n e n a n}

d N

_{o r}

p pa,

19 8

7

₎

.

S C

E

w

as

i

n

d

u c e

d i

n

C h i

n e s e

h

a

m

ste r o v a r_y c e

l l

s e x

_p

o s e

d

to v

i

n_y

l

a c etate

i

n

b

ot

h

t

h

e _pr e s enc e a n

d

a

b

s e n c e o

f m

eta

b

ol

i

c a ct

i

v at

i

o n.

"

A

l

t

h

o u

_gh

v

i

n

_{y l}

a c etate a_{p p}e a r s to a ct

a s a

di

r e ct

m

uta

_g

e n,

i

t

i

s

m

o st pr o

b

a

b

l y n ot a ct

i

v e a s s u ch, a s

i

t

i

s

k

n o

w

n to

b

e

h

_y

d

r o

l

_yz e

d

in viv o an

d i

n c u

l

tu r e

d

c e

l l

s to a c et

i

c a c

i d

an

d

a c eta

l d

e

h

_y

d

e

b

_y c a r

b

o x_y

l

e ste r a s e s"

(

S i

_p

i

et a

l

, 1

9 9

2

)

. T

h

o ug

h V A i

n

d

u c e s

S C

E, in vitr o po

i

nt

m

utat

i

o n a s s ays

a_{p p}e a r to

b

e n e_gat

i

v e.

Sim

i

la r ge n oto x

i

c ef fe cts

w

e r e o

b

s e r v e

d w i

t

h

a c etal

d

e

h

y

d

e. "

B e c a u s e s u c

h

e

f f

e cts

w

e r e a

l

s o

i

n

d

u c e

d b

_y a c eta

l d

e

h

_y

d

e,

i

t

h

a s

b

e e n s ug ge ste

d

t

h

at t

h

e

S C

E o

b

s e r v e

d w i

t

h

v

i

n_y

l

a c etate c o u

l d b

e e

l i

c

i

te

d b

_y a c eta

l d

e

h

_y

d

e a s

m

eta

b

o

l i

te"

(

Si m

o n

et a

l

, 1

9

8 5

)

. T

h

e

d

ata a

l

s o s u

g g

e sts t

h

at a c eta

l d

e

h

y

d

e

h

a s s

l

o

w

tu r n

-_{o v e r}

i

_n

h

_u

m

_an

l

_y

m

_{p h}o c_yte s in vitr o , an

d

m

ay a c c u

m

ulate

i

n c el

l

s an

d

g

i

ve r

i

s e to s

i

ste r

-chr o

m

at

i d

e x c

h

a n_ge a n

d

D

N A

c r o s s-

l i

_n

k

_s

(

H

_{e a n}

d

L _a

m b

_{e rt}

, 1

9

8 5

)

.

V

i

n_{y l} a c etate

f

a

i l

e

d

to

i

n

d

u c e

m

utat

i

o n s

i

n

S

a

l

mo n el

l

a t_{y p}

h

i mu r i m o r

S O S

r e_pa

i

r

f

u n ct

i

o n s

i

n Es c

h

e ric

h

ia c o

l

i

(

L

i

_j

i

n s

k

_y a n

d A

n

d

r e

w

s, 1

9

8 0

)

V

A d i d i

n

d

u c e D

N A p

r ote

i

n

c r o s s-

l i

_n

k

_s

i

_n

E

7

pr o

du c e

D

N A

a

d du c

ts

i

n t

h

e

l i

v e r s o

f

r ats e x_po s e

d

e

i

the r o r a

l l

_y o r

b

_y

in

h

a

l

at

i

o n

(

l A R C

,

8

2.1.2

C

a r cin o

g

e n

i

ci t y

T

h

e e v

i d

en c e

i

s c o ntr a

d ic

to r_y

i

n the

l i

te r atu r e a s to

w h

et

h

e r o r n ot v

i

n_y

l

a c etate

i

s

a

h

u

m

a n c a r c

in o

_gen. l

A R C d

o c u

m

en te

d

t

w

o ep

i d

e

m

io

lo g

i

c al stu d

i

e s, a c oho rt o

f

4 8 0

6

e x_po s ed

m

ale

w

o rke r s

in

t

h

e

U

n

i

te

d S

tate s

fr

o

m

1 9 4 8- 1 9 7 3 _{a n} d _{a c a s e}-_{c o ntr o}l _stu

d

y o

f

2 9,1 3 9 e xpo s e

d m

ale

w

o r

k

e r s

in

t

w

o s epa r ate

U

n

i

te

d S

tate s

m

a n u

f

a ctu

ri

ng s

i

te s

fr

o

m

1 9 4 0- _{1 9 7 8}

. In the c ohort stud y b y

W

a x

w

ei le r et al, 1 9 9 9 9 8 1, the de ath c e rti fi c ate s

in

d i

c ate

d

a n e x c e s s o

f l

u n_g c a n c e r

ri

s

k i

n t

h

e e x _po s e

d

_po_pu

l

at

i

o n

w h

en c o

m

_pa r e

d w i

t

h

n at

i

o n a

l

r ate s

₍

m

ort a

l i

t y r at

i

o o

f

1.5

)

.

T h

e c a s e

-_{c on}tr o

l

_st_u

d

y

b

y

O

t t et a

l

, r eport e

d

an

in c r e a s e

i

n

ri

s

k

o

f

e x _po s e

d w

o r

k

e r s to n o n -

H

_o

d g k i

_n '

s

l

_y

m

_p

h

o

m

a

(

o

d d

s r at

i

o,

1

.

2

)

,

m

u

l

t

i

_p

le

m

_y

l

e n o

m

a

(

o

d d

s r atio, 1.

6

)

a n

d l

y

m

p

h

at

i

c

l

e u

k

e

m

i

a

(

o

d d

s r at

io

,

1

.

8

)

.

V A

c an

not

b

e c o n s

i d

e r e

d

a s t he o n

l

_{y p}otent

i

al c a r c

i

n o_ge n

i

c a_ge nt

i

n t

h

e s e stu

d ie s

d

u e to t

w

o

c o n

f

o u n d

in

_{g f}

a cto r s :

m

u

l

t

i p l

e c

h

e

m ic a

ls

w

e r e

in v o

l

v e

d i

n

b

ot

h

m

anu

f

a ctu

ri

n

_g

s

i

te s a n

d

als o the a

m

o u nt o f v

in

_{y l} a c etate e x_po s u r e e a ch in

d i

v

i d

u a

l

r e c e

i

v e

d w

a s n ot dete r

m i

n e

d i

n

e

i

t

h

e r stu

d

_y.

C h

r o n

i

c

i

n

h

a

la

t

io

n stu

di

e s

i

n

m

i

c e

h

a v e

f

a

i l

e

d

to

d

e

m

o n str ate a

c a r c

in o

_ge n

i

c e

f f

e ct

(

Bo_g

d

an

f f

_y et a

l

, 1 9 9 4a

)

.

C hr o n

i

c

i

n

h

a

l

atio n e xpo s u r e to r ats

h

a v e

s

h

o

w

n , e spe c

i

a

l l

y at

h i

g

h d

o s e s, a c

l

e a r

f

o r

m

at

i

on o

f

n a s a

l

tu

m

o r s

(

B og

d

an

f f

y et a

l

,

1

9 9

4a

)

. Bo g

d

a n

f f

y et a

l

s u g ge sts "

f

a cto r s

in c

l

u

d in

_g r e_g

i

o n a

l

_part

i

t

io n

i

n_g o

f

v a_po r s

in

to

r e s

_{p i}

r ato r_y a n

d

o

l f

a cto r_{y t}

i

s s u e s, tis s u e s e n s

i

t

iv

i

t y, a n

d d i f fe r e n

tia

l

m

eta

b

o

l i

c c a

p

a c

i

t y. "

c o u

l d h

a v e at tri bute

d

to t

h

e

d i f f

e r e n c e s o

b

s e r v e

d b

et

w

e e n

m ic e a

n

d

r ats

w i

t

h

r e s_pe ct to

tu

m

o r

f

o r

m

at

io n

.

T he e vi

d

e n c e in

d

ic ate s t

h

at t

h

e _pote n t

ia

l c a r c

i

n o_ge n

ic c o

m

_po n e nt o

f

v

i

n_y

l

a c etate

i

s

i

ts

'

m

eta

b

o

l i

te, a c eta

l d

e

h

y

d

e

(

P

l

o

w

c

h

a

l k

et a

l

, 19 97

)

. T

h i

s c r e ate s a u n

i

qu e s c e n a

ri

o

f

o r e x_po s u r e

b

e c a u s e a c eta

l d

e

h

_y

d

e

h

a s

b

e e n

i

n

d i

c ate

d

a s t

h

e _poten t

i

a

l

c a r c

in o

_ge n

i

c

m

eta

b

o

l i

te of

m

a n_y othe r c o

m

_po u n

d

s

i

n c

l

u

d in

_g et

h

a n o

l

. T

h

e

m

o st c o n v

i

n c

in

g

e

_{p i d}

e

m i

o

l

o_g

ic a

l d

ata

f

o r et

h

a n o

l in

d

u c e

d

c a r c

in o

_ge n

i

c

i

t y

i

s

d

e

ri

v e

d fr

o

m i

n_ge st

io n

o

f

a

l

c o

h

o

l i

c

b

e v e r a_ge s a s a

m

o

d

e o

f

a ct

io n

(

l

A R C

, 19 8 8

)

. In

h

a

la

tio n

d

ata

fo r e

t

h

a n o

l

a r e

n ot r e a

d i l

_y a v a

i l

a

b l

e

i

n

h

u

m

a n s.

A

n

im

a

l

stu

d i

e s

h

a v e

i

n

d ic a

te

d

a

l

a c

k

o

f

e v

i d

e n c e

f

o r

alc ohol

in

du c e

d

c a n c e r.

A c eta

l d

e

h

_y

d

e

i

s a u

b i

_qu

i

to u s a

i

r _po

l l

uta nt r e s u

l

t

in

_g

f

r o

m

t

h

e c o

m b

u st

io n

o

f

wo o

d

o r toba c c o

(M

o r

ri

s et a

l

, 1 9 9

3

)

. I t

i

s c

la s s

i fi

e

d

a s a pr o

b

a

b l

e hu

m

a n c a r c

i

n o

U

.

S

. En v

i

r o n

m

e ntal Pr ote ctio n

A

ge n c y

(

E P

A

)

b

a s ed o n data

fr

o

m

r at a n

d

ha

m

ste r

i

n

h

a

l

at

i

o n stu

d i

e s. T

h

e

E

P

A

c o n s

i d

e r e

d

t

h

e

h

u

m

a n

d

ata o n t

h

e a c eta

l d

e

h

y

d

e to

b

e

i

n a

d

e

_q

u ate to esta

b l i

s

h i

t a s a

k

no

w

n

h

u

m

a n c a r c

i

n o_ge n.

C h

r o n

i

c aceta

l d

e

h

y

d

e

i

n

h

a

l

at

i

o n

stu

d i

e s

i

n r ats

d

e

m

o n str ate

d

t

h

e

f

o r

m

at

i

o n o

f

s_qu a

m

o u s c el l c a r c

i

n o

m

a s at

d

o s e le v e

l

s o

f

7 5 0 p p

m

a n

d h i g h

e r.

M

o r r

i

s et a

l d

e

m

o n str ate

d

t

h

at

d

o s e le v e

l

s

b

e

l

o

w

7 5 0 p p

m

d

i

d

n ot

r e s u l t

i

n s_qu a

m

o u s c el l c a r c

i

n o

m

a

f

o r

m

at

i

on. I t

i

s

i

m

po rtan t to n ote t

h

at ne a r

l

y al l

c a r c

i

n o_ge nic

i

t_y stud ie s o n a c etal de_{h y d}e ha v e ind ic ated the tu

m

o r fo r

m

atio n is _pri

m

a r_{i l y}

fo u nd

i

n the r at n a s al ol fa cto r_y

m

u c o s a. T h is is si gn

i f

i c a nt

w

he n c o n s

i

de r

i

n g an d

e st

i m

at

i

n_{g p}ote n t

i

al hu

m

a n c a n c e r risk,

b

e c a u s e r at n a s al p

h

ys

i

o log y

i

s v e ry d

i

f fe r e nt

fr

o

m

h

u

m

an u_p

_p

e r r e s_p

i

r ato r_{y p}

h

_ys

i

olo _{g y}. T

h

e s e

d i f f

e r e n c e s a r e

d i

s c u s s e

d i

n

gr e ate r

10

2 .2 Cu r r e nt

M

odels

In t

h

e c u r r e nt

l i

te r atu r e t

h

e r e a r e

f

o u r P B P

K b

a s e

d m

o

d

els t

h

at r e

_p

r e s en t t

h

e

u_pta

k

e a n

d m

etabol

i

s

m

o

f

v

i

n_y

l

a c etate o r s

i m i l

a r c o

m

_po u n

d

s.

O

f tho s e

f

o u r

m

o

d

els_,

o n

l

_y on e

i

s s c ale

d

to s

i

m

u

l

ate

h

u

m

a n n a s al c a v

i

t y e x_po s u r e to

V A

.

M

o r r

i

s et a_{l p}ub l

i

s

h

e

d

t

h

e

fi

r st P B P

K

m

odel fo r n a s al u_ptake an

d

m

eta

b

o

l i

s

m

o

f

n o n

-r e a ct iv e v a_po r s in 1 9 9 3

₍

s e e F i gu r e 1

₎

. T h is

m

o del

w

a s de v elo

ped fo r F 3 4 4 r ats a n d

"

i

n c o r_po r ate s n a s a

l

e n z _y

m

e

d i

str

i b

ut

i

o n a s

w

e

l

l a s n a s al a

i

r f

l

o

w p

at te r n s"

(M

o r r

i

s et a

l

,

1 9 9 3

₎

.

T h

e

m

o

d

e

l

a s s u

m

e s t wo a

i

r

f l

o

w p

atte r n s a c r o s s t

h

e n a s a

l

c a v

i

t y ; a

d

o r s a

l m

e

d i

a

l

f l

o

w

a n

d l

ate ra

l /

v e ntr a

l

a

i

r

fl

o

w

.

T h i

s

i

s

d

u e to e v

i d

e n c e

fi

-o

m

stu

di

e s

b y

M

o r

_g

an et. a

l

.

that de

m

o n str ate

d

"t he n a s al c a v

i

_{t y}

i

s n ot un

i f

o r

m

_{l y} v e nt i late

d

,

(

b

ut

)

r at he r,

i

n sp

i

r ato ry

a

i

r str e a

m

s fol lo

w

in a

d i

st

i

n ct a s_y

m

m

etr

i

c _pat te rn

w

h ic

h

n o

d

o u

b

t

i

n

f l

u e n c e s t

h

e r e_g

i

o n al

d

e

l i

v e r e

d d

o s e o

f i

n s_p

i

r e

d

a_ge n ts"

(M

o r r

i

s et a

l

_, 1

9

9 3

)

. T

h

e n a s a

l

c o

m

pa rt

m

e nt

i

s

d

i

v

i

de

d i

nto thr e e a r e a s. Ea c

h

a r e a

i

s

f

u rthe r d

i

v

i d

e

d i

nto equ a

l d

ept

h

sta c

k

s. Ea ch sta c

k

r e_pr e s e nts d

i f f

e r e nt c e

l l

t_{y p}e s c a_pa

b l

e o

f

v a r_y

i

n _g

d

e_gr e e s o

f m

eta

b

o

l i

s

m

. T he

m

u c o u s

i

s

r e

_p

r e s e nte

d b

_y o n e sta c

k

, t

w

o to

f

o u r sta c

k

s r epr e s ent t

h

e ep

i

t

h

e

l i

a

l

c e

l l

s an

d

t wo sta c

k

s

r e

_p

r e s e nt t

h

e su

b

m

u cos a

l

s

_p

a c e.

"

I

t

i

s a s s u

m

e

d

t

h

at t

h

e

m

u c o u s c o

m p

a rt

m

e nt

i

s

e

_q

u

i l i b

r ate

d

(

i

n a c c o r

d

a n c e

w i

t

h H

en r_y

'

s L a

w

)

w i

t

h

t

h

e a

i

r

fl

o

w i

n _g o v e r

i

t

w i

t

h

t

h

e

b l

o o

d

r a

i

r _pa rt

i

t

i

o n c o e

f f

i c

i

e nt

b

e

i

n

_g

r e_pr e s entat

i

v e o

f

t

h

e

m

u c u s : a

i

r e_qu

i l i b

r at

i

o n "

(

M

o r r

i

s

et a

l

, 1 9

9 3

)

. Ea c

h

c o

m

pa rt

m

e nt r e

m

o v e s v apo r s

b

y

d i f f

u s

i

o n _,

m

eta

b

o

l i

s

m

, o r c

i

r c u

l

at

i

o n

a n

d m

eta

b

o

l i

s

m

r ate s a r e

b

e

l i

e v e

d

to

f

o

l l

o

w

M

i

c

h

a e

l i

s-

M

_{e n}t_{e n}

k i

n_et

i

_{c s}

w i

t h _{r e s}

pe ct to

c o

m

_pa rt

m

e nta

l

e n z_y

m

e a c t

i

v

i

_{t y}.

F

i

gu r e 1:

M

o r ris et al

M

odel D e s c ri b ing the U ptake a nd

M

etabolism of No n-_{r e a ct}i_{v e} V_a

po r s in F 3 4 4 Rats

Do r s al Med ial A irf low Pat h way

Dor s al Med ial A irf low Pat riway

Re sp ir ato r_y

Mu c o s a

O lfa cto r_y

Mu c o s a

La te r al/v e ntr al A irf low Pat h way

Res_{p i}r ator_y

!Mu c o s a !

Re s_{p i}r ato r_y

i t

LLl

i t

fs {}—B lood i l

fi

_|p

—B lo od

O lfa cto r_y

LA I

4 t

m

i t

g ^

i

1 1

T he s e c o n

d

m

o

d

e

l d

e s cri

b

e

d

in t he hte r atu r e

is

ve r_y s

i m i

la r to

M

o r

ri

s et al

(

s e e

F

i

_gu r e 2

)

. P

l

o

w

c

h

a

l k

et a

l

, 1

9 9

7

d

e s c

ri b

e

d

a P B P

K m

o

d

el

f

o r t

h

e up tak e,

m

eta

b

o

l i

s

m

a n

d i

ntr a c e

l lu

l

a r

_{p H}

c

h

a n

_g

e s

in

the r at n a s a

l

c a v

it

_y

w

he n e x

_p

o s e

d

c

hr o n

i

c al l y to v

i

n_y

l

a c etate. T he

m

o

d

e

l w

a s

"

c onstr u cted to de s c

ri b

e t he

d

e_po sit

io n

o

f V A

in t he n a s al c a v

it

_y

o

f

the r at a n

d p

r o v

i d

e e st

i

m

ate s o

f

r e_g

io n a

l

t

i

s s u e e x_po s u r e to

_{V A}

,

A

A

l d

(

a c eta

l d

e

h

y

d

e

)

a nd

A A

₍

a c et

i

c a c

i d

₎

"

₍

P lo

w

chal k et al, 1 9 9 7

)

. T he

m

odel str u ctu r e uti l iz e s de s cri ptions

of air f lo

w

, b lo od

f lo

w

a nd d i f fu sio n si

m

i lar to

M

o rri s et.al.. T he

m

odel de s cri be s the

n a s a

l

c a v

i

t_y a s thr e e s e

_p

a r ate c o

m

_pa rt

m

e nts

i

n c o nta ct

w i

t

h

two s e_pa r ate a

ir s

tr e a

m

s. T

h

e

t

h

r e e c o

m

_pa rtme n_ts a r e

d i

v

i d

e

d i

nto 1 0 i^

m

th ic

k

sta c

k

s T

h

e

i

n

di

v

i d

u a

l

sta c

k

s a r e

r e_pr e s e nte

d b

_y t

h

e

f

o

l lo

w i

n_g c e

l l

u

la r s

tr u ctu r e s_{; t}

h

e

m

u c o s a, ep

it

h

e

l i

a

l

c e

l l

s,

b

a s a

l

c e

l l

s,

an

d

s u

b

m

u c o s a. T

h

e a

i

rf lo

w

patte r n s

d

e s c

ri b

e

d i

nc

lu

d

e the

d

o r s a

l m

e

d i

a

l

a

i

r str e a

m

an

d

t

h

e

l

ate r a

l/

v e ntr a

l

a

ir s

tr e a

m

.

"

T

h

e

d

o r s a

l

m

e

d i

a

l

a

i

r str e a

m

r e_pr e s e nts t

h

e a

ir

f lo

w i

n

_g

o v e r

o n

l

_y t

h

e

d

o r s a

l m

e

d i

a

l m

e atu s,

w h i

c

h is c o

m

po s e

d

o

f

a s

m

a

l l

a nte

ri

o r

p

atc

h

o

f

r e sp

i

r ato ry

m

u c o s a an

d m

u c

h l

a r_ge r a r e a o

f

o

l f

a cto r_y

m

u c o s a. . T

h

e

la

te r a

l

v e ntr a

l

a

ir s

tr e a

m

i

s

d

e

fi

n e

d

a s a c o

m

_po s

i

te o

f

a

ir

fl

o

w i

n_g o v e r t

h

e

d

o r s a

l l

ate r a

l

, v e n tr a

l

late r a

l

, v entr a

l m

e

d ia

,

a n

d m i d d l

e

m

e

d i

a

l

m

e atu s e s "

(

P

l

o

w

c

h

a

l k

et a

l

, 1 9 9

7

)

. I t

i

sas su

m

e

d

t

h

at

V A w i l l

e_qu

i l i b

r ate

w i

t

h

m

u c o u s

l

a

_y

e r s a s

i

_{t p}a s s e s o v e r n a s a

l

t

i

s s u e, a n

d

t

h

at V

A w i l l

e

i

t

h

e r

b

e

r e

m

o v e

d b

_y

f

u rt

h

e r

d i f f

u s

i

o n ,

m

eta

b

o

l i

s

m

o r ta

k

e n up

i

nto the

b lo o

d

s up p

l

y.

"

T

h

e e x ten t

to

w h i

c

h V A

c a n

b

e

m

eta

b

o

l i

z e

d w i

t

h i

n a t

i

s s u e c o

m

_pa rt

m

e nt

i

s

d

e_pe n

d

e nt u_po n t

h

e

c o

m

_{p l}e

m

e nt o

f

e n z_y

m

e s _pr e s ent

i

n _t

h

e t

i

s s u e"

(

P

lo

w

c

h

al

k

et a

l

, 1 9 9 7

)

.

F

i

gu r e 2:

P lowchalk et al.

M

odel De s cri b ing the U ptake a nd

M

etabol ism of V A T hr o u gh the RatNa s al C_{a v}it y

V A

P L OWC H A L K A N D ERS E N A N D B O G D A N FF Y Do r s alMed ial A ir str e am _N

a s o_pham_yx * V A

-A -A Id __{[^ J}_^

A A O Hac tory Re splrat of_y

A A

v e n o us B lo od

► _{V A}

Arterial B lo od 88%

Late r alNe ntr al A ir str e am

= Me tabolite s ub model

'

12

T he th ird

m

odel inc o r_po r ate s the

w

hole

b

od y s_yste

m

in r elation to e x_po s u r e of

a c

i d i

c v a_po r s

(

s e e

F i

_gu r e

3

)

. Fr e

d

e r

i

c

k

et a

l

, 1

9 9 8

,

d

e s

i

gn e

d

a "

h

_y

b

r

i d

c o

m

_putat

i

on a

l

f l

u

i d d

_yn a

m i

c s a n

d

P B P

K d

o s

i m

etr_y

m

o

d

e

l

. . . to e st

i m

ate t

h

e r e

g i

o n a

l

t

i

s s u e

d

o s e o

f

o r_ga n

i

c a c

i

ds

i

n the r oden t a n

d

hu

m

a n n a s al c a v

it

_y "

(

Fr e

d

e r

i

ck et al, 1 9 9 8

)

. T

h i

s

m

o

d

e

l

i

s d

i

v

i

de

d i

nto s e v e n c o

m

_pa rt

m

e nts,

f i

v e o

f w

h

i

c

h

a r e

i

n

d i

r e ct c o nta ct

w i

th

b

ot

h

v e n o u s .

an

d

a rte r

i

al

b

lo o

d

f lo

w

s. T he f

i

r st c o

m

pa rt

m

e nt, the n a s a

l

v e st

i b

u

l

e,

i

s a c o n

d

u

it

f

o r

a

i

r f lo

w

on_{l y}, a nd n eithe r b lo od f lo

w

n o r

m

etabol

i

c a ctiv ation o c c u r s in th is r eg io n

(

F

r e

d

e r

i

c

k

et a

l

,

1

9 9

8

)

. T

h

e s e c o n

d

c o

m

pa rt

m

e nt

i

s t

h

e n a s a

l

c a v

i

t y,

w h i

c

h i

s s u

b d i

v

i d

e

d

b

_y a nte r

i

o r an

d

_po ste r

i

o r c o

m

_pa rt

m

e nts s

i

m

i l

a r to

M

o r r

i

s et a

l

"

A

l l a

i

r

fi

-o

m

t

h

e n a s a

l

c a v

i

t y t

h

e n _pa s s es o v e r a

[

t

h i

r

d

co

m

_pa rt

m

ent, t

h

e n a s op

h

a ryn x

]

b

e

f

o r e e nte r

i

n g a

c o

m

_po s

it

e lo

w

e r r e s_{p i}r ato r_y tr a ct c o

m

_pa rt

m

e nt"

(

Fr ede r

i

ck et al, 1

9

9

8

)

T he

n a s o_p

h

a r_yn x

i

s

d

e s c r

i b

e

d

s

i

m

i l

a r

l

_y to t

h

e n a s a

l

v e st

i b

u

l

e,

i

n t

h

at n e

i

t

h

e r v e n o u s n o r

a r te r

i

al

b

lo o

d f

lo

w i

nto t

h i

s r e_g

i

on. T

h

e lu ngs a r e the n the n e x t s o u r c e

f

o r c o nta ct

w it

h

t

h

e

b

o

di

e s

b l

o od

f l

o

w

. T he

f i

n a

l

t

h

r e e c o

m

pa rtme nts a r e t

h

e l

i

v e r_, r

i

c

h l

_{y p}e r

f

u s e

d

t

i

s s u e s,

a n

d

_po o r

l

_{y p}e r

f

u s e

d

tis s u e s, a

l l

o

f w h i

c

h

a r e c o n s

i d

e r e

d d

eto x

i f

icat

i

on s

i

te s.

F

i

gu r e

3

:

Fr ede rick et al

M

odel De s c ribes U p take a nd

M

etabolism o f Acidic V a_po r s in Rats a nd Hu

m

a n s

H Y B R I D C F D-P B P K N A S A L D O SIME T R Y MO D E L

Na s al Ca vit_y

Ve n ous

B lo od

K

In spired Airw it h Vap or

k

t

T

'

N a s al Ves ti bule

j

INa s op haryn x

^ Lu ngs

■

/ |

\

Richly

■

Perf u s ed T is s u e s

-

/

1

\ _^

Po o rly Pe rfu s ed T is sue s

V

t

\

^

R=r esp ira t or_yepit helium O= ol fac_to ry ep ithel ium

Arterial B lo od

13

Bo_g

d

a n f f y et al, 1 9 9 9,

d

e v eloped the fo u rth

m

o del

(

s e e F i gu r e 4

)

. T h is

m

o

d

e

l i

s a

m

o

d i f

i e

d

r at n a s a

l m

o

d

e

l

e x_pr e s s

i

n _g

h

u

m

a n n a s a

l

a n a_to

m

_y a n

d i

n

h

a

l

at

i

o n r

i

s

k

a s s e s s

m

e nt

s_pe c

i fi

c a

l l

_y

f

o r

V A

.

T h

o u g

h

v e ry s

i m i l

a r to

M

o r r

i

s et a

l

a n

d

P

l

o

w

c

h

a

l k

et a

l

, t

h i

s

m

o

d

e

l

i

s c o

m

_pa rtme ntal

i

z e

d i

n to

f

i v e s e ct

i

o n s

f

o r the r at a n

d f

o u r s e ct

i

o n s

f

o r t

h

e

h

u

m

an

w i

t

h

i

ntr a c e

l l

u

l

a r _p

H

c o n s

i d

e r at

i

o n s.

"

T

h

e

fi

v e c o

m

_pa rt

m

e nt r at

m

o

d

e

l d i

v

i d

e s t

h

e ol

f

a cto r

_y

r e_g

i

on

i

nto t

w

o c o

m

_pa rtme nts_, a s

m

a

l l d

o r s a

l

a nte r

i

o r c o

m

_pa rtme nt an

d

a

l

a r_ge r _po ste r

i

o r

c o

m

_pa rt

m

e nt T he r e s_{p i}r ato r_y

m

u c o s a o n the v e ntr al si de

i

s als o d ivi ded into a n a nte r

i

o r

a n

d

a

_p

o ste r

i

o r c o

m

_pa r t

m

e n t, r e s ult

i

n g

i

n

fi

v e c o

m

p

a rt

m

e nts

. . .

"

(

Bo

_{g d}

an_{f f y} et a

l

, 1

9 9

9

)

.

Ea c

h

c o

m

_pa rt

m

e nt

i

s

fi

i rt

h

e r

d i

v

i d

e

d i

nto sta c

k

s r e_pr e s e nt

i

n_g

d i f f

e r e nt c e

l l

u

l

a r t y pe s. T

h

e

h

u

m

an

m

o

d

e

l i

s

d i

v

i d

e

d

s

i

m

i l

a r

l

_y to t

h

e r at, e x c ept t

h

e o

l f

a cto ry r eg

i

o n

i

s not

d i

v

i d

e

d i

n to

do r s a

l

a nte r

i

o r a n

_d

do r s al

_p

o ste r

i

o r c o

m

_pa rt

m

e nts. Bot

h

t

h

e r at a n

d h

u

m

a n

m

o

d

e

l

ut

i l i

z e

t

h

e t

w

o-_a

i

_{r str e a}

m

_a

p p

r o a c

h p

r e v

i

o u s

l

_y

d

e s c r

i b

e

d b

_y

M

o r r

i

s et a

l

a n

d P l

o

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