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s of w i
sd
om
st
i l l
ri
ng
in
m
y
e a r st
od
ay
a nd
t
h
e c o n st
a nt
em
p
h
a sis
h
e
p
l
a c ed
o n ed
u c ati
o nh
a sb
r o ug
h
t
m
et
oth i
st
i m
ei
nm
y
l i f
e.T
h
a nk
y
o
ud
ad
.D
i
s c
l
a
i
m
e
r
T
h
e r es
e a r ch
p
r e s e nt
ed i
nt
h i
st
e
ch
n
i
c al
r ep
o rt
w
a s s up p
o rt
b
y t
h
eU
n
it
ed S
t
at
e sE
n vi
r o nm
e nt
al
P
r ot
e ct
i
o nA
g
e n cy
an
d d
o e s n ot
r ef l
e ct
E P
A
p
ol
i
cy
.A
n
y
m
e nt
i
o n of
t
r ad
en a
m
e s o rp
r od
u
ct
s
u s ed i
nth i
s r e s e a r ch d
o es
n ot
c
o n st
it
ut
e a n e nd
o r se
m
e nt
.I
.I
n
t
r o
d
u c
t
i
o n
A
r s e nic
i
s a n ele
m
en
t t
h
at
h
a sb
e e ni
nf
ol k l
o r ef
o rt
h
o u s a nd
s of
y
e a r s.D
at
i
ng
b
a ck
t
o3 8 7 B
.C
,
i
t
w
a s ci
t
ed b y T h
e op h
r a st
u s of E
r eb
u s(
G
oy
e r,1 9 9 1
)
.A
r s e ni
cw
a s aw i d
el
y
u s ed
p
oi
s o nd
u rin
g
t
h
em i d d l
ea
g
e s a nd w
a
sfr
eq
u en
t
l y
c al l
ed
t
h
e "i
nh
eri
t
a n c ep
ow d
e r"b
e c a u s e of i
t
s 'w i d
e sp
r e ad
u s ei
nh
o
m i
ci d
e s.A
r s e ni
ci
s c o n si d
e r ed
at
o xi
cm
et
al
a nd i
s
ub i q
ui
t
o u si
n o u r e n vir o n
m
e nt
.I t
h
a sb
e e nm
e a s u r ed i
n air
,w
at
e
r, a
n
d
s oi l
s a
m
p
le s
.A
r s e ni
c c om
p
o u nd
s a r e n at
u r al l
y
o c c u rri
ng i
nt
h
e e a rt
h
's
c r ust
a nd
c a nc o n
t
am
in a
t
ew
at
e r s o u r c e st
h
r o ug h
n at
u r al
l
e a ch
in
g
p
r o c e s s e si
n
t
og
r o u nd w
a
t
e r or
t
h
r o ug
h m i
ni
n
g
p
r o c e s s e sw h
e r et
h
eb
y
-p
r od
u ct
s a r e n ot
c on
t
ain e
d p
r op
e rl
y
{
e.g
. o r em
i
n
i
n
g
a nd
sm
el
t
e r op
e r at
i
o n s) (
G
oy
e r,1 9 9
1
a nd U
.S
.E
P
A
,
1
9 9 8
)
.E l
e
v at
ed
a r s en
i
cc o
n
c e nt
r at
i
o n si
nw
at
e r a nd
s oi
l
s c a n als o
b
ei
n c r e a s ed b
y t
h
e u s e of
a r s e ni
ci
n c ert
ain
in
d
u st
ri
e ss
u ch
a s
w
o
od p
r es
e r v at
io n
an
d
ag ri
c ul
t
u r e(
U
.S
.E
PA
,1
9 9 8
)
.B
e c a u s e of
t
h
ew i d
e sp
r e ad
u s e of
a r s en
ic a s a c
ri
m
i
n al w
e ap
o n(
p
oi
s o n)
,i
t
w
a so
n eo
f
t
h
e
fi
r st
p
o
i
s o ns
t
ob
ei
s ol
a
t
ed
an
d d
et
e ct
ed i
nh
um
a nb
od y
t
is s u e s a
n
d f lu
i d
sa
r o u nd
t
h
e1
7
0 0
's(
G
oy
e r,19 9 1
)
.T
h
ep ri m
a ry
r o ut
e of
a r s en
i
c e xp
o s u r ei
nh
um
a n sis
i
n
g
e st
i
o n of
c o nt
am in a
t
ed w
at
e r a nd f
o od
s.C h
r on
ic
h
um
an
e xp
os
u r et
o a r s e ni
ch
a sb
e en
l i
nk
ed
t
o
sk i
n c a n c e rs
t
h
ro u
g h i
ng
e st
i
o n an
d
t
olu
n
g
c
an
c e r st
h
r o ug h i
nh
ala
t
i
o
n(
T
s e ng
et
a
l
,1
9 6 8
,E
nt
e rl i
ne
et
al
,19 9 5
)
.B
a s ed
o n e xt
en
si
v e ep i d
em i
o
l
og i
c al
e vi d
e n c e,t
h
eI
nt
e r n at
io n a
l A
g
e n cy
f
o rR
e s e a r ch
o nC
an
c e r(
LA
R
C
)
h
a s cla s s
i f
i ed
a r s e ni
c a s ak
n
ow
nh
um
an
c a rc
in
o
g
e
n(
l A
R
C
,1 9 8
7
)
.T
h
eU
ni
t
ed S
t
at
e sE
n vi
r o nm
e nt
al Pr o
t
e ct
i
o nA g
e n cy
h
a s al
s oi d
e nt
i fi
ed
a r se
ni
c a s ag
r o up
A
"k
n
ow
nh
um
a n c a r cin o
g
e n"
U
.S
.E P
A
,1 9 9 3
)
.M
o r e r e c e nt
l y
, at t
e nti
o nh
a st
u r n ed
t
oth
ep
o s si b i l i
t
y
t
h
at
ch
r o ni
ce
xp
o s u r et
oa
r s e ni
ct
h
r o ug h d
ri
nk i
ng w
at
e r s o u r c e sm
ay
b
e a s s o ci
at
ed w it
h i
nt
e r n al
c a n c e r s, s u c
h
a sl
un
g
,b l
ad d
e r,l i
v e r, a nd k i d
n ey
(
Ch
i
o u et
al,
2
0
0 1
,Sm
i
t
h
et
al
,1
9 9 8
,F
e r ri
c
ci
o et
al
,2
0 0 0
,St
ei
nm
a u s et
al
,2
0 0 0
,M
o r al
e s et
al
,2
0 0 0
a nd H
op
e nh
ay
n-
R
i
ch
et
a
l
,1 9 9 6
)
.A
l
o ng
w i
t h t
h
e a s s o ci
ati
o n of b
ot
h i
nt
e r n al
a nd
sk i
n c a n c e r sfr
om
ch
r o ni
ce
xp
os
u r ew i
t
h
a
rs
e ni
c
, oth
er
no
n-c a n c e r
e
ndp
oi
nt
s s u ch
a s c a rd io
v a sc
ul
a r a nd
n e u r o
l
ogi
c al
ef f
e ct
sh
a v eb
e
e n r ep
o rt
ed
(
H
e rt
z-P i
c ci
ot
t
o et
al
,
2 0 0 0
a nd Y
u e-z
h
e n et
al
,1 9 9 2
)
.I
nW
e st B
e ng
al
,I
nd
i
a,t h
e c o n c e nt
r at
i
o n of
a r s e ni
ci
nd
ri
nk in
g
w
at
e r s o u r ce
si
se x
t
r em
el
y
h i
g
h
a nd
t
h
ep
op
ul
at
i
o nh
e r eh
a sb
e e n sh
ow
nt
o e xh i b i
t
si g
n s of
ch
r on
i
ca r s e n
i
ct
o xi
ci
t y
i
n cl
ud i
ng
n
o n-c a n c e rm
a ni
f
e st
at
i
o n s s u ch
a s ab
n
o rm
al
e
l
e ct
r om
y
og
r ap h y
s,g
a st
r oi
nt
e
sti
na
l
sy
m
p
t
om
s, e nl
a rg
ed l i
v e r sa
nd
oth
e rl i
v e rp
r ob l
em
s(
el
e v at
ed l i
v e r e n zy
m
e s a nd N C P
-fi b
r o si
s)
,
t
h i
ck
e ni
ng
of
th
ep
a
l
m
sa n
d
s
ol
e s, an
d
h
y p
e rp
i g m
e nt
at
i
o n of
t
h
e sk i
n(
G
uh
aM
a z um d
e r et
al
,1 9 9
8
)
.A
rs
en
i
cM
et
a
b
ol
i
sm
a nd T
o xi
cit
y
A
r s en
i
ci
s a v e ry
r e a ct
i
v e a nd
co
m
p
l
e x el
em
e nt t
h
at
f
o rm
sm
a ny
i
n o rg
a
ni
ca
nd
o
rg
a nic
co
m
p
o
u nd
s
an
d
eit
h
e
r of
th
e s ef
o rm
s(
sp
e ci
e s)
c a n e xi
st
i
nth
et
ri
v al
e nt
o rp
e nt
a
v al
e nt
v al
e n c e st
at
e.H
um
a n e xp
o s u r ei
sm
ai
nl
y t
h
r o ug
h w
at
e r a nd f
o od
s o u r c e s.T
y p
i
c al l
y
, a r s e ni
c-c o n
t
am
i
n at
ed w
at
e r c o nt
ai
n si
n o rg
a n
i
ca
r s e ni
c c om
p
o un
d
sw
h i l
ef
o od
u s u a
l l y
c o nt
ai
n st
h
e o rg
a ni
cf
o rm
s of
a r s e ni
c.H i
st
o ri
c al l
y
,th
em
o st t
o xi
cf
o rm
w
a str
iv a
l
en
t
an
d p
en
t
a v al
en
t
, a r et
h
ep
r ed
om
i
n
an
t
f
o rm
sf
ou n
d i
n
w
a
t
e
r(
U
.S
.E
P
A
,1 9
9 8
)
.In
o rg
an
i
c s al
t
s an
d
a ci d
s of
a r s e ni
ci
n
g
e st
ed i
nw
at
e r u nd
e rg
o am
et
ab
ol
ic
p
at
h w
ay
in
t
h
eh
um
a nb
od
y
k
n
ow
n a sm
et
h yl
ati
o n .T h i
sp
at
h w
ay
(
s e eF
i g
u r e1
)
b
eg i
n sw i
t
h
t h
ei
n o rg
a ni
c a r s e n at
e(
A
sO
4'
) (
u s u al l
y
in
th
ep
en
t
a va
l
en
t
st
at
eb
e c a u s e of
st
ab i l i
t y
)
r e
d
u c ed
t
oin o r
g
a ni
c a r s e ni
t
e(
A
s' ^O
a ^')
.S
te
p 2
in
v olv e s
th
e e n zy
m
at
i
c o xi d
at
i
v em
et
h
y
l
at
i
on
of
th
e a r s e ni
c c om
p
o u nd
t
of
o rm m
et
h
y
la r s o n
ic
a
ci d
(
C H
bA
s ^O
s ^')
,w h i
ch i
sa
p
e nt
a v ale n
t
m
eth
y
l
at
ed
sp
e ci
e s.St
ep
3 i
n v ol
v e st
h
e r edu c
ti
o n of
t
h i
s sp
e ci
e st
o atr
i
v al
e nt
m
o n om
et
h
y
l
at
ed
sp
e cie s
,m
eth
y
l
a r s o n o u s a ci d
(
C H
3A
s' "
0
2^'
)
p
ri
o rt
oth
ee n z
y
m
at
i
c o xi d
at
i
v em
et
h y l
at
io n
f
o r a s e c o nd
ti
m
e,w
h i
ch
y
i
el d
sd i
m
e
t
h yl
a rs
in
i
ca c
i d
((
C H
3)
2A
s ^0
2 ") (
St
y
b l
o et
al
,1 9
9 9
)
.T
h i
sm
et
ab
ol i
sm
of
a r s e ni
c r eq
ui
r e s r edu c
ti
o n of A
s^t
oA
s ' "p
ri
o rt
ot
h
ee n z
y
m
at
i
c ad d it
i
o n of m
et
h
y
l
g
r o up
st
oth
e a r s en
i
c al
s.T
h
e r edu c
t
io n
of
a r s e ni
ct
oa
t
ri
v al
e nt
st
at
ei
sp
r ef
o rm
ed b
y
e nd
og
e n o u st
h i
ols s u c
h
a sg
l
ut
at
h i
o n e(
G SH
)
o rb
y
A
s ^r e
d
u ct
a
s e s(
L i
n et
al
,2 0 0 2
)
.I
n19 9 5
,Z
ak h
a ry
a n et
al
r ep
o
rt
ed
t
w
od i f f
e r e nt
e n zy
m
ea c
t
i
vit
i
e sp
u ri f
i ed fr
om
r ab b i
t
l i
v e r cy t
o s ol
t
h
at
alo
n
g
w i
th S
-ad
en
o sy
l
-L
-m
e
t
h i
o nin e
(
SA
M )
an
d
ath i
ol w
e r e ab l
et
om
et
h
y
l
at
eb
ot
h
a r s e nit
e a nd
m
on
om
eth
y
l
a r s on
ate
(M M
A
)
(
1
9 9 5
)
.T h
e s e e n zy
m
e ac
ti
vi
ti
e s
w
e re
d
e si g
n
at
ed
ar s e
n
i
t
em
et
h y l
t
r a ns
f
e r a s e a nd
m
et
h
y
l
a r s o ni
t
em
et
h
y
l
t
r an
sf
e r a s e, r e sp
e cti
v el
y
,b
ut
w
e r e n ot
s eq
u en
c ed
(
Z
ak h
a ry
a n et
al
,1
9 9 5
)
.H
ow
e v e r, a s e
q
u e n c ew
a
s r e c e ntl
y
r ep
o rt
ed fr
om
ap
r ot
ei
ni
s ol
at
ed fr
om
r at
Uv e r
c
y t
o s ol
th
at
c
at
al
y
z e st
h
et
ra
n sf
er
of
am
eth
y
l g
r o up fr
om SA
M
t
ot
riv a
l
e
nt
a
rs
en
i
c a
l
sp
r od
u cin
g
m
et
h
y
la
t
ed
a nd d i m
et
h
y
l
at
ed
a r s e ni
c al
s(
L i
n et
al
,2 0 02
)
.T h i
sn
o v el p
r ote
i
nh
a sb
e e nd
e si
g
n ate
d S
-ad
e n o sy
l
-L
-m
eth i
o ni
n eI
n
o
r
g
a
n
i c
A
r
s
e
n
i
c
IV/i
e t
a
b o i i
s
m
3
G
S
H
A
s
V
2
G
S H
G
S S
G
^
A
s
'tJt
J
i t
S A
M
•
-
A
s
'"
(
G
S
)
3
G
S S
G
2
G
S H
C H
3A
S
i
l l
2
G
S H
G
S
S
G
(
C H
3
)
2A
s
' ^^
H
i
.S
A
M
^
C
H
3
A
s
' "
(
G
S
)
(
C
H
3
)
.
A
s
^G
S H
I I
L
■*
-(
C
H
3
)
^
A
s
' "
(
G
S
)
F i
g
u r e1
:T h
em
et
a
b
ol i
c
p
at
h
w
ay
o
f i
no
rg
an
i
c a r s en
i
c.T
h
ep
r op
o s ed
e n zy
m
e re
sp
o n si b l
ef
o rc
ata
l
y
zi
ng
t
h
e r e a ct
i
o
ni
s am
et
h
y
lt
r a n sf
e r a s e.G l
ut
h
ath i
on
e(
G S H
)
i
sth
e r ed
u cin
g
a
g
e nt
an
d S
-A d
e n sy l
m
et
h io n
i
n e(
S A
M )
is
t
h
em
et
h
y
l d
o n o r.T
h i
sf i g
u r e sh
ow
s
i
n
o rg
a n
i
c
a r s e ni
c(
A
s^
)
in
th
ep
e nt
a v al
e nt
st
at
eb
ein
g
m
et
ab
oh
z ed i
n
t
oth
e o rg
an
i
c sp
e cie
s
d im
et
h
y
la r s
i
ni
c a ci d
((
C H
3)
2A
s(
L in
et
al,
2 0 0
2
)
.T h
e e n zy
m
e r e sp
o n si b le
f
o
rth i
s
m
et a
b
oHc
p
ath w
ay
i
nh
um
an
c el l
sh
a sn o
t
y
et
b
e e ni d
e nt
i fi
ed
o r s eq
u e n c ed b
ut
r e s e a r ch is o n
g
oi
ng i
nt
h i
sfi
el
d
.T h
eb io
m
et
h y l
ati
on
of
a r se
nic
h
a sl
o ng b
e e n c o n si d
e r ed
ad
et
o xi fi
c ati
on
p
at
h w
ay
,h
ow
e v e r , a n ot
h
e rt
o xi
cf
o rm h
a sb
e e ni d
e nt
i fi
ed i
nh
um
a n u rin
e,m
on o
m
et
h y l
a r so
no
us
a c
i d
(
C H
3A
s(
O H
)
2)
,w h i
ch
c o nt
ai
n sth
etr
i
va
le
n
t
a
r s e nic
sp
e ci
e s(A p
o sh i
a n et
al,
2 0
0
0
)
.T h is s u
g g
e st
st
h
at
m
et
h y l
ati
o nm
ay
n ot
b
e co n
si d
e
r ed
a
d
eto x
i f
i ca
t
i
on
p
ath w
ay
of
a r s e ni
cin
h
um
a n s.T h
eb i
om
et
h
y
l
at
io n
of
a r s e ni
c c om
p
o im dsi
st
h
o ug h
t t
o o c c u rm
a
in
l y i
n
th
e
l i
v e r(
St
y b l
o et
al
,19 9 9
)
.A
r ep
o rt
p
ub l i
sh
ed in
19 9 9
r ef
e r st
ot
h
ei
n ab i l i
t
y
of
i
n v e st
i g
at
o r st
od
et
e ct
a r s e ni
cm
eth
y
l
t
r an
sf
e r a s e a cti
vi
t
y i
n
e xtr a c
t
s of
s u rg i
c
al l y
r em
o v ed
h
um
an
l iv e r s a n
d
th
e r e a r e n od
at
a a v ai
l
ab l
efi
-o
m
ot
h
e rh
um
a nt
i
s s u e sd
e s c ri b i
ng
t
h
em
et
h y l
at
io n
of
a r s e ni
c(
Z
ak h
a ry
a n et
al
,19 9 9
)
.H
ow
e v e r,th
e c ap
ab i l i
t y t
om
et
h y l
at
ein o r
g
an
i
c a r s e nic
i
n vi
t
r oh
a sb
e e n sh
ow
n u si
ng
p
ri m
a ry h
um
an
c el l
c ult
u r e s a nd
r at
h
ep
at
o cy
e s(
S
t y
b lo
et
al
,19 9 9
)
.A
c ut
e
,h i g h
-c o
n
ce
ntr a
t
io n
a r s e nic
p
oi
s o ni
ng i
n
h
um
an
s c a n c a u s ed
ea
t
h
.H
ow
e v e r,t h
e r e a r e st
i l l
u n ce
rt
ai
nt
ie s a s s o c
ia
t
ed w i
th
chr o n
ic
e xp
o s u r e st
o a r s en
i
c at
l
ow
e r c o n c en
t
r at
i
o
n s(
c om
p
a
r ed
t
op
oi
so n
in
g
e v e nt
s)
a nd
th
e ob
s e r v ed h
e al
t
h
ef fe c
t
s,s u c
h
a s c an
c e r an
d
n o n-c an
c e r ef f
e
ct
s se
e nth
r o ug h
o ut
t
h
ew
o rl d
.T
h
ep
o s si b l
em
od
e of
a c
t
i
on
f
o r a rs
e ni
c c a r cin
og
e ni
ci
t
y h
a sb
e e nw i d
el
y
st
ud i
ed
o v e rt
h
ep
a st
d
e c ad
e a nd
in c
l
ud
e ss
e v e ra
l
g
e n ot
o
xi
ce
f f
ec
t
s
s uc
h
as c o
m
ut
a
g
e nic
i
t
y w i
th
s u
ch m
ut
a
g
en s
a sa
l k
y
l
at
i
ng
ag
e nt
s an
d U V
r ad i
at
i
o nb y
i
nt
e rf
e rin
g w i
t
h
D
N A
r ep
ai
rp
r o c e s s e s(
e n zy
m
e s)
,a
lt
e r at
i
o n si
nD
N A m
et
h
y
l
at
i
o n st
atu s
, o xi d
at
iv e s
t
r e s s, a nd i
n
c r e a s e sin
ce
l l
ul
a rp
r ol i f
e r at
i
o n .A
n
oth
e rp
o s si b l
em
o
d
eo
f
a ct
i
o n ad d
r e ss
ed i
nth i
s r ep
o rt
i
st
h
ep
o s si b i l i
t y
c
h
r om
o s om
al
al
t
e r at
i
o n s an
d
cl
a st
og
e n et
i
c ef f
e ct
s.T
h
et
r u e n at
u r e of
a r s e ni
cc a r c
i
n og
e ni
ci
t y
i
ss
t
i l l
n ot
cl
e a r a nd m
ay
i
n v ol
v ea n
y
o r al l
of
t
h
eh
y
p
ot
h
e si
z ed m
od
e st
od
at
e
(
N
at
i
o n al A
c ad
em
y
of S
ci
e n c e s,N
R
C
r ep
o rt
,1
9 9 9
)
.W
o rl d
a
nd U
.S
.A
r s e ni
cE
xp
o s u r e sS
e
v e ra
l p
a rt
s of
t
h
ew
o rl d
u
t
i l i
z ed
ri
nk i
ng w
at
e r s o u r c e st
h
at
a r e c o nt
am
i
n at
ed
w i
t h
h i
g
h l
e v el
s of
a r s en
i
c.A
v e ry
e a rl
y p
ub l i
c at
i
o nb
y T
s e ng
et
al
sh
ow
ed
t
h
at
vi l l
ag
e si
n ap
a rt
i
c ul
a r r eg i
o n of
T
ai w
a nh
a
d
c om
m
un
i
t y
w
el l w
at
e rt
h
at
w
a s c on
t
am i
n at
e
d w i
t
h
a r s e n
i
c r a ng
i
ng f
r om 0
.0
1 t
o1
.8
2
m g /1
.T
h
e r e a re
a r e a si
nI
n
di
aw h
e r et
e n s of
t
h
o u s a nd
so
f p
e op
l
eg
et
t
h
ei
rd
ri
nk i
ng w
at
e rfr
om d
e ep
w
el
l
st
h
at
h
a v e a r s e ni
cl
e v el
sb
et
w
e e n0
.0
5
m g/ 1
a nd
3
.2
m
g
/
1
of
a r s e ni
c(
G
uh
aM
a z um d
e r et
al
,1
9 9 8
)
.T
h i
sp
r ob l
em i
nI
n
d i
ah
a sg
a r n e r ed
m
u ch
at t
e
nt
i
o nb
y
b
ot
h
t
h
e s ci
e nt
i fi
c c om m
u ni
t y
, a sw
el l
a s,t
h
ep
op
ul
a rm
ed i
aa
t
l
a rg
e.I
n
S
o ut
h A
m
e ri
c a, a r s e n
i
c c o nt
am i
n at
ed d
ri
nk i
n
g w
at
e rh
a sb
e e n st
ud i
e
d i
n as
m
al l
n
o rt
h
e rn
r eg i
on
i
nC h i l
e,
w h
e r et
h
e a rs
e ni
cl
e v el
s
ra
ng
e
fr
om 0
.0
4
0
-0
.
8 7 0
m
g / 1
o v e rt
h
ep
a st
fi ft
y y
e a r s(
Sm
i
t
h
et
al
,1 9 9
8
)
.I
n a c e nt
r al A
rg
en
t
i
n ap
r o vi
n c e,t
h
e
a r se
ni
cc o n c e n
t
r at
i
o n si
n s om
et
ow
n s
'd
ri
nk i
ng w
at
e rh
a v eb
e en
r ep
o rt
ed b
et
w
e e n0
.0 4 0
an
d
0
.5 3 3 m
g
/ 1
(
H
op
e nh
ay
n -R i
ch
e
t
al,
1
9 9 6
)
.P
e op
l
el i
vi
ng
i
nt
h
eZ im
a
p
an
va
l l
ey
,l
o c at
ed
i
n a sm
al l
c e nt
r al
M
e xi
c a nt
ow
n,