Hazard
Identification
and
Toxicology
Endpoint
Selection
February
18,
2004
Timothy
F.
McMahon,
Ph.
D.
and
Jonathan
Chen,
Ph.
D.
U.
S.
Environmental
Protection
Agency
Office
of
Pesticide
Programs
Antimicrobials
Division
TABLE
OF
CONTENTS
0.0
INTRODUCTION
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1
1.0
HAZARD
CHARACTERIZATION
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2
1.1
Hazard
Characterization
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Arsenic
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2
1.1.1
Acute
Toxicity
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2
1.1.2
Non­
Acute
Toxicity
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3
1.1.3
Metabolism
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7
1.2
Hazard
Characterization
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Chromium
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8
1.2.1
Acute
Toxicity
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9
1.2.2
Non­
Acute
Toxicity
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11
1.2.3
Metabolism
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17
2.0
DOSE­
RESPONSE
ASSESSMENT
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19
2.1
Inorganic
Arsenic­
Endpoint
Selection
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20
2.1.1
Acute
Reference
Dose
(
aRfD)
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20
2.1.2
Chronic
Reference
Dose
(
cRfD)
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20
2.1.3
Short
(
1­
30
days
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and
Intermediate
(
30­
180
days)
Incidental
Oral
Exposure
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20
2.1.4
Dermal
Absorption
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22
2.1.5
Short
(
1­
30
days
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and
Intermediate
(
30­
180
days)
Dermal
Exposure
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23
2.1.6
Long­
Term
Dermal
Exposure
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23
2.1.7
Short­,
Intermediate­,
and
Long­
term
Inhalation
Exposure
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23
2.1.8
Carcinogenicity
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24
2.2
Inorganic
Chromium
Endpoint
Selection
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29
2.2.1
Acute
Reference
Dose
(
aRfD)
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29
2.2.2
Chronic
Reference
Dose
(
cRfD)
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29
2.2.3
Short­
Term
(
1­
30
days)
and
Intemediate­
Term
(
30­
180
days)
Incidental
Oral
Exposure
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29
2.2.4
Dermal
Absorption
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30
2.2.5
Short­,
Intermediate­,
and
Long­
term
Dermal
Exposure
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31
2.2.6
Inhalation
Exposure
(
all
durations)
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31
2.2.7
Carcinogenicity
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32
3.0
REFERENCES
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34
1
INTRODUCTION
The
Agency
recognizes
that
inorganic
arsenic
and
inorganic
chromium
are
the
compounds
of
toxicological
concern
with
respect
to
exposure
to
CCA­
treated
wood.
In
any
risk
assessment,
the
toxicity
of
the
primary
chemicals
of
concern
must
be
adequately
described,
either
through
submission
of
guideline
toxicology
studies
that
are
reviewed
by
the
Agency,
or
through
citation
of
scientific
studies
in
the
peer­
reviewed
literature.
The
following
sections
characterize
the
hazards
of
inorganic
arsenic
and
inorganic
chromium.
Information
was
summarized
from
submitted
toxicology
studies,
the
open
scientific
literature,
and
from
published
documents
by
the
USEPA
and
the
Agency
for
Toxic
Substances
and
Disease
Registry
(
ATSDR).
It
is
noted
for
inorganic
arsenic
that
in
most
cases,
human
data
(
in
the
form
of
epidemiology
studies
and
case
reports)
provide
the
basis
for
the
hazard
identification,
as
most
laboratory
animal
models
appear
to
be
substantially
less
susceptible
to
arsenic
toxicity
than
humans.

For
chromium,
hazard
data
show
clearly
that
Cr(
VI)
demonstrates
more
significant
toxicity
than
Cr
(
III).
The
Agency
has
not
identified
any
endpoints
of
concern
for
Cr(
III).
For
exposure
to
Cr(
VI),
the
Agency
has
identified
toxicological
endpoints
of
concern
and
has
used
these
endpoints
in
conjunction
with
exposure
to
Cr(
VI)
for
evaluating
risks
associated
with
Cr
(
VI).

Copper
as
a
component
of
CCA­
treated
wood
is
not
considered
in
this
document.
Copper
is
an
essential
nutrient
which
functions
as
a
component
of
several
enzymes
in
humans,
and
toxicity
of
copper
in
humans
involves
consumption
of
water
contaminated
with
high
levels
of
copper,
suicide
attempts
using
copper
sulfate,
or
genetic
disorders
such
as
Wilson's
disease.

1.0
HAZARD
CHARACTERIZATION
1.1
Hazard
Characterization
­
Arsenic
Arsenic
is
a
naturally
occurring
element
present
in
soil,
water,
and
food.
In
the
environment,
arsenic
exists
in
many
different
forms.
In
water,
for
example,
arsenic
exists
primarily
as
the
inorganic
forms
As
+
3
(
arsenite)
and
As
+
5
(
arsenate),
while
in
food,
arsenic
exists
primarily
in
organic
forms
(
seafood,
for
example,
contains
arsenic
as
arsenobetaine,
a
form
which
is
absorbed
but
rapidly
excreted
unchanged).
Human
activities
also
result
in
the
release
of
arsenic
into
the
environment,
such
as
residual
arsenic
from
former
pesticidal
use,
smelter
emissions,
and
the
use
of
chromated
copper
arsenicals
(
CCA)
in
the
pressure­
treatment
of
wood
for
construction
of
decks,
fences,
playgrounds,
and
other
structural
uses.

Inorganic
arsenic,
prior
to
1991,
was
used
as
an
agricultural
pesticide.
In
1991,
the
Agency
proposed
cancellation
of
the
sole
remaining
agricultural
use
of
arsenic
acid
(
As+
5)
on
cotton.
Subsequently,
this
registration
was
voluntarily
canceled
by
the
sponsor
and
made
immediately
effective
by
the
Agency
(
Federal
Register,
1993).
However,
inorganic
arsenic
contained
within
CCA­
treated
wood
continues
to
be
widely
used
for
decking
and
fencing
lumber
as
well
as
playground
equipment.
2
A.
Acute
Toxicity
The
acute
toxicity
summary
of
inorganic
arsenic
(
arsenic
acid
7.5%)
is
summarized
in
Table
1.
Humans
are
very
sensitive
to
arsenic
toxicity
when
compared
with
other
experimental
animals.
Inorganic
arsenic
is
acutely
toxic,
and
ingestion
of
large
doses
leads
to
gastrointestinal
symptoms,
disturbances
of
cardiovascular
and
nervous
system
functions,
and
eventually
death.
The
effects
seen
after
short­
term
arsenic
exposure
(
appearance
of
edema,
gastrointestinal
or
upper
respiratory
symptoms)
differ
from
those
after
longer
exposure
(
symptoms
of
skin
and
neuropathy).
Some
of
the
effects
after
short­
term
exposure
tended
to
subside
gradually
from
the
5th
day
of
the
illness,
despite
continuous
intakes
of
the
poison.
In
contrast,
symptoms
of
peripheral
neuropathy
appeared
in
some
individuals
even
after
the
cessation
of
arsenical
intakes
The
acute
oral
toxicity
of
inorganic
arsenic
in
humans
shows
lethal
effects
in
the
range
of
22­
121
mg/
kg,
which
is
consistent
with
results
of
animal
studies
showing
LD
50
in
the
range
of
15­
175
mg/
kg
(
ATSDR
,
2000a).
There
are
no
studies
reporting
death
in
humans
after
dermal
exposure
to
inorganic
arsenic,
which
is
consistent
with
results
of
animals
studies
showing
no
mortality
at
dermal
doses
up
to
1000
mg/
kg.
Mortality
in
humans
from
short­
term
inhalation
exposure
to
inorganic
arsenic
has
not
been
observed
in
occupational
settings
at
air
levels
up
to
100
mg/
m3.
One
study
in
pregnant
rats
reported
lethality
of
inorganic
arsenic
at
a
concentration
of
20
mg/
m3.
Arsenic
has
been
shown
to
result
in
contact
dermatitis
in
humans
exposed
occupationally,
and
animal
studies
are
also
suggestive
of
mild
to
severe
dermal
irritation
after
application
of
arsenic
to
skin.
Severe
ocular
irritation
was
observed
in
an
acute
eye
irritation
study
(
MRID
#
00026356).
Arsenic
does
not
produce
skin
sensitization
in
a
guinea
pig
model
(
MRID
#
40646201).

1.1.2
Non­
Acute
Toxicity
Subchronic
studies
with
arsenic
in
experimental
animal
models
have
produced
only
generalized
toxicity,
i.
e.,
weight
loss,
and
decreased
survival,
while
data
from
human
exposures
have
shown
more
specific
toxic
effects,
such
as
neurotoxicity
and
hyperkeratoses
of
the
skin
of
the
hands
and
feet
(
ATSDR,
2000a).

Chronic
toxicity
studies
with
inorganic
arsenic
in
experimental
animals
also
show
a
lack
of
specific
toxic
effects,
whereas
the
scientific
literature
that
describes
chronic
human
exposure
shows
a
clear
relationship
between
chronic
exposure
to
inorganic
arsenic
and
the
development
of
skin
cancer
as
well
as
cancers
of
the
lung,
liver,
and
bladder
(
ATSDR,
2000;
NRC,
1999).
The
most
notable
example
of
this
is
the
data
of
Tseng,
(
1968,
1977)
who
conducted
epidemiological
studies
of
chronic
oral
exposure
of
humans
to
arsenic
contained
in
food
and
water.
From
these
studies
it
was
noted
that
hyperpigmentation,
keratosis
and
possible
vascular
complications
[
Blackfoot
disease]
occurred
at
a
dose
of
0.17
mg
arsenic
per
liter
of
water,
equivalent
of
0.014
mg/
kg/
day.
Several
follow­
up
studies
of
the
Taiwanese
population
exposed
to
inorganic
arsenic
in
drinking
water
showed
an
increase
in
fatal
internal
organ
cancers
as
well
as
an
increase
in
skin
cancer.
Other
investigators
found
that
the
standard
mortality
ratios
(
SMR)
and
cumulative
mortality
rates
for
cancers
of
the
bladder,
kidney,
skin,
lung,
and
liver
were
significantly
greater
in
the
Blackfoot
disease
endemic
area
of
Taiwan
when
compared
with
the
age
adjusted
rates
for
the
general
population
of
Taiwan.
3
Data
on
the
developmental
and
reproductive
toxicity
of
inorganic
arsenic
in
humans
is
not
extensive.
One
study
conducted
in
Sweden
among
copper
smelter
workers
showed
significantly
reduced
live
birth
weights
in
offspring
of
women
employed
at
the
copper
smelter
and
increased
incidence
of
spontaneous
abortion
among
those
who
worked
at
the
smelter
or
lived
in
proximity
to
it.
However,
effects
from
exposure
to
lead
or
copper
in
this
study
could
not
be
ruled
out.
Hopenhayn­
Rich
(
2000)
conducted
a
retrospective
study
of
late
fetal,
neonatal
and
postnatal
mortality
in
Antofagasta,
Chile
for
the
years
1950
to
1996.
The
data
from
this
study
indicated
an
elevation
in
late
fetal,
neonatal
and
postnatal
mortality
compared
to
a
comparison
group
in
Valparaiso,
Chile
during
the
period
when
drinking
water
in
Antofagasta
was
contaminated
[
860
ug/
L]
with
arsenic
(
1958
to
1970).
There
was
a
decline
in
late
fetal,
neonatal
and
postnatal
mortality
when
the
concentration
of
arsenic
in
the
drinking
water
declined
due
to
installation
of
a
water
treatment
plant.
After
installation
of
the
plant,
the
mortality
rates
in
Antofagasta
were
indistinguishable
from
those
in
Valparaiso.
It
was
noted
that
the
mothers
involved
in
this
incident
had
characteristic
arsenic­
induced
skin
lesions.
A
prospective
cohort
study
was
conducted
in
these
two
cities
during
the
period
in
the
period
when
drinking
water
arsenic
levels
in
Antofagasta
is
40
µ
g/
L
and
in
Valparaiso
is
less
than
1
µ
g/
L.
By
comparing
the
preganancy
and
birth
4
Table
1.
Acute
Toxicity
Summary
of
Arsenic
Acid
(
75%)

Guideline
Reference
No.
Study
Type
MRID/
Data
Accession
No.
Results
Toxicity
Category
81­
1
(
OPPTS
870.1100)
Acute
Oral
404090­
01
Mouse
LD50
=

141
mg/
kg
=

160
mg/
kg
M+
F
=
150
mg/
kg
II
26356
Rat
LD50
=

76
mg/
kg
=

37
mg/
kg
M+
F
=
52
mg/
kg
I
81­
2
(
OPPTS
870.1200)
Acute
Dermal
26356
Rabbit
LD50
=

1750
mg/
kg
=

2300
mg/
kg
II
81­
3
(
OPPTS
870.1300)
Acute
Inhalation
404639­
02
Mouse
LC50
=

1.153
mg/
L
=

0.79
mg/
L
M+
F
=
1.040
mg/
L
II
81­
4
(
OPPTS
870.2400)
Primary
Eye
Irritation
26356
Rabbit
3/
6
animals
died
by
day
7.
The
3
surviving
animals
were
sacrificed
on
day
9
because
of
severe
ocular
irritation
and
corrosion.
I
81­
5
(
OPPTS
870.2500)
Primary
Skin
Irritation
26356
Rabbit
At
30
minutes,
all
animals
showed
moderate
to
severe
erythema
and
slight
to
severe
edema.
All
animals
died
prior
to
the
24
hour
observation.
I
81­
6
(
OPPTS
870.2600)
Dermal
Sensitization
406462­
01
Guinea
Pig
Not
a
Sensitizer
information
form
these
two
cities,
the
results
suggests
that
moderate
arsenic
exposure
(<
50
µ
g/
L)
durign
preganancy
may
associated
with
reduction
in
birth
weight
(
Hopenhayn
et
al.,
2003).

In
laboratory
animals,
the
major
teratogenic
effect
induced
by
inorganic
arsenic
is
neural
tube
defect,
characterized
by
exencephaly
and
encephalocele.
However,
this
effect
has
not
been
observed
in
humans
(
IPCS,
2001).
In
addition,
data
on
the
developmental
and
reproductive
toxicity
of
inorganic
arsenic
submitted
to
the
Agency
show
effects
on
offspring
only
at
doses
that
are
maternally
toxic.

In
a
developmental
toxicity
study
(
Nemac,
1968b),
pregnant
Crl:
CD­
1(
ICR)
BR
mice
(
25
per
dose
group)
received
a
single
daily
gavage
of
aqueous
Arsenic
Acid
(
75%)
from
day
6
through
15
of
gestation.
Doses
were
0,
10,
32
and
64
mg/
kg/
day.
Controls
received
deionized
water.
Body
5
weights
were
recorded
at
six
hour
periods.
Cesarean
section
was
on
day
18.
Fetuses
were
weighed,
sexed
and
examined
for
external
skeletal
and
soft
tissue
malformations
and
variations.
At
the
high
dose,
two
dams
died.
Signs
included
lethargy,
decreased
urination
and
defecation,
soft
stool
or
mucoid
feces.
Brown
urogenital
matting,
and
red
material
around
the
eyes.
Necropsy
showed
bilateral
reddening
of
cortico­
medullary
junction
(
kidneys)
and
a
red
areas
in
the
stomach.
At
mid
and
(
especially)
top
dose,
the
dams
showed
weight
loss
and
an
elevated
incidence
of
total
litter
resorption.
An
increase
in
exencephaly
occurred
in
the
both
the
low
(
1/
231
fetuses
per
1
litter)
and
the
high
(
2/
146
fetuses
per
1
litter)
doses,
but
statistical
significance
was
not
seen.
The
Maternal
Toxicity
NOAEL
was
determined
to
be
32
mg/
kg/
day,
and
the
Maternal
toxicity
LOAEL
was
determined
to
be
64
mg/
kg/
day,
based
on
increased
total
litter
resorption,
reduced
body
weight,
and
increased
maternal
mortality.
The
Developmental
Toxicity
NOAEL
was
determined
to
be
32
mg/
kg/
day
and
the
Developmental
Toxicity
LOAEL
was
determined
to
be
64
mg/
kg/
day,
based
on
reduced
mean
viable
fetuses,
reduced
fetal
weights,
increased
post
implantation
loss
and
increased
incidence
of
exencephaly
(
not
statistically
significant).

In
a
prenatal
developmental
toxicity
study
(
Nemec,
1988a),
artificially
inseminated
New
Zealand
White
rabbits
(
20/
dose)
received
aqueous
arsenic
acid
(
75%)
by
gavage
from
days
6
through
18
of
gestation
inclusive
at
doses
of
0,
0.25,
1,
and
4
mg/
kg/
day.
At
the
4
mg/
kg/
day
dose
level,
seven
dams
died
or
were
sacrificed
in
extremis.
Reduced
body
weight
gain,
clinical
signs
of
toxicity
(
prostration,
ataxia,
decreased
defacation
and
urination,
mucoid
feces),
and
histo­
logical
alterations
in
dams
sacrificed
or
dead
at
the
high
dose
(
pale,
soft,
or
mottled
kidneys;
pale
and
soft
liver;
dark
red
areas
of
the
stomach;
dark
red
lungs)
were
observed.
Fetal
data
showed
increased
post­
implantation
loss
at
the
4
mg/
kg/
day
dose
(
1.8
vs.
0.5
in
control)
and
reduced
mean
viable
fetuses
(
4.9
vs.
6.7
in
control).
There
was
no
evidence
from
the
data
of
increased
incidence
of
fetal
alterations
(
variations,
malformations)
related
to
treatment
with
test
article.
The
Maternal
NOAEL
was
determined
to
be
1
mg/
kg/
day,
and
the
Maternal
LOAEL
was
determined
to
be
4
mg/
kg/
day,
based
on
increased
mortality,
decreased
body
weight
gain,
clinical
signs,
and
histological
alterations
of
the
kidney
and
liver.
The
Developmental
NOAEL
was
determined
to
be
1
mg/
kg/
day,
and
the
Developmental
LOAEL
was
determined
to
be
4
mg/
kg/
day,
based
on
increased
post­
implantation
loss
and
decreased
viable
fetuses.

With
regard
to
the
susceptibility
of
offspring
to
the
toxicity
of
inorganic
arsenic,
DeSesso,
(
1998)
in
a
review
paper
exploring
the
reproductive
and
developmental
toxicity
of
arsenic
acid
(
As+
5)
noted
that
in
three
repeated
oral
dose
studies
carried
out
under
EPA
guidelines
for
assaying
developmental
toxicity,
arsenic
acid
was
not
teratogenic
in:
mice
by
oral
gavage
(
10
to
64
mg/
kg/
day),
rabbits
by
oral
gavage
(
1
to
4
mg/
kg/
day)
and
in
a
mouse
two­
generation
feeding
study
(
20
to
500
ppm).
Other
animal
developmental
and
reproductive
toxicity
data
based
on
the
published
literature
also
showed
no
increased
sensitivity
to
arsenic
(+
5)
when
given
orally
by
repeated
doses.

In
a
tranplacental
carcinoginicity
study
(
Waalkes
et
al.,
2003),
pregnant
C3H
mice
were
given
drinking
water
containing
sodium
arsenic
at
0,
42,5
and
85
ppm
ad
libitum
from
day
8
to
18
of
gestation.
These
dosages
were
well
tolerated
and
did
not
decrease
the
body
weight
of
the
dams
during
gestation
and
the
birth
weight
of
the
offspring
after
birth.
However,
after
weaning
at
4
weeks,
the
offsprings
were
put
into
separate
gender­
base
groups
according
to
maternal
exposure
6
level.
The
offspring
received
no
additional
arsenic
treatment.
The
study
lasted
74
weeks
in
males
and
90
weeks
in
females.
A
complete
necropsy
was
performed
on
all
mice
and
tissues
were
examined.
In
male,
there
was
a
dose­
related
increases
in
the
incidences
of
heptatocellular
carcinoma,
liver
tumor,
adrenal
tumor.
In
females
offsprin,
dose­
related
increases
occurred
in
ovarian
tumors
incidence
and
lung
carcinoma
incidence
were
observed.(
Waalkes
et
al.,
2003)

The
same
authors
note
that
"
there
is
a
paucity
of
human
data
regarding
inorganic
arsenic
exposure
during
pregnancy
and
potential
adverse
effects
on
progeny.
The
available
epidemiological
studies
were
neither
rigorously
designed
nor
well
controlled.
These
studies
failed
to
find
a
definitive
or
consistent
association
between
arsenic
exposure
and
adverse
pregnancy
outcome.
Consequently,
claims
of
potential
adverse
effects
of
inorganic
arsenic
on
human
development
remain
unsubstantiated."
This
conclusion
is
consistent
with
ATSDR
(
2000a),
which
noted
that
"
Although
several
studies
have
reported
marginal
associations
between
prolonged
low­
dose
human
arsenic
exposure
and
adverse
reproductive
outcomes,
including
spontaneous
abortion,
stillbirth,
developmental
impairment,
and
congenital
malformation,
none
of
these
studies
have
provided
convincing
evidence
for
such
effects.
"

The
January
22,
2001
Federal
Register
Notice
(
Vol.
66,
No.
14,
pages
7027­
7028),
in
which
the
arsenic
drinking
water
standard
was
discussed
in
relation
to
susceptibility
of
certain
human
subpopulations
including
infants
and
children
also
supports
the
view
that
inorganic
arsenic
does
not
pose
a
special
sensitivity
to
children.
In
that
notice,
the
Agency
agreed
with
a
report
by
the
National
Research
Council
noting
"
that
there
is
a
marked
variation
in
susceptibility
to
arsenicinduced
toxic
effects
which
may
be
influenced
by
factors
such
as
genetic
polymorphisms,
life
stage
at
which
exposures
occur,
sex,
nutritional
status,
and
concurrent
exposures
to
other
agents
or
environmental
factors."
However,
the
view
was
also
shared
between
the
EPA
and
NRC
that
"
there
is
insufficient
scientific
information
to
permit
separate
cancer
risk
estimates
for
potential
subpopulations...
and
that
factors
that
influence
sensitivity
to
or
expression
of
arsenic­
associated
cancer
and
non­
cancer
effects
need
to
be
better
characterized.
The
EPA
agrees
with
the
NRC
that
there
is
not
enough
information
to
make
risk
conclusions
regarding
any
specific
subpopulations."
In
the
latest
update
to
this
issue
(
NRC,
2001),
it
is
noted
that
while
"
evidence
from
human
studies
suggests
the
potential
for
adverse
effects
on
several
reproductive
endpoints...
"
there
are
no
reliable
data
that
indicate
heightened
susceptibility
of
children
to
arsenic."

Neurotoxicity
of
inorganic
arsenic
is
not
evident
in
studies
with
experimental
animals.
However,
there
is
a
large
body
of
epidemiology
studies
and
case
reports
which
describe
neurotoxicity
in
humans
after
both
acute
and
chronic
exposures,
characterized
by
headache,
lethargy,
seizures,
coma,
encephalopathy
(
after
acute
exposures
of
2
mg/
kg/
day
and
above),
and
peripheral
neuropathy
(
after
repeated
exposures
to
0.03­
0.1
mg/
kg/
day)
(
ATSDR,
2000a).

Mutagenicity
studies
using
inorganic
arsenic
have
shown
mixed
results.
Sodium
arsenite
is
not
genotoxic
to
Chinese
hamster
ovary
(
CHO)
cells
(
Rossman
et
al.,
1980)
or
Syrian
hamster
embryo
cells
(
Lee
et
al.,
1985b)
when
selecting
for
ouabain­
(
ATPase)
or
thioguanine­
resistant
(
hypoxanthine
phosphoribosyl
transferase,
HPRT)
mutants.
In
the
L5178Y
mouse
lymphoma
assay,
sodium
arsenite
is
weakly
genotoxic
at
the
thymidine
kinase
locus
without
metabolic
7
activation
(
Oberly
et
al.,
1982;
Moore
et
al.,
1997a).
Sodium
arsenate
is
even
a
weaker
mutagen
with
(
Oberly
et
al.,
1982)
and
without
metabolic
activation
(
Moore
et
al.,
1997a).
The
type
of
effects
reported
by
Moore
et
al.
(
1997a)
were
chromosomal
aberrations,
micronuclei
(
arsenite
only)
polyploidy
and
endoreduplication.

Sodium
arsenate
and
sodium
arsenite
induce
sister
chromatid
exchanges
and
chromosomal
aberrations
in
hamster
embryo
cells
(
10­
7mol/
litre­
10­
4mol/
litre)
(
Larramendy
et
al.,
1981;
Lee
et
al.,
1985b;
Kochhar
et
al.,
1996).
The
aberrations
are
characterized
by
chromatid
gaps,
breaks,
and
fragmentation,
endoreduplication
and
chromosomal
breaks.
These
clastogenic
effects
are
observed
at
lower
doses
of
arsenite
than
arsenate.
The
difference
may
be
due
to
greater
in
vitro
cellular
uptake
of
arsenite
than
arsenate
(
Lerman
et
al.,
1983;
Bertolero
et
al.,
1987).
GaAs
(
2.5­
10
µ
g/
ml)
did
not
induce
micronuclei
in
Syrian
hamster
embryo
cells
(
Gibson
et
al.,
1997).

Recently,
methylated
trivalent
forms
of
arsenic
have
been
shown
to
nick
and/
or
completely
degrade
 X174
DNA
in
vitro
(
Mass
et
al.,
2001),
while
sodium
arsenite,
arsenate,
and
the
pentavalent
methylated
forms
of
arsenic
were
without
effect.
In
the
single­
cell
gel
assay
(
COMET
assay)
using
human
lymphocytes,
inorganic
arsenite
and
arsenate
produced
concentrationdependent
linear
increases
in
DNA
damage,
but
the
methylated
trivalent
forms
of
arsenic
were
observed
to
be
54­
77
times
more
potent
in
this
assay
than
the
non­
methylated
forms.
DNA
damage
occurred
in
the
absence
of
metabolic
activation
in
both
assays.

1.1.3
Metabolism
Metabolism
of
inorganic
arsenic
first
proceeds
through
non­
enzymatic
reduction
of
arsenate
to
arsenite,
which
can
then
undergo
enzymatic
methylation
to
the
products
monomethylarsinic
acid
and
dimethylarsinic
acid.
These
products
are
then
reduced
to
the
monomethylarsinous
acid
and
dimethylarsinous
acid
produts.
The
major
site
of
methylation
appears
to
be
liver,
where
the
methylation
reaction
is
mediated
by
methyltransferase
enzymes
using
S­
adenylmethionine
as
a
cosubstrate.
The
products
of
inorganic
arsenic
metabolism
in
urine
have
been
identified
as
As(+
3),
As(+
5),
monomethylarsinous
acid,
and
dimethylarsinous
acid.
Urinary
products
appear
similar
among
species
studied
(
ATSDR,
2000a),
but
the
relative
proportions
of
these
products
vary
greatly.

1.2
Hazard
Characterization
­
Chromium
Chromium
is
a
naturally
occurring
element
found
in
animals,
plants,
rocks,
in
soil,
and
in
volcanic
dust
and
gases.
In
the
trivalent
(+
3)
state,
chromium
compounds
are
stable
and
occur
in
nature
in
this
state
in
ores
such
as
ferrochromite.
Chromium
(
VI)
is
second­
most
stable
relative
to
the
(+
3)
form,
but
rarely
occurs
naturally
and
is
usually
produced
from
anthropogenic
sources
(
ATSDR,
2000b).
The
general
population
is
exposed
to
chromium
by
inhalation
of
ambient
air,
ingestion
of
food,
and
drinking
of
water.
Dermal
contact
with
chromium
can
also
occur
from
skin
contact
with
products
containing
chromium
or
from
soils
containing
chromium.

In
humans
and
animals,
chromium
(
III)
is
an
essential
nutrient
that
plays
a
role
in
glucose,
fat,
and
8
protein
metabolism.
The
biologically
active
form
of
chromium
exists
as
a
complex
of
chromium
(
III),
nicotninc
acid,
and
possibly
the
amino
acids
glycine,
cysteine,
and
glutamic
acid
to
form
glucose
tolerance
factor.
GTF
is
believed
to
function
by
facilitating
the
interaction
of
insulin
with
its
cellular
receptor
sites
although
the
exact
mechanism
is
not
known.
The
National
Research
Council
recommends
a
dietary
intake
of
50­
200
micrograms
per
day
for
chromium
III.

Chromium
in
the
ambient
air
occurs
from
natural
sources,
industrial
and
product
uses,
and
burning
of
fossil
fuels
and
wood.
The
most
important
industrial
sources
of
chromium
in
the
atmosphere
originate
from
ferrochrome
production.
Ore
refining,
chemical
and
refractory
processing,
cement­
producing
plants,
automobile
brake
lining
and
catalytic
converters
for
automobiles,
leather
tanneries,
and
chrome
pigments
also
contribute
to
the
atmospheric
burden
of
chromium
(
Fishbein,
1981).

Surface
runoff,
deposition
from
air,
and
release
of
municipal
and
industrial
waste
waters
are
the
sources
of
chromium
in
surface
waters.

Ingested
hexavalent
chromium
is
efficiently
reduced
to
the
trivalent
form
in
the
gastrointestinal
tract
(
DeFlora
et
al.,
1987).
In
the
lungs,
hexavalent
chromium
can
be
reduced
to
the
trivalent
form
by
ascorbate
and
glutathione.
Given
the
rapid
reduction
of
Cr(
VI)
to
Cr(
III)
in
vivo,
it
is
relevant
to
consider
whether
environmental
exposures
to
Cr(
VI)
or
administration
of
Cr(
VI)
in
controlled
animal
experiments
is
essentially
identical
to
environmental
exposures
to
Cr(
III)
or
administration
of
Cr(
III)
in
controlled
experiments.
For
chromium,
hazard
data
show
clearly
that
Cr
(
VI)
demonstrates
more
significant
toxicity
than
Cr
(
III).
The
Agency
has
not
identified
any
endpoints
of
concern
for
Cr(
III).
For
exposure
to
Cr(
VI),
the
Agency
has
identified
toxicological
endpoints
of
concern
and
has
used
these
endpoints
in
conjunction
with
exposure
to
Cr(
VI)
for
evaluating
risks
associated
with
Cr
(
VI).

1.2.1
Acute
Toxicity
The
acute
toxicity
summary
of
the
Chromium
(
VI)
is
summarized
in
Table
2.
In
acute
toxicity
animal
studies,
administration
of
chromium
(
VI)
(
as
chromic
acid)
by
the
oral,
dermal,
and
inhalation
routes
resulted
in
significant
acute
toxicity
as
measured
by
lethality.
The
measured
oral
LD50
in
rats
was
reported
as
52
mg/
kg,
the
dermal
LD50
as
57
mg/
kg,
and
the
inhalation
LC50
as
0.217
mg/
L,
placing
chromium
(
VI)
in
Toxicity
Category
I
for
acute
lethality.
Human
reports
of
death
after
ingestion
of
chromium
show
lethality
at
similar
dose
levels
(
ATSDR,
1998).
Chromium
(
VI)
is
a
significant
eye
and
skin
irritant,
and
severe
allergic
reactions
consisting
of
redness
and
swelling
of
the
skin
have
also
been
noted
in
exposed
animals
and
humans.
Case
reports
of
humans
who
have
intentionally
or
accidentally
ingested
chromium
have
also
shown
severe
respiratory
effects
(
pulmonary
edema,
bronchitis,
bronchopneumonia),
cardiovascular
effects
(
cardiac
arrest),
and
gastrointestinal
effects
(
hemorrhage,
ulceration).

In
contrast
to
the
acute
toxicity
of
chromium
(
VI),
acute
toxicity
data
for
chromium
(
III)
show
less
severe
acute
toxicity,
with
oral
LD50
values
in
rats
reported
as
183­
200
mg/
kg
or
2365
mg/
kg.
There
are
no
reports
of
lethality
in
experimental
animals
after
acute
inhalation
or
acute
dermal
exposure
to
chromium
(
III).
However,
skin
irritation
and
sensitization
have
also
been
9
observed
from
exposure
to
chromium
(
III).

The
dermal
irritancy
and
sensitization
potential
of
chromium
compounds
are
worthy
of
note.
The
potent
skin
allergenicity
of
chromium
has
been
well
documented
in
the
literature,
and
chromium
compounds
have
been
reported
to
be
the
most
frequent
sensitizing
agents
in
man
(
IRIS,
2000).
The
prevalence
of
Cr(
VI)
sensitivity
among
the
general
U.
S.
population
is
estimated
to
be
0.08%,
based
on
studies
conducted
by
Proctor
et
al
(
1998).
Most
of
the
occurrences
of
contact
dermatitis
and
sensitization
cited
are
from
the
result
of
occupational
exposures,
but
include
the
wood
preserving
industry
(
Burrows,
1983).
For
previously
sensitized
individuals,
very
low
dosage
of
Cr(
VI)
can
elicit
allergic
contact
dermatitis.
Several
studies
document
the
sensitization
reactions
observed
in
humans
previously
exposed
dermally
to
chromium
(
VI)
compounds.
Sensitization
can
also
be
observed
in
humans
with
chromium
(
III)
if
exposure
concentration
is
high
enough
(
ATSDR,
2000b).
Bagdon
(
1991)
collected
skin
hypersensitivity
data
for
trivalent
chromium
compounds
in
human
subjects
and
concluded
that
the
threshold
level
for
evoking
hypersensitivity
reactions
from
trivalent
chromium
compounds
is
approximately
50­
fold
higher
than
for
hexavalent
chromium
compounds.

Experimental
animal
models
also
show
that
sensitization
to
chromium
compounds
can
occur,
and
in
some
cases,
the
sensitization
response
observed
is
similar
using
an
equivalent
dose
of
either
chromium
(
VI)
or
chromium
(
III)
(
ATSDR,
2000b).
10
Table
2:
Acute
Toxicity
Summary
of
the
Chromium
(
VI)

Guideline
Study
Type
[
Substance]
MRID/
Literature
Results
Toxicity
Category
81­
1
(
OPPTS
870.1100)
Acute
Oral/
Rat
[
Chromic
Acid,
100%
a.
i.]
434294­
01
LD50
=

56
mg/
kg
=

48
mg/
kg
M+
F
=
52
mg/
kg
I
81­
2
(
OPPTS
870.1200)
Acute
Dermal/
Rabbit
[
Chromic
Acid,
100%
a.
i.]
434294­
02
LD50
=

>
48
mg/
kg
=

48
mg/
kg
M+
F
=
57
mg/
kg
I
81­
3
(
OPPTS
870.1300)
Acute
Inhalation/
Rat
[
Chromic
Acid,
100%
a.
i.]
434294­
03
LC50
=

0.263
mg/
L
=

0.167
mg/
L
M+
F
=
0.217
mg/
L
I
81­
4
(
OPPTS
870.2400)
Primary
Eye
Irritation
[
Various
Cr(
VI)
compounds]
Literature
Waiver
Corrosive
I
81­
5
(
OPPTS
870.2500)
Primary
Dermal
Irritation
[
Various
Cr(
VI)
compounds]
Literature
Waiver
Corrosive
I
81­
6
(
OPPTS
870.2600)
Dermal
Sensitization
/
Guinea
Pig
[
Various
Cr(
VI)
compounds]
Literature
Strong
sensitizer
11
1.2.2
Non­
Acute
Toxicity
Subchronic
toxicity
studies
in
experimental
animals
have
demonstrated
hematologic
and
hepatic
effects
from
repeated
oral
exposure
to
chromium
(
VI).
In
a
9
week
study
in
which
male
and
female
Sprague­
Dawley
rats
were
fed
diets
containing
potassium
dichromate
at
dose
levels
of
0,
15,
50,
100,
or
400
ppm
potassium
dichromate
[
NTP,
1996],
there
were
no
treatment
related
findings
noted
in
mean
body
weights,
water
and
feed
consumption,
organ
weights
or
microscopic
pathology
of
the
liver,
kidneys
and
ovaries.
Hematology
findings
effects
consisted
of
decreases
in
mean
corpuscular
volume
(
MCV)
and
mean
corpuscular
hemoglobin
(
MCH)
at
the
high
dose
(
8.4
and
9.8
mg/
kg/
day
in
male
and
female
rats
respectively).
There
were
no
reported
hepatic
effects
in
this
study.
However,
Kumar
and
Rana
(
1992)
reported
increased
accumulation
of
hepatic
lipids
after
gavage
treatment
of
rats
with
13.5
mg/
kg
chromium
(
VI)
(
as
potassium
chromate)
after
20
days
of
treatment.

In
a
9­
week
feeding
study
in
mice
conducted
by
the
National
Toxicology
Program
(
1996)
in
which
mice
were
fed
diets
containing
1.1,
3.5,
7.4,
and
32
mg/
kg/
day
chromium
(
males)
or
1.8,
5.6,
12,
and
48
mg/
kg/
day
chromium
(
females),
hepatic
cytoplasmic
vacuolization
was
observed
to
be
slightly
increased
at
the
high
dose
in
males
and
females,
and
the
appearance
of
the
vacuoles
was
suggestive
of
lipid
accumulation.
Additional
endpoints
examined
in
this
study
included
body
weights,
feed
and
water
consumption,
organ
weights,
microscopic
evaluation
of
the
liver,
kidney
and
ovaries,
hematology,
histology
of
the
testis
and
epididymis
for
Sertoli
nuclei,
and
preleptotene
spermatocyte
counts
in
Stage
X
or
XI
tubules
and
chromatin
analysis.
Slight
decreases
in
body
weight
were
observed
during
this
study,
but
there
was
no
significant
effect
of
treatment
on
clinical
signs,
necropsy
findings,
or
microscopic
histology.
Hematologic
effects
were
observed
and
consisted
of
a
2­
4%
decrease
in
MCV
at
weeks
3,
6,
and
9
in
high
dose
males
and
females
and
at
week
6
in
the
100
ppm
females.
The
MCV
returned
to
normal
in
the
female
mice
after
the
recovery
period
(
week
17);
however
the
MCV
increased
2.8%
in
the
400
ppm
males.

The
MCV
changes
at
weeks
3,
6
and
9
were,
in
general
associated
with
small
decreases
in
the
RBC,
and
small
decreases
in
the
MCH,
although
only
the
MCH
values
from
the
400
ppm
males
(
week
9),
the
400
ppm
females
(
Weeks
3
and
6),
the
15
and
100
ppm
females
(
week
3)
were
decreased.

Occupational
exposure
to
chromium
by
inhalation
has
been
studied
in
the
chromate
manufacturing
and
ferrochromium
industries;
however,
exposures
all
include
mixed
exposures
to
both
Cr(
III)
and
Cr(
VI).
The
Cr(
VI)
species
is
widely
considered
to
be
the
causative
agent
in
reports
of
excess
cancer
risk
in
chromium
workers.
However,
studies
are
inadequate
to
rule
out
a
contribution
by
Cr(
III),
and
Cr(
VI)
cannot
be
unequivocally
demonstrated
to
be
the
causative
agent
for
noncarcinogenic
effects
following
inhalation.

A
number
of
epidemiologic
studies
have
considered
the
association
between
inhalation
of
chromium
and
noncarcinogenic
endpoints,
including
upper
respiratory
irritation
and
atrophy,
lower
respiratory
effects,
and
systemic
effects.
Symptoms
reported
from
inhalation
exposure
to
mists
and
dusts
containing
chromium
have
included
nasal
tissue
damage,
perforated
septum,
12
ulcerated
septum,
chrome
holes,
nosebleed,
inflamed
mucosa,
nasal
septal
perforation,
and
nasal
septal
ulceration
(
USEPA
IRIS,
1998).
Exposure
to
vapors
of
chromium
salts
has
also
been
suspected
as
a
cause
of
asthma,
coughing,
wheezing,
and
other
respiratory
distress
in
ferrochromium
workers.

Despite
the
consistency
of
the
reported
effects
from
inhalation
of
chromium
contained
in
dusts
and
mists,
the
actual
Cr(
III)
and
Cr(
VI)
exposure
levels
in
many
of
the
studies
attributing
respiratory
effects
to
chromium
were
unknown.
In
addition,
data
on
other
confounding
factors
such
as
smoking
were
frequently
unavailable.
These
caveats
significantly
complicate
determination
of
the
potential
health
effects
associated
with
inhalation
exposure
to
chromium
(
ATSDR,
2000b).

Although
human
data
examining
developmental
endpoints
are
scarce,
animal
studies
have
consistently
shown
that
chromium,
particularly
chromium(
VI),
is
a
developmental
toxicant.
Oral
ingestion
of
chromium
(
VI)
compounds
in
experimental
animals
results
in
significant
developmental
toxicity.
Studies
describing
the
effects
observed
have
been
published
in
the
IRIS
Toxicological
Reviews
for
both
chromium
(
VI)
and
chromium
(
III)
as
well
as
from
submitted
studies
to
the
Agency
and
are
summarized
here.

Trivedi
et
al.
(
1989)
exposed
mice
to
250,
500,
and
1,000
ppm
potassium
dichromate
daily
through
drinking
water
during
the
entire
gestational
period.
The
authors
reported
decreased
fetal
weight,
increased
resorptions,
and
increased
abnormalities
(
tail
kinking,
delayed
ossification
of
the
cranium)
in
exposed
mice.
The
medium­
and
high­
dose
groups
registered
significant
reductions
in
body
weight
gain
when
compared
to
controls.
The
most
significant
finding
of
the
study
was
the
complete
absence
of
uterine
implantation
in
the
high­
dose
group.
The
250
and
500
ppm
dose
groups
also
showed
significant
incidences
of
resorption
as
compared
to
controls.
The
authors
observed
significant
increases
in
preimplantation
and
postimplantation
losses
and
dosedependent
reductions
in
total
weight
and
crown­
rump
length
in
the
lower
dose
groups.
Additional
effects
included
treatment­
related
increases
in
abnormalities
in
the
tail,
wrist
forelimbs
and
subdermal
hemorrhagic
patches
in
the
offspring.

Junaid
et
al.
(
1996)
exposed
female
Swiss
albino
mice
to
250,
500,
or
750
ppm
potassium
dichromate
in
drinking
water
to
determine
the
potential
embryotoxicity
of
hexavalent
chromium
during
days
6­
14
of
gestation.
No
notable
changes
in
behavior
or
clinical
signs
were
observed
in
the
control
or
treated
dams.
Chromium
levels
in
blood,
placenta,
and
fetus
increased
in
a
dosedependent
fashion
over
the
course
of
the
study.
The
authors
reported
retarded
fetal
development
and
embryo­
and
fetotoxic
effects
including
reduced
fetal
weight,
reduced
number
of
fetuses
(
live
and
dead)
per
dam,
and
higher
incidences
of
stillbirths
and
postimplantation
loss
in
the
500
and
750
ppm
dosed
mothers.
Significantly
reduced
ossification
in
nasal,
frontal,
parietal,
interparietal,
caudal,
and
tarsal
bones
was
observed
in
the
high­
dose
group,
while
reduced
ossification
in
only
the
caudal
bones
was
observed
in
the
500
ppm
dose
group.
Based
on
the
body
weight
of
the
animals
(
30
+/­
5
g)
and
the
drinking
water
ingested
by
the
animals
in
the
250
ppm
dose
group
(
8.0
ml/
mouse/
day),
the
dose
level
in
the
250
ppm
group
can
be
identified
as
67
mg/
kg­
day.
The
maternal
NOAEL
was
63
[
22.3]
mg/
kg/
day
while
the
LOAEL
was
42.1
mg/
kg/
day
and
was
based
on
a
decreased
gestational
body
weight.
At
the
lowest
dose
tested,
the
incidence
of
resorptions
was
increased
and
a
developmental
NOAEL
was,
therefore,
not
13
determined.

Kanojia
et
al.
(
1996)
exposed
female
Swiss
albino
rats
to
250,
500,
or
750
ppm
potassium
dichromate
in
drinking
water
for
20
days
3
months
prior
to
gestation
to
determine
the
potential
teratogenicity
of
hexavalent
chromium.
No
notable
changes
in
behavior
or
clinical
signs
were
observed
in
the
control
or
treated
dams.
Chromium
levels
in
blood,
placenta,
and
fetus
were
significantly
increased
in
the
dams
of
the
500
and
750
ppm
dose
groups.
The
authors
reported
a
reduced
number
of
corpora
lutea
and
implantations,
retarded
fetal
development,
and
embryo­
and
fetotoxic
effects
including
reduced
number
of
fetuses
(
live
and
dead)
per
dam
and
higher
incidences
of
stillbirths
and
postimplantation
loss
in
the
500
and
750
ppm
dosed
mothers.
Significantly
reduced
parietal
and
interparietal
ossification
was
observed
in
the
high­
dose
group.
Based
on
the
body
weight
of
the
animals
(
175
+/­
25
g)
and
the
drinking
water
ingested
by
the
animals
in
the
250
ppm
dose
group
(
26
ml/
mouse/
day)
the
dose
level
in
the
250
ppm
group
can
be
identified
as
37
mg/
kg­
day.

Tyl
(
1991)
examined
the
developmental
and
maternal
effects
of
daily
administration
of
chromic
acid
(
55.0%
a.
i.)
at
dosages
of
0,
0.1,
0.5,
2.0
or
5.0
mg/
kg/
day
by
gavage
in
rabbits.
Clinical
signs
of
toxicity
,
including
diarrhea,
and
slow,
audible
or
labored
breathing
were
observed
in
predominately
in
the
2.0
and
5.0
mg/
kg/
day
groups.
However,
these
signs
did
not
show
a
doseresponse
and
were
observed
in
lesser
incidence
at
5.0
mg/
kg/
day
vs.
2.0
mg/
kg/
day.
However,
the
incidence
of
mortality
(
at
2.0
mg/
kg/
day,
one
doe
died
on
gestation
day
(
GD)
28;
at
5.0
mg/
kg/
day,
5
does
died
(
one
each
on
GD
10,
14,
and
two
on
GD
15)
and
the
magnitude
of
decreased
body
weight
gain
during
the
dosing
period
(
average
weight
loss
of
48
grams
at
2.0
mg/
kg/
day,
and
average
weight
loss
of
140
grams
at
5.0
mg/
kg/
day
during
gestation
days
7­
19)
were
observed
to
occur
in
a
dose­
related
fashion
at
2.0
and
5.0
mg/
kg/
day.
Food
efficiency
was
also
observed
to
be
significantly
lower
during
the
dosing
period
in
the
5.0
mg/
kg/
day
dose
group.
Cesarean
section
observations
were
unremarkable
in
this
study
at
any
dose
level.
No
treatment
related
effects
on
either
fetal
malformations
or
variations
were
observed.
The
Maternal
NOAEL
=
0.5
[
0.12]
mg/
kg/
day
and
LOAEL
=
2.0
[
0.48]
mg/
kg/
day
(
based
on
the
increased
incidence
of
maternal
mortality
and
decreased
body
weight
gain
).
The
Developmental
NOAEL
=
2.0
[
0.48]
mg/
kg/
day
and
LOAEL
>
2.0
[>
0.48]
mg/
kg/
day
based
on
the
lack
of
developmental
effects
at
any
dose
level
tested.

By
contrast
to
effects
of
chromium
(
VI),
effects
on
development
and
reproduction
from
exposure
to
Cr
(
III)
show
either
negative
results
or
effects
only
at
high
doses.
For
example,
male
and
female
rats
treated
with
1,806
mg
Cr(
III)
kg/
day
as
Cr(
III)
oxide
5
days/
week
for
60
days
before
gestation
and
throughout
the
gestation
period
had
normal
fertility,
gestational
length,
and
litter
size
(
Ivankovic
and
Preussman,
1975).
Elbetieha
and
Al­
Hamood
(
1997)
examined
fertility
following
chromium
chloride
exposures
in
mice.
Sexually
mature
male
and
female
mice
were
exposed
to
1,000,
2,000,
or
5,000
mg/
L
chromium
chloride
in
drinking
water
for
12
weeks.
Exposure
of
male
mice
to
5,000
ppm
trivalent
chromium
compounds
for
12
weeks
had
adverse
impacts
on
male
fertility.
Testes
weights
were
increased
in
the
males
exposed
in
the
2,000
and
5,000
mg/
L
dose
groups,
while
seminal
vesicle
and
preputial
gland
weights
were
reduced
in
the
5,000
mg/
L
exposed
males.
The
number
of
implantation
sites
and
viable
fetuses
were
significantly
reduced
in
females
exposed
to
2,000
and
5,000
mg/
L
chromium
chloride.
Water
consumption
was
14
not
reported
precluding
calculation
of
the
doses
received.
However
it
is
evident
that
adverse
effects
were
observed
only
at
a
high
dose
of
Cr
(
III).

The
National
Toxicology
Program
conducted
a
three­
part
study
to
investigate
oral
ingestion
of
hexavalent
chromium
in
experimental
animals
(
NTP,
1996a,
b,
1997).
The
study
included
a
determination
of
the
potential
reproductive
toxicity
of
potassium
dichromate
in
Sprague­
Dawley
rats,
a
repeat
of
the
study
of
Zahid
et
al.
(
1990)
using
BALB/
C
mice,
and
a
Reproductive
Assessment
by
Continuous
Breeding
study
in
BALB/
C
mice.
The
study
in
the
Sprague­
Dawley
rat
(
NTP,
1996a)
was
conducted
in
order
to
generate
data
in
a
species
commonly
used
for
regulatory
studies.
Groups
of
24
males
and
48
females
were
exposed
to
0,
15,
50,
100,
or
400
ppm
potassium
dichromate
daily
in
the
diet
for
9
weeks
followed
by
a
recovery
period
of
8
weeks.
Six
male
and
12
female
rats
were
sacrificed
after
3,
6
or
9
full
weeks
of
treatment
or
after
the
full
recovery
period.
Animals
were
examined
for
body
weights;
feed
and
water
consumption;
organ
weights;
microscopic
evaluation
of
the
liver,
kidney,
and
ovaries;
hematology;
histology
of
the
testis
and
epididymus
for
Sertoli
nuclei
and
preleptotene
spermatocyte
counts
in
Stage
X
or
XI
tubules;
and
chromatin
analysis.
No
treatment­
related
hematology
findings
were
reported
except
for
slight
decreases
in
MCV
and
MCH
values
in
the
male
and
female
treatment
groups
receiving
400
ppm
potassium
dichromate
(
24
mg/
kg­
day).
While
the
trends
in
MCV
and
MCH
were
not
large
and
were
within
the
reference
ranges,
they
are
consistent
with
the
findings
of
the
companion
studies
in
BALB/
C
mice
and
were
characterized
by
the
authors
as
suggestive
of
a
potential
bone
marrow/
erythroid
response.
The
authors
considered
the
100
ppm
(
6
mg/
kg­
day)
dose
group
to
be
representative
of
the
NOAEL
for
the
study.

The
reproductive
study
in
BALB/
C
mice
(
NTP,
1996b)
was
conducted
to
reproduce
the
conditions
utilized
by
Zahid
et
al.
(
1990)
in
their
examination
of
comparative
effects
of
trivalent
and
hexavalent
chromium
on
spermatogenesis
of
the
mouse.
Groups
of
24
male
and
48
female
BALB/
C
mice
were
exposed
to
0,
15,
50,
100,
or
400
ppm
potassium
dichromate
in
the
diet
for
9
weeks
followed
by
a
recovery
period
of
8
weeks.
Six
male
and
12
female
mice
were
sacrificed
after
3,
6,
or
9
full
weeks
of
treatment
or
after
the
full
recovery
period.
Animals
were
examined
for
body
weights;
feed
and
water
consumption;
organ
weights;
microscopic
evaluation
of
the
liver,
kidney,
and
ovaries;
hematology;
histology
of
the
testis
and
epididymus
for
Sertoli
nuclei
and
preleptotene
spermatocyte
counts
in
Stage
X
or
XI
tubules;
and
chromatin
analysis.
Treatment­
related
effects
included
a
slight
reduction
in
the
mean
body
weights
in
the
400
ppm
males
and
the
100
ppm
females,
a
slight
increase
in
food
consumption
at
all
dose
levels,
a
slight
decrease
in
MCV
and
MCH
at
400
ppm,
and
cytoplasmic
vacuolization
of
the
hepatocyte
at
50,
100
and
400
ppm.
None
of
the
effects
on
spermatogenesis
reported
by
Zahid
et
al.
(
1990)
were
observed
in
this
study.
On
the
basis
of
the
cytoplasmic
vacuolization
of
the
hepatocyte
in
the
50,
100,
and
400
ppm
dose
groups,
the
authors
selected
15
ppm
(
4
mg/
kg­
day)
as
the
NOAEL.

Increased
resorptions
and
increased
post­
implantation
loss
as
well
as
gross
fetal
abnormalities
were
observed
in
offspring
of
pregnant
mice
exposed
to
potassium
dichromate
at
57
mg/
kg/
day
in
drinking
water
during
gestation
(
ATSDR,
2000b).
At
a
higher
dose
of
234
mg/
kg/
day,
no
implantations
were
observed
in
maternal
mice.
In
a
second
study
in
mice,
potassium
dichromate
was
administered
in
the
diet
for
7
weeks
at
dose
levels
of
15.1
and
28
mg/
kg/
day.
Reduced
sperm
counts
and
degeneration
of
the
outer
layer
of
the
seminiferous
tubules
was
observed
at
the
15.1
15
mg/
kg/
day
dose,
and
morphologically
altered
sperm
was
observed
at
the
28
mg/
kg/
day
dose.

In
male
rats
administered
20
mg/
kg/
day
chromium
trioxide
for
90
days
by
gavage,
reduced
testicular
weight,
decreased
testicular
testosterone,
and
reduced
Leydig
cell
number
was
observed
(
Chowdhury
and
Mitra,
1995).

Despite
the
wealth
of
animal
studies
on
the
developmental
and
reproductive
toxicity
of
chromium
VI,
there
are
too
few
human
data
with
which
to
make
any
reliable
conclusion
regarding
the
susceptibility
of
the
developing
fetus,
infants,
or
children
to
the
toxic
effects
of
chromium
VI.
The
evidence
available
suggests
similar
toxic
effects
in
adults
and
children
from
ingestion
of
chromium
VI
(
ATSDR,
2000b).

Hexavalent
chromium
(
Cr
VI)
is
known
to
be
carcinogenic
in
humans
by
the
inhalation
route
of
exposure.
Results
of
occupational
epidemiologic
studies
of
chromium­
exposed
workers
are
consistent
across
investigators
and
study
populations.
Dose­
response
relationships
have
been
established
for
chromium
exposure
and
lung
cancer.
Chromium­
exposed
workers
are
exposed
to
both
Cr(
III)
and
Cr(
VI)
compounds.
Because
only
Cr(
VI)
has
been
found
to
be
carcinogenic
in
animal
studies,
however,
it
was
concluded
that
only
Cr(
VI)
should
be
classified
as
a
human
carcinogen.

Animal
data
are
consistent
with
the
human
carcinogenicity
data
on
hexavalent
chromiumby
the
inhalation
route.
Hexavalent
chromium
compounds
are
also
carcinogenic
in
animal
bioassays
by
other
routes
of
exposure,
such
as:
intramuscular
injection
site
tumors
in
rats
and
mice,
intrapleural
implant
site
tumors
for
various
Cr(
VI)
compounds
in
rats,
intrabronchial
implantation
site
tumors
for
various
Cr(
VI)
compounds
in
rats,
and
subcutaneous
injection
site
sarcomas
in
rats
(
IRIS,
2001).
However,
these
routes
of
administration
are
not
relevant
to
exposures
of
chromium
in
CCA­
treated
wood.

Data
addressing
human
carcinogenicity
from
exposures
to
Cr(
III)
alone
are
not
available,
and
data
are
inadequate
for
an
evaluation
of
human
carcinogenic
potential.
Two
oral
studies
located
in
the
available
literature
(
Schroeder
et
al.,
1965;
Ivankovic
and
Preussman,
1975)
reported
negative
results
for
rats
and
mice.
Several
animal
studies
have
been
performed
to
assess
the
carcinogenic
potential
of
Cr(
III)
by
inhalation.
These
studies
have
not
found
an
increased
incidence
of
lung
tumors
following
exposure
either
by
natural
routes,
intrapleural
injection,
or
intrabronchial
implantation
(
Baetjer
et
al.,
1959;
Hueper
and
Payne,
1962;
Levy
and
Venitt,
1975;
Levy
and
Martin,
1983).

The
data
from
oral
and
inhalation
exposures
of
animals
to
trivalent
chromium
do
not
support
determination
of
the
carcinogenicity
of
trivalent
chromium.
IARC
(
1990)
concluded
that
animal
data
are
inadequate
for
the
evaluation
of
the
carcinogenicity
of
Cr(
III)
compounds.
Furthermore,
although
there
is
sufficient
evidence
of
respiratory
carcinogenicity
associated
with
exposure
to
chromium,
the
relative
contributions
of
Cr(
III),
Cr(
VI),
metallic
chromium,
or
soluble
versus
insoluble
chromium
to
carcinogenicity
cannot
be
elucidated.
16
In
vitro
data
are
suggestive
of
a
potential
mode
of
action
for
hexavalent
chromium
carcinogenesis.
Hexavalent
chromium
carcinogenesis
may
result
from
the
formation
of
mutagenic
oxidatitive
DNA
lesions
following
intracellular
reduction
to
the
trivalent
form.
Cr(
VI)
readily
passes
through
cell
membranes
and
is
rapidly
reduced
intracellularly
to
generate
reactive
Cr(
V)
and
Cr(
IV)
intermediates
a
reactive
oxygen
species.
A
number
of
potentially
mutagenic
DNA
lesions
are
formed
during
the
reduction
of
Cr(
VI).
Hexavalent
chromium
is
mutagenic
in
bacterial
assays,
yeasts,
and
V79
cells,
and
Cr(
VI)
compounds
decrease
the
fidelity
of
DNA
synthesis
in
vitro
and
produce
unscheduled
DNA
synthesis
as
a
consequence
of
DNA
damage.
Chromate
has
been
shown
to
transform
both
primary
cells
and
cell
lines
(
ATSDR,
2000b).

Intracellular
reduction
of
Cr(
VI)
generates
reactive
chromium
V
and
chromium
IV
intermediates
as
well
as
hydroxyl
free
radicals
(
OH)
and
singlet
oxygen.
A
variety
of
DNA
lesions
are
generated
during
the
reduction
of
Cr(
VI)
to
Cr(
III),
including
DNA
strand
breaks,
alkali­
labile
sites,
DNAprotein
and
DNA­
DNA
crosslinks,
and
oxidative
DNA
damage,
such
as
8­
oxo­
deoxyguanosine.
The
relative
importance
of
the
different
chromium
complexes
and
oxidative
DNA
damage
in
the
toxicity
of
Cr(
VI)
is
unknown.

Hexavalent
chromium
has
been
shown
to
be
genotoxic
only
in
the
presence
of
appropriate
reducing
agents
in
vitro
or
in
viable
cell
systems
in
vitro
or
in
vivo.
Hexavalent
chromium
has
been
shown
to
be
mutagenic
in
bacterial
systems
in
the
absence
of
a
mammalian
activating
system,
and
not
mutagenic
when
a
mammalian
activating
system
is
present.
Hexavalent
chromium
is
also
mutagenic
in
eukaryotic
test
systems
and
clastogenic
in
cultured
mammalian
cells.

Hexavalent
chromium
in
the
presence
of
glutathione
has
been
demonstrated
to
produce
genotoxic
DNA
adducts
that
inhibit
DNA
replication
and
are
mutagenic
(
IRIS,
2000).
Chromium
(
III)
has
also
produced
positive
mutagenic
responses
in
vitro
(
IRIS,
2000).

1.2.3
Metabolism
Absorption
of
chromium
by
the
oral
route
ranges
from
essentially
zero
for
the
insoluble
chromium
III
compound
chromic
oxide
to
10%
for
potassium
chromate.
Absorption
through
exposure
in
the
diet,
in
water,
or
from
contaminated
soil
is
consistently
low,
with
values
reported
in
the
range
of
1­
5%
(
ATSDR,
2000b;
USEPA,
1998).
Hexavalent
chromium
can
be
reduced
to
the
trivalent
form
in
the
epithelial
lining
fluid
of
the
lungs
by
ascorbate
and
glutathione
as
well
as
by
gastric
juice
in
the
stomach,
which
contributes
to
the
low
oral
absorption.
Absorption
by
the
dermal
route
is
also
low
(
1.3%
after
24
hours
as
reported
by
Bagdon
et
al.,
1991)

Once
absorbed,
chromium
compounds
are
distributed
to
all
organs
of
the
body
without
any
preferential
distribution
to
any
one
organ.
However,
exposures
to
higher
levels
of
chromium,
such
as
can
occur
in
the
chrome
plating
industry
and
chrome
refining
plants,
may
result
in
accumulation
of
chromium
in
tissues.
Witmer
et
al.
(
1989,
1991)
studied
chromium
distribution
in
tissues
of
rats
administered
chromium
via
gavage.
In
one
experiment,
the
highest
dose
of
sodium
chromate
[
5.8
mg
Cr(
VI)/
kg/
day
for
7
days]
resulted
in
concentrations
of
chromium
in
the
tissues
in
the
following
order:
liver
(
22

g
chromium/
whole
organ)
>
kidney
(
7.5

g)
>
lung
(
4.5

g)
>
blood
17
(
2

g)
>
spleen
(
1

g).
These
tissues
combined
retained
about
1.7%
of
the
administered
dose;
however,
some
tissues
were
not
analyzed.
At
the
two
lower
doses
administered
(
1.2
or
2.3
mg/
kg/
day),
very
little
chromium
was
detected
(<
0.5
µ
g/
organ)
in
the
organs
analyzed.

Maruyama
(
1982)
studied
the
chromium
content
in
major
organs
of
mice
exposed
to
potassium
dichromate
[
Cr(
VI)]
or
chromium
trichloride
([
Cr(
III)]
for
1
year
in
drinking
water.
Groups
of
mice
received
4.4,
5.0
or
14.2
mg
Cr(
VI)/
kg/
day
or
4.8,
6.1
or
12.3
mg
Cr(
III)/
kg/
day.
Examination
of
organs
and
blood
in
mice
that
received
Cr(
VI)
revealed
that
the
liver
and
spleen
had
the
highest
levels
of
chromium,
although
some
chromium
accumulation
was
observed
in
all
tissues.
In
mice
that
received
Cr(
III),
the
liver
was
the
only
organ
with
detectable
amounts
of
chromium,
and
at
levels
that
were
about
40­
90
times
less
than
in
mice
that
received
the
Cr(
VI)
compound.
MacKenzie
et
al.
(
1958)
reported
that
in
rats
following
the
administration
of
similar
concentrations
of
Cr(
VI)
as
potassium
chromate
or
Cr(
III)
as
chromium
trichloride
in
drinking
water
for
1
year,
tissue
levels
were
approximately
9
times
greater
in
rats
that
received
the
Cr(
VI)
compound,
compared
to
rats
that
received
the
Cr(
III)
compound.

If
hexavalent
chromium
is
absorbed,
it
can
readily
enter
red
blood
cells
through
facilitated
diffusion,
where
it
will
be
reduced
to
the
trivalent
form
by
glutathione.
During
reduction
to
the
trivalent
form,
chromium
may
interact
with
cellular
macromolecules,
including
DNA
(
Wiegand
et
al.,
1985),
or
may
be
slowly
released
from
the
cell
(
Bishop
and
Surgenor,
1964).
Chromium
III
can
be
cleared
rapidly
from
the
blood
but
more
slowly
from
tissues,
which
may
be
related
to
the
formation
of
trivalent
chromium
complexes
with
proteins
or
amino
acids
(
Bryson
and
Goodall,
1983).

The
liver
is
a
primary
site
of
chromium
metabolism
and
has
been
studied
in
animals.
Incubation
of
Cr(
VI)
with
rat
liver
microsomes
in
the
presence
of
the
enzyme
cofactor
nicotinamide
adenine
dinucleotide
phosphate
(
NADPH)
resulted
in
the
reduction
of
Cr(
VI)
to
Cr(
III)
(
ATSDR,
2000b).
Exclusion
of
the
co­
factors
necessary
for
the
production
of
NADPH
resulted
in
a
large
decrease
in
the
reduction
of
Cr(
VI)
to
Cr
(
III).

Chromium
metabolism
can
result
in
the
formation
of
species
that
interact
with
deoxyribonucleic
acid
(
DNA).
The
reduction
of
Cr(
VI)
to
a
Cr(
V)
intermediate
involves
a
single
electron
transfer
from
the
microsomal
electron­
transport
cytochrome
P­
450
system
(
Jennette
1982).
These
reactive
Cr(
V)
complexes/
intermediates
are
relatively
unstable
and
persist
for
approxim­
ately
1
hour
in
vitro.
During
this
time
the
Cr(
V)
complexes/
intermediates
can
interact
with
deoxyribonucleic
acid
(
DNA),
which
may
eventually
lead
to
cancer.
When
Cr(
VI)
interacts
with
glutathione,
Cr(
V)
complexes
and
glutathione
thonyl
radicals
were
produced,
and
when
Cr(
VI)
interacts
with
DNA
and
glutathione,
DNA
adducts
were
formed
(
Aiyar
et
al.
1989).
The
formation
of
Cr(
V)
was
found
to
correlate
with
DNA
adduct
formation.
Following
reactions
of
Cr(
VI)
with
hydrogen
peroxide,
hydroxyl
radicals
were
produced;
the
addition
of
DNA
resulted
in
the
formation
of
an
8­
hydroxy
guanine
adduct
and
DNA
strand
breakage.

The
elimination
of
chromium
after
oral
exposure
has
been
studied
in
both
humans
and
animals.
In
one
study,
human
volunteers
received
an
acute
oral
dose
of
radiolabeled
Cr(
III)
or
Cr(
VI)
18
(
Donaldson
and
Barreras
1966).
Fecal
samples
were
collected
for
24
hours,
and
urine
samples
were
collected
for
6
days
and
analyzed
for
chromium.
Approximately
99.6%
of
the
Cr(
III)
compound
was
recovered
in
the
6­
day
fecal
sample,
while
89.4%
of
the
Cr(
VI)
compound
was
recovered.
The
results
of
the
analysis
of
the
24­
hour
urine
samples
indicated
that
0.5%
and
2.1%
of
the
administered
dose
of
the
Cr(
III)
and
the
Cr(
VI)
compounds,
respectively,
were
recovered
in
the
urine.
Other
potential
routes
of
excretion
include
hair,
fingernails
and
breast
milk
(
ATSDR
2000b).

In
several
studies
in
which
rats
and
hamsters
were
fed
Cr(
VI)
compounds,
fecal
excretion
of
chromium
varied
slightly
from
97%
to
99%
of
the
administered
dose,
and
urinary
excretion
of
chromium,
administered
as
Cr(
III)
or
Cr(
VI)
compounds,
varied
from
0.6%
to
1.4%
of
the
dose
(
Donaldson
and
Barreras
1966,
Henderson
et
al.
1979,
Sayato
et
al.
1980).
Following
the
gavage
administration
of
13.92
mg
chromium/
kg/
day
as
calcium
chromate
for
8
days,
the
total
urinary
and
fecal
excretion
of
chromium
on
days
1
and
2
of
dosing
were
<
0.5%
and
1.8%,
respectively
(
Witmer
et
al.
1991).
The
total
urinary
and
fecal
excretion
of
chromium
on
days
7
and
8
of
dosing
were
0.21%
and
12.35%,
respectively.
Donaldson
et
al.
(
1984),
reported
that
excretion
of
Cr(
III)
and
creatinine
clearance
were
almost
equal
suggesting
that
tubular
absorption
or
reabsorption
of
chromium
in
the
kidneys
was
minimal.

2.0
DOSE­
RESPONSE
ASSESSMENT
The
process
of
dose­
response
assessment
as
part
of
a
total
risk
assessment
involves
describing
the
quantitative
relationship
between
the
exposure
to
a
chemical
and
the
extent
of
toxic
injury
or
disease.
Following
the
process
of
hazard
identification,
in
which
the
available
toxicology
data
is
reviewed
and
selection
of
NOAELs
and
LOAELs
is
made
for
each
study,
the
reviewed
data
for
a
pesticide
chemical
is
presented
to
a
committee
of
scientists
within
the
Office
of
Pesticide
Programs
who
reach
concurrence
on
toxicology
endpoints
that
best
represent
the
toxic
effects
expected
from
various
routes
of
exposure
and
durations
of
exposure.
For
most
pesticide
chemicals,
the
process
results
in
selection
of
acute
and
chronic
Reference
Dose
values
(
which
can
be
used
as
benchmark
values
for
acute
and
chronic
dietary
risk
calculations),
as
well
as
endpoint
values
for
non­
dietary
risk
assessments
involving
occupational
and/
or
residential
exposures
by
the
oral,
dermal,
and
inhalation
routes.
Endpoints
are
selected
for
non­
dietary
exposures
to
represent
short­
term
(
1­
30
days),
intermediate­
term
(
30­
180
days),
and
long­
term
exposure
scenarios,
as
needed.
In
addition,
incidental
oral
exposure
endpoints
are
selected
for
short­
term
and
intermediate
term
exposure
durations
to
represent
ingestion
of
pesticide
chemical
residues
that
may
occur
from
hand­
to­
mouth
behaviors.
In
general,
toxicity
endpoint
selection
should,
to
the
extent
possible,
match
the
temporal
and
spatial
characteristics
of
the
exposure
scenarios
selected
for
use
in
the
risk
assessment.
These
endpoints
are
then
used
in
conjunction
with
exposure
values
to
calculate
risks
associated
with
various
types
of
exposure,
depending
upon
the
uses
of
the
pesticide
chemical.

Toxicology
endpoints
for
both
inorganic
arsenic
and
chromium
have
been
selected
for
the
residential
exposure
assessment
and
are
presented
below:
19
2.1
Inorganic
Arsenic­
Endpoint
Selection
On
August
21,
2001,
the
OPP's
Hazard
Identification
Assessment
Review
Committee
(
HIARC)
evaluated
the
toxicology
data
base
of
Inorganic
Arsenic
and
established
the
toxicological
endpoints
for
occupational
exposure
risk
assessments.
On
October,
23­
25
2001,
the
FIFRA
Scientific
Advisory
Panel
(
SAP)
met
and
discussed
some
issues
about
the
end
points
proposed
by
the
HIARC.
The
inorganic
arsenic
toxicological
end­
points
selected
for
CCA
occupational
risk
assessment
are
summarized
in
Table
4.

2.1.1
Acute
Reference
Dose
(
aRfD)

In
the
Office
of
Pesticide
Program
(
OPP)
in
EPA,
the
acute
reference
dose
(
aRfD)
was
used
in
the
risk
assessment
associated
with
oral
exposure
to
food
related
chemicals.
Inorganic
arsenic
is
not
registered
for
any
food
uses
and
there
are
no
existing
tolerances.
For
inorganic
arsenic
as
contained
within
CCA­
treated
wood,
therefore,
an
acute
RfD
is
not
relevant
to
the
exposures
from
registered
use.

2.1.2
Chronic
Reference
Dose
(
cRfD)

The
U.
S.
EPA
has
published
a
chronic
RfD
value
for
inorganic
arsenic
(
USEPA
IRIS,
1998).
However,
as
with
the
acute
RfD,
in
OPP,
the
chronic
RfD
in
OPP
was
considered
for
evaluating
risks
associated
with
food
and/
or
drinking
water
related
chemical
uses.
Because
there
are
no
exposure
scenarios
relevant
to
the
currently
registered
uses
of
inorganic
arsenic,
and
specifically
the
registered
uses
in
CCA­
treated
lumber.
No
chronic
RfD
value
is
need
for
the
current
inorganic
arsenic
use
in
CCA­
treated
wood
use.
However,
if
the
Agency
determines
in
the
future
that
an
aggregate
assessment
is
needed
for
calculation
of
risk
from
exposure
to
arsenic
in
treated
lumber
and
exposure
in
drinking
water
and/
or
food,
the
chronic
RfD
value
can
be
utilized.

2.1.3
Short
(
1­
30
days
)
and
Intermediate
(
30­
180
days)
Incidental
Oral
Exposure
Based
on
the
registered
use
of
CCA­
treated
lumber
for
fencing
and
decking
materials
in
residential
settings,
incidental
oral
exposure
is
expected,
based
on
potential
ingestion
of
soil
contaminated
with
arsenic
as
a
result
of
leaching
from
wood,
and
from
ingestion
of
arsenic
residues
from
the
palm
as
a
result
of
direct
dermal
contact
with
treated
wood.
The
studies
selected
for
short­
and
intermediate­
term
incidental
oral
exposure
are
the
human
case
reports
of
Franzblau
and
Lilis
(
Arch.
of
Envir.
Health
44(
6):
385­
390,
1989)
and
Mizuta
et
al.
(
Bull.
Yamaguchi
Med.
Sch.
4(
2­
3):
131­
149,
1956).
The
LOAEL
of
0.05
mg/
kg/
day
was
selected,
based
on
facial
edema,
gastrointestinal
symptoms,
neuropathy,
and
skin
lesions
observed
at
this
dose
level
Franzblau
et
al.,
(
1989)
reported
2
cases
of
subchronic
(
2
months)
arsenic
intoxication
resulting
from
ingestion
of
contaminated
well
water
(
9­
10.9
mg/
L)
sporadically
(
once
or
twice
a
week)
for
about
2
months.
Acute
gastrointestinal
symptoms,
central
and
peripheral
neuropathy,
bone
marrow
suppression,
hepatic
toxicity
and
mild
mucous
membrane
and
cutaneous
changes
were
20
presented.
The
calculated
dose
was
0.03
­
0.08
mg/
kg/
day
based
on
a
body
weight
of
65
Kg
and
ingestion
of
from
238
to
475
ml
water/
day.

Mizuta
et
al.
(
1956)
reported
a
poisoning
incident
involving
the
presence
of
arsenic
[
probably
calcium
arsenate]
contained
in
soy­
sauce.
The
duration
of
exposure
was
2­
3
weeks.
The
arsenic
content
was
estimated
at
0.1
mg/
ml.
Out
of
417
patients,
the
authors
reported
on
220
(
age
not
specified
for
all
patients.
The
age
of
the
46
paints
with
age
information
are
ranging
from
15
­
69).
An
early
feature
of
the
poisoning
was
appearance
of
facial
edema
that
was
most
marked
on
the
eyelids.
Other
symptoms
presented
included
multifaceted
gastrointestinal
symptoms,
liver
enlargement,
upper
respiratory
symptoms,
peripheral
neuropathy
and
skin
disorders.
In
the
majority
of
the
patients,
the
symptoms
appeared
within
two
days
of
ingestion
and
then
declined
even
with
continued
exposure.
There
was
evidence
of
minor
gastrointestinal
bleeding
(
occult
blood
in
gastric
and
duodenal
juice).
There
were
abnormalities
in
electrocardiograms
(
altered
Q­
T
intervals
and
P
and
T
waves).
These
changes
were
not
evident
on
reexamination
after
recovery
from
the
clinical
symptoms.
An
abnormal
patellar
reflex
was
evident
in
>
50%
of
the
cases.
This
effect
did
not
return
to
normal
during
the
course
of
the
investigation.

Based
on
the
consumption
of
the
arsenic
in
the
contaminated
soy­
sauce,
the
pattern
of
soy­
sauce
consumption
and
on
measured
urinary
arsenic
levels,
the
authors
estimated
consumption
of
arsenic
at
3
mg/
day.
Although
the
body
weight
was
not
reported,
the
EPA
assumes
an
average
body
weight
of
55
kg
in
the
Asian
population.
The
estimated
exposure
was,
therefore,
0.05
mg/
kg/
day
and
was
considered
the
LOAEL.
The
LOAEL=
0.05
mg/
kg/
day
(
edema
of
the
face;
gastrointestinal,
upper
respiratory,
skin,
peripheral
and
neuropathy
symptoms).

These
two
case
reports
are
appropriate
for
both
short­
and
intermediate­
term
incidental
oral
endpoints
for
the
following
reasons:

1)
Symptoms
reported
in
the
Mizuta
study
(
gastrointestinal
disorders,
neuropathy,
liver
toxicity)
occurred
after
2­
3
weeks
of
exposure,
making
this
endpoint
appropriate
for
the
short­
term
(
1­
30
days)
exposure
period.
This
study
also
examined
toxicity
by
the
relevant
route
of
exposure
(
oral).

2)
Similar
symptoms
were
observed
in
the
Franzblau
study,
and
are
appropriate
for
the
intermediate­
term
endpoint
as
they
were
observed
to
occur
after
longer­
term
(
2
months)
exposure.

USEPA
Region
8
has
also
published
a
report
on
selection
of
acute
and
chronic
Reference
Doses
for
Inorganic
Arsenic,
intended
to
apply
to
exposures
of
1­
14
days
and
15
days­
7
years
(
USEPA
Region
8,
2001).
The
use
of
the
term
"
reference
dose"
in
the
Region
8
report
"
apply
to
readily
soluble
forms
of
arsenic
and
are
intended
to
include
total
oral
exposure
to
inorganic
arsenic,
that
is
drinking
water,
food,
and
soil.
"
The
report
concludes
that
a
NOAEL
value
of
0.015
mg/
kg/
day
from
a
study
by
Mazumder
et
al
(
Int.
J.
Epidem.
27:
871­
877)
can
be
used
for
acute
and
subchronic
reference
dose
values,
with
an
uncertainty
factor
of
1.
Alternately,
the
LOAEL
of
0.05
mg/
kg/
day
and
an
uncertainty
factor
of
3
(
for
extrapolation
from
the
LOAEL
to
the
21
NOAEL)
could
be
selected
from
this
same
study.
A
full
factor
of
10
was
not
employed
by
Region
8
based
on
the
reasoning
that
a
No
Adverse
Effect
Level
"
is
likely
at
an
exposure
only
slightly
below
the
effect
level"
(
USEPA
Region
8,
2001).
However,
this
report
did
not
discuss
severity
or
irreversibility
of
effects
observed
in
the
Mizuta
et
al.
report
as
a
factor
in
selecting
the
uncertainty
factor,
which
was
taken
into
consideration
by
the
OPP
HIARC.
Further,
the
effect
observed
in
the
Mazumder
et
al.
study
of
hyperkeratosis
is
a
result
of
chronic
exposure
and
not
short­
or
intermediate­
term
exposure
and
was
thus
felt
to
be
inappropriate
for
determination
of
short­
and
intermediate­
term
incidental
oral
risk.
The
Region
8
report
was
part
of
the
background
documents
presented
to
the
2001
SAP.

For
the
risk
assessment,
based
on
the
recommendations
of
the
SAP,
the
Agency
decided
to
use
a
Margin
of
Exposure
(
MOE)
of
30.
This
value
of
30
was
recommended
on
the
basis
that
the
severity
of
symptoms
near
or
moderately
above
the
LOAEL
(
0.05mg/
kg/
day)
warranted
a
full
uncertainty
factor
of
10
and
an
uncertainty
factor
of
3
for
protection
of
children.

2.1.4
Dermal
Absorption
Dermal
absorption
of
inorganic
arsenic
is
represented
by
the
study
of
Wester
et
al.
(
Fund.
Appl.
Toxicol.
20:
336­
340,
1993).
In
this
study,
the
percutaneous
absorption
of
arsenic
acid
(
H
3
AsO
4)
from
water
and
soil
both
in
vivo
using
rhesus
monkeys
and
in
vitro
with
human
skin
was
examined.
In
vivo,
absorption
of
arsenic
acid
from
water
(
loading
5
µ
l/
cm2
skin
area)
was
6.4
±
3.9%
at
the
low
dose
(
0.024
ng/
cm2)
and
2.0
±
1.2%
at
the
high
dose
(
2.1
µ
g/
cm2).
Absorption
from
soil
(
loading
0.04
g
soil/
cm2
skin
area)
in
vivo
was
4.5
±
3.2%
at
the
low
dose
(
0.
04
ng/
cm2)
and
3.2
±
1.9%
at
the
high
dose
(
0.6
µ
g/
cm2).
Thus,
in
vivo
in
the
rhesus
monkey,
percutaneous
absorption
of
arsenic
acid
is
low
from
either
soil
or
water
vehicles
and
does
not
differ
appreciably
at
doses
more
than
10,000­
fold
apart.
Wester
et
al.
(
1993)
also
reported
that
for
human
skin,
at
the
low
dose,
1.9%
was
absorbed
from
water
and
0.8%
from
soil
over
a
24­
h
period.

For
children
playing
around
playground
equipment,
however,
it
is
assumed
the
dermal
exposure
would
be
arsenic
in
wood
surface
residue
and/
or
arsenic
in
soil,
a
dermal
absorption
value
of
3%
will
be
used
(
SAP,
2001).
Because
the
handlers
and
workers
are
exposed
to
the
arsenic
residue
from
the
aqueous
solution
during
mixing,
loading,
and
handling
or
are
exposed
to
newly
treated,
or
"
wet'
wood
which
has
arsenic
residues
on
the
surface
of
the
wood,
in
the
occupational
assessment,
a
dermal
absorption
factor
of
6.4
percent
is
used.
The
value
of
6.4%
dermal
absorption
was
chosen
based
on
the
use
of
non­
human
primates
for
derivation
of
this
value
and
the
fact
that
this
was
a
well­
conducted
study.
It
is
observed
in
this
study
that
a
higher
dose
on
the
skin
resulted
in
lower
dermal
absorption
as
noted
above,
but
the
data
in
this
and
other
studies
suggests
sufficient
variability
in
the
absorption
such
that
use
of
the
6.4%
dermal
absorption
value
is
sufficiently
but
not
overly
conservative.

2.1.5
Short
(
1­
30
days
)
and
Intermediate
(
30­
180
days)
Dermal
Exposure
22
Since
there
are
no
appropriate
dermal
studies,
same
as
studies
selected
for
short­
and
intermediate­
term
incidental
oral
exposure,
the
case
reports
of
Franzblau
and
Lilis
(
Arch.
of
Envir.
Health
44(
6):
385­
390,
1989)
and
Mizuta
et
al.
(
Bull.
Yamaguchi
Med.
Sch.
4(
2­
3):
131­
149,
1956)
were
selceted
for
short
(
1­
30
days
)
and
intermediate
(
30­
180
days)
term
dermal
exposure
scenarios.
The
LOAEL
of
0.05
mg/
kg/
day
was
selected,
based
on
facial
edema,
gastrointestinal
symptoms,
neuropathy,
and
skin
lesions
observed
at
this
dose
level.
An
Margin
of
Exposure
(
MOE)
of
30
should
be
applied
to
the
LOAEL.
This
value
consists
of
a
10x
factor
for
intraspecies
variation
and
a
3x
factor
for
extrapolating
from
a
LOAEL
to
a
NOAEL.

2.1.6
Long­
Term
Dermal
Exposure
While
no
long­
term
dermal
exposures
are
expected
from
residential
exposure
to
arsenic
in
CCAtreated
lumber,
long­
term
dermal
exposure
is
expected
in
the
occupational
setting.
Thus,
for
this
exposure
scenario,
the
dose
and
endpoint
selected
are
the
NOAEL
of
0.0008
mg/
kg/
day
from
the
Tseng
et
al.
(
1968)
study,
which
examined
chronic
non
­
cancer
and
cancer
effects
from
arsenic
exposure
through
well
water
in
a
large
cohort
in
Taiwan.

In
Taiwan,
Tseng,
(
1977),
Tseng,
(
1968)
[
U.
S.
EPA,
1998]
noted
that
hyperpigmentation,
keratosis
and
possible
vascular
complications
were
seen
at
the
LOAEL
of
0.17
mg/
L,
converted
to
0.014
mg/
kg/
day.

The
NOAEL
was
based
on
the
arithmetic
mean
of
0.009
mg/
L
in
a
range
of
arsenic
concentration
of
0.001
to
0.017
mg/
L.
The
NOAEL
also
included
estimation
of
arsenic
from
food.
Since
oral
arsenic
exposure
data
were
missing,
arsenic
concentrations
in
sweet
potatoes
and
rice
were
estimated
as
0.002
mg/
day.
Other
assumptions
included
consumption
of
4.5
L
water/
day
and
55
kg
body
weight
(
Abernathy,
(
1989).
Thus,
the
converted
NOAEL
=
[(
0.009
mg/
L
x
4.5
L/
day)
+
0.002
mg/
day]/
55
kg
=
0.0008
mg/
kg/
day.
The
LOAEL
dose
was
estimated
using
the
same
assumptions
as
the
NOAEL
starting
with
an
arithmetic
mean
water
concentration
from
Tseng,
(
1977)
of
0.17
mg/
L.
LOAEL
=
[(
0.17
mg/
L
x
4.5
L/
day)+
0.002
mg/
day]/
55
kg
=
0.014
mg/
kg/
day.
Therefore
the
NOAEL
=
0.0008
mg/
kg
and
the
LOAEL=
0.014
mg/
kg/
day
(
based
on
hyperpigmentation,
keratosis
and
possible
vascular
complications
)

An
MOE
of
3
is
applied
to
this
risk
assessment.
A
factor
of
3
and
not
10
is
used
based
on
the
large
sample
size
of
the
Tseng
study
(>
40,000)
and
is
in
agreement
with
the
published
value
and
rationale
in
the
1998
IRIS
document
on
inorganic
arsenic.

2.1.7
Short­,
Intermediate­,
and
Long­
term
Inhalation
Exposure
Short­,
intermediate­,
and
long­
term
endpoints
were
not
identified
in
the
HIARC
report
for
inhalation
exposures
to
arsenic.
Since
no
inhalation
studies
are
available,
committee
selected
the
23
same
studies
as
for
the
dermal
risk
assessments.
Since
the
dose
identified
for
inhalation
risk
assessments
are
from
oral
studies,
route­
to­
route
extrapolation
should
be
as
follows:

Step
I:
The
inhalation
exposure
component
(
i.
e.,
g
a.
i./
day)
using
a
100%
(
default)
absorption
rate
and
application
rate
should
be
converted
to
an
equivalent
oral
dose
(
mg/
kg/
day);

Step
II:
The
dermal
exposure
component
(
i.
e.,
mg/
kg/
day)
using
6.4
%
absorption
factor
and
application
rate
should
be
converted
to
an
equivalent
oral
dose.
The
dose
should
be
combined
with
the
converted
oral
dose
in
Step
I.

Step
III:
To
calculate
the
MOE's,
the
combined
dose
from
Step
I
and
II
should
then
be
compared
to
the
oral
LOAEL
of
0.05
mg/
kg/
day
for
short
and
intermediate
term
exposure
and
the
oral
NOAEL
of
0.0008
mg/
kg/
day
for
long­
term
exposure.

As
discussed
in
endpoints
selected
for
dermal
exposure
scenarios
(
Sections
2.1.5
and
2.1.6),
acceptable
Margin
of
Exposure
(
MOE)
of
30
should
be
applied
to
the
short­
and
intermediate
inhalation
scenarios.
For
long­
term
inhalation
exposure
scenarios,
an
acceptable
margin
of
exposure
of
3
should
be
applied.

2.1.8
Carcinogenicity
There
is
sufficient
evidence
from
human
data
indicating
arsenic
exposure
can
cause
cancer.
In
1975,
the
U.
S.
Environmental
Protection
Agency
(
EPA)
adopted
a
drinking
water
regulation
for
arsenic
based
on
a
U.
S.
Public
Health
Service
standard
set
in
1942.
The
drinking
water
standard
of
50
micrograms
per
liter
(
g/
L),
which
is
equivalent
to
50
parts
per
billion
(
ppb),
remains
in
effect
until
2006.
EPA
conducted
risk
assessments
for
arsenic­
induced
skin
cancer
in
1980,
1988,
and
1992.
The
Agency's
Integrated
Risk
Information
System
(
IRIS)
carcinogenic
risk
from
oral
exposure
to
arsenic
is
based
on
southwestern
Taiwanese
skin
cancer
studies
published
in
1977
and
1968.
The
slope
factor
published
by
EPA's
Integrated
Risk
Information
System
(
IRIS)
is
1.5
(
mg/
kg/
day)­
1
.

In
1996,
EPA
charged
the
National
Academy
of
Sciences
(
NAS)
to
review
the
Agency's
characterization
of
potential
health
risks
from
ingestion
of
arsenic;
the
available
data
on
carcinogenic
and
non­
carcinogenic
effects
of
arsenic
in
drinking
water;
the
data
on
metabolism,
kinetics,
and
mode(
s)
of
action
of
arsenic;
and
research
priorities.
An
increased
lung
cancer
mortality
was
observed
in
multiple
human
populations
exposed
primarily
through
inhalation.
Also,
increased
mortality
from
multiple
internal
organ
cancers
(
liver,
kidney,
lung,
and
bladder)
and
increased
incidences
of
skin
cancer
were
observed
in
populations
consuming
drinking
water
high
in
inorganic
arsenic.
In
order
to
evaluate
the
cancer
risk
associated
with
arsenic
exposure
in
drinking
water,
in
1997,
at
EPA's
request,
the
National
Academy
of
Sciences'
(
NAS)
Subcommittee
on
Arsenic
of
the
Committee
on
Toxicology
of
the
National
Research
Council
(
NRC)
met.
The
NAS/
NRC
Subcommittee
finished
their
work
in
March
1999.
In
general,
the
24
NRC
report
confirms
and
extends
concerns
about
human
carcinogenicity
of
drinking
water
containing
arsenic
and
offers
perspective
on
dose­
response
issues
and
needed
research.
The
NRC
recommended
that
EPA
analyze
risks
of
internal
cancers
both
separately
and
combined.
NRC
used
data
from
Wu
et
al.
1989
and
Chen
et
al.
1992
to
address
several
risk
assessment
issues.

EPA
applied
many
of
the
recommendations
from
the
1999
NRC
report
in
the
risk
haracterization
used
to
support
the
January
2001
revised
arsenic
drinking
water
regulation.
The
Agency
based
its
new
10
ppb
arsenic
standard
on
the
risk
of
bladder
and
lung
cancers
from
the
Taiwanese
data
used
by
NRC
and
estimated
1­
6
x
10­
4
risk
to
the
90th
percentile
of
the
U.
S.
population.

In
April
2001,
EPA
charged
the
NRC
to
review
the
risk
analysis
used
to
support
the
revised
arsenic
drinking
water
regulation
in
light
of
studies
published
since
the
1999
NRC
report.
NRC
released
its
update
report
in
September
2001.

EPA
applied
many
of
the
recommendations
from
the
1999
NRC
report
in
the
risk
characterization
used
to
support
the
January
2001
revised
arsenic
drinking
water
regulation.
In
the
risk
assessment,
EPA
used
risk
estimates
taken
from
Morales
et
al.
(
2000).
Morales
et
al.
fit
a
variety
of
dose­
response
models
to
lung
and
bladder
cancer
data
from
an
arseniasis­
endemic
region
of
southwestern
Taiwan.
Risk
was
assumed
to
increase
linearly
with
dose,
from
zero
to
the
effective
dose
(
central
estimate)
at
which
1%
of
population
is
affected
by
the
chemical
(
ED01).
The
slope
of
the
line
extrapolated
from
ED01
to
the
origin
was
calculated
and
used
as
the
cancer
slope
factor
for
cancer
risk
assessment
(
see
Plot
1
as
an
example).
In
the
risk
assessment
associated
with
inorganic
arsenic
in
drinking
water
in
2000
(
EPA,
2001),
EPA
presented
two
sets
of
risk
estimates,
higher
and
lower:

°
For
the
higher
set
of
risks:
For
the
higher
set
of
risks:
EPA
used
the
theoretical
risk
estimates
taken
directly
from
Morales
et
al.
(
2000).
Assumed
drinking
water
consumption
in
Taiwanese
population
is
3.5
L/
day
for
male
and
2.0
L/
day
for
female.
A
drinking
water
consumption
rate
of
1.2
L/
day
is
assumed
for
both
male
and
female
in
U.
S.
population.

°
For
the
lower
set
of
risks:
For
the
lower
set
of
risks:
EPA
adjusted
the
theoretical
risks
to
take
into
account
possible
higher
arsenic
consumption
in
Taiwan.
For
these
estimates,
EPA
assumed
that
people
in
Taiwan
consumed
an
additional
1
L/
d
of
water
in
cooking,
due
to
dehydration
of
rice
and
sweet
potatoes,
and
a
further
50
µ
g/
d
of
arsenic
directly
from
their
food.
A
drinking
water
consumption
rate
of
1.0
L/
day
is
assumed
for
both
male
and
female
in
U.
S.
population.

Following
the
risk
assessment
associated
with
inorganic
arsenic
in
drinking
water
are
presented
in
2000,
EPA
asked
the
National
Research
Council
(
NRC)
to
meet
again
to:
(
1)
review
EPA's
characterization
of
potential
human
health
risks
from
ingestion
of
inorganic
arsenic
in
drinking
water;(
2)
review
the
available
data
on
the
carcinogenic
and
non­
carcinogenic
effects
of
inorganic
25
arsenic;
(
3)
review
the
data
on
the
metabolism,
kinetics
and
mechanism(
s)/
mode(
s)
of
action
of
inorganic
arsenic;
and
(
4)
identify
research
needs
to
fill
data
gaps.

In
2001,
NRC
published
an
update
to
the
1999
NRC
report
and
concluded
that
(
1)
arsenic­
­
induced
bladder
and
lung
cancers
still
should
be
the
focus
of
an
arsenic­
related
cancer
risk
assessment;
(
2)
the
southwestern
Taiwan
data
are
still
the
most
appropriate
for
arsenic­
related
cancer
risk
assessments;
and
(
3)
present
modes
of
action
data
are
not
sufficient
to
depart
from
the
default
assumption
of
linearity.
The
2001
NRC
update
also
made
specific
recommendations
with
respect
to
the
overall
cancer
risk
estimate.

The
Agency
is
currently
considering
the
best
way
to
address
all
the
NRC's
recommendations.
Based
on
the
Agency's
considerations
of
these
recommendations,
the
current
proposed
cancer
potency
number
may
change
in
the
final
version
of
this
risk
assessment.
For
this
risk
assessment,
an
oral
cancer
slope
factor
of
3.67
(
mg/
kg/
day)­
1
was
used.
This
is
the
mean
slope
factor
derived
from
the
higher
risk
approach
for
both
lung
and
bladder
cancers.
This
slope
factor
was
used
by
the
EPA's
Office
of
Water
when
it
established
the
MCL
for
arsenic
in
drinking
water
(
U.
S.
EPA,
2001)
and
also
by
the
Consumer
Product
Safety
Commission
when
it
performed
its
deterministic
assessment
for
children's
risks
from
CCA­
treated
playsets
in
March
2003
(
CPSC,
2003).

The
slope
factor
published
by
EPA's
Integrated
Risk
Information
System
(
IRIS),
1.5
(
mg/
kg/
day)­
1
,
is
also
being
revisited
in
FY2003
due
to
the
recommendation
by
the
NRC
in
2001.
If
the
Agency
had
used
the
current
IRIS
cancer
slope
factor
(
1.5
(
mg/
kg/
day)­
1
)
instead
of
the
slope
factor
used
in
the
Office
of
Water's
arsenic
MCL
document
(
3.67
(
mg/
kg/
day)­
1)(
U.
S.
EPA,
2001),
the
cancer
risk
would
be
approximately
41%
of
the
current
cancer
risk
estimates
in
this
document
.
For
example,
a
reported
cancer
risk
of
5.0E­
4
using
the
cancer
slope
factor
of
3.67(
mg/
kg/
day)­
1
would
be
equivalent
to
2.0E­
4
using
the
IRIS
cancer
slope
factor
of
1.5
(
mg/
kg/
day)­
1.
All
the
EPA
proposed
oral
cancer
slope
factors
are
summarized
in
Table
3.

The
inhalation
unit
risk
(
IUR)
for
a
continuous
24­
hour
exposure
is
4.3
x
10­
3
(

g/
m3)­
1
which
is
equivalent
to
a
cancer
slope
factor
of
15.1
(
mg/
kg/
day)­
1
for
the
general
population.
To
assess
inhalation
cancer
risks
from
an
8­
hour
work
day,
the
24­
hour
derived
CSF
is
adjusted
to
an
8­
hour
exposure
representing
a
typical
work
day
(
i.
e.,
24­
hour
CSF
x
(
8­
hr/
24­
hr))
or
a
potency
factor
(
CSF)
is
5.0
(
mg/
kg/
day)­
1.
26
Table
3.
Oral
Cancer
Slope
Factor
used
for
Assessing
Cancer
Risks
Associated
with
Occupational
Exposures/
Risks
to
Inorganic
Arsenic
Oral
Cancer
Slope
Factors
(
CSF)
Based
on
the
EPA's
Integrated
Risk
Information
System
(
IRIS)
(
Last
Revised
­­
04/
10/
1998)
Oral
Cancer
Slope
Factor
(
a)
1.5E+
0
per
(
mg/
kg)/
day
Oral
Slope
Factors
(
CSF)
Based
on
the
EPA's
Risk
Assessment
Associated
with
Drinking
Water
(
EPA,
2001)
Higher
Set
(
a)
Lower
Set
(
a)

(
per
(
mg/
kg)/
day)
(
per
(
mg/
kg)/
day)

Based
on
Bladder
Cancer
Male:
1.49
0.18
Female:
2.15
0.25
Based
on
Lung
Cancer:
Male:
1.60
0.23
Female:
2.10
0.27
Based
on
Bladder+
Lung
Cancer:
Male:
3.09
0.30
Female:
4.25
0.37
Combine
Male
and
Female
3.67
(
b)
0.33
Note:
(
a).
EPA's
assumptions
for
its
high
and
low
risk
estimates
is
as
follows:
Low
High
risk
risk
Drinking
water
consumption,
U.
S.
L/
d
1
1.2
Cooking
water
consumption,
Taiwan
L/
d
1
0
Additional
drinking
water
consumed
in
food,
Taiwan
µ
g/
d
50
0
(
b).
CSF
of
3.67
per
(
mg/
kg)/
day
is
the
number
be
used
in
this
risk
assessment.
Attachment
1
presents
how
the
slope
factor
was
derived.
27
Table
4.
Toxicological
Endpoints
for
Assessing
Occupational
Exposures/
Risks
to
Arsenic
(
V)

EXPOSURE
SCENARIO
DOSE
(
mg/
kg/
day)
ENDPOINT
STUDY
Acute
Dietary
This
risk
assessment
is
not
required.

Chronic
Dietary
This
risk
assessment
is
not
required.

Incidental
Short­
and
Intermediate­
Term
Oral
LOAEL=
0.05
MOE
=
30
Based
on
edema
of
the
face,
gastrointestinal,
upper
respiratory,
skin,
peripheral
and
neuropathy
symptoms
Franzblau
et
al.(
1989)
and
Mizuta
et
al.
(
1956)

Dermal
Short­
and
Intermediate­
Term
(
a)
(
b)
LOAEL=
0.05
MOE
=
30
Based
on
edema
of
the
face,
gastrointestinal,
upper
respiratory,
skin,
peripheral
and
neuropathy
symptoms
Franzblau
et
al.(
1989)
and
Mizuta
et
al.
(
1956)

Dermal
Long­
Term
(
a)
(
b)
NOAEL=
0.0008
MOE
=
3
Based
on
hyperpigmentation,
keratosis
and
possible
vascular
complications.
Tseng
et
al.
(
1968)
and
Tseng
(
1977)

Inhalation
Short­
and
Intermediate­
Term(
c)
LOAEL=
0.05
MOE
=
30
Based
on
edema
of
the
face,
gastrointestinal,
upper
respiratory,
skin,
peripheral
and
neuropathy
symptoms
Franzblau
et
al.(
1989)
and
Mizuta
et
al.
(
1956)

Inhalation,
Long­
Term
NOAEL=
0.0008
MOE
=
3
Based
on
hyperpigmentation,
keratosis
and
possible
vascular
complications.
Tseng
et
al.
(
1968)
and
Tseng
(
1977)

Carcinogenicity
­
Inhalation
(
Inhalation
Risk)
CSF=
15.1
(
d)
(
mg/
kg/
day)­
1
(
For
general
Population)
Lung
cancer
Chronic
epidemiological
inhalation
study
on
humans
CSF=
5.0
(
e)
(
mg/
kg/
day)­
1
(
For
8
hour
working
day)

Carcinogenicity
­
Oral
Ingestion
(
Oral
and
Dermal
Risks)
CSF
=
3.67
(
f)
(
mg/
kg/
day)­
1
Internal
organ
cancer
(
liver,
kidney,
lung
and
bladder)
and
skin
cancer
Chronic
epidemiological
oral
study
on
humans
Note:
(
a).
MOE
=
Margin
of
Exposure;
NOAEL
=
No
observed
adverse
effect
level;
and
LOAEL
=
Lowest
observed
adverse
effect
level.
(
b).
The
dermal
absorption
factor
=
6.4%.
(
Note:
The
FIFRA
Scientific
Advisory
Panel
recommended
use
of
a
lower
value
of
2­
3%.
The
occupational
assessment
in
the
risk
assessment
uses
6.4
percent
dermal
absorption
because
the
handlers
and
workers
are
exposed
to
the
arsenic
residue
from
the
aqueous
solution
during
mixing,
loading,
and
handling
or
are
exposed
to
newly
treated,
or
"
wet'
wood
which
has
arsenic
residues
on
the
surface
of
the
wood).
(
c).
For
inhalation
exposure,
a
default
absorption
factor
of
100%
is
used.
Route­
to­
route
extrapolation
is
used
to
estimate
the
exposed
dose.
(
d).
Inhalation
unit
risk
(
IUR)
is
derived
from
a
24
hour
exposure
inhalation
unit
risk
with
a
value
of
4.3
x
10­
3
(
µ
g/
m3)­
1.
To
convert
the
IUR
to
a
cancer
slope
factor
in
units
of
(
mg/
kg/
day)
­
1
for
the
general
population
=
IUR
(
µ
g/
m3)­
1
x
1/
70
kg
x
20
m3/
day
x
1
mg/
1,000
µ
g
(
EPA,
1989).
(
e).
For
workers
working
8
hour
per
day,
the
inhalation
cancer
slope
factor
(
CSF)
derived
from
the
24
hour
IUR
for
general
population,
is
adjusted
for
an
8
hour
work
day.
CSF
for
8­
hr
work
day
=
general
population
CSF
of
15.1
(
mg/
kg/
day)­
1
x
(
8hrs/
24
hrs)
=
5.0
(
mg/
kg/
day)­
1.
(
f).
CSF
is
derived
from
the
risk
assessment
associated
with
inorganic
in
drinking
water
are
presented
in
2000.
The
2001
National
Research
Council
(
NRC)
update
made
specific
recommendation
with
respect
to
the
overall
cancer
risk
estimates.
The
Agency
is
currently
considering
these
recommendations
and
their
potential
impact
on
the
cancer
potency
estimate.
Based
on
the
Agency's
considerations
of
these
recommendations,
the
current
proposed
cancer
potency
number
may
change
in
the
final
version
of
this
risk
assessment.
28
2.2
Inorganic
Chromium
Endpoint
Selection
On
August
28,
2001,
the
OPP's
Hazard
Identification
Assessment
Review
Committee
(
HIARC)
evaluated
the
toxicology
data
base
of
Cr(
VI)
and
established
the
toxicological
endpoints
for
occupational
exposure
risk
assessments.
On
October,
23­
25
2001,
the
FIFRA
Scientific
Advisory
Panel
(
SAP)
met
and
discussed
some
issues
about
the
end
points
proposed
by
the
HIARC.
The
recommended
toxicity
endpoints
related
to
inorganic
chromium
(
VI)
are
summarized
in
Table
5.

2.2.1
Acute
Reference
Dose
(
aRfD)

An
acute
RfD
value
was
not
selected
for
inorganic
chromium.
Inorganic
chromium
is
not
registered
for
any
food
uses
and
there
are
no
existing
tolerances.
For
inorganic
chromium
as
contained
within
CCA­
treated
wood,
therefore,
an
acute
RfD
is
not
relevant
to
the
exposures
from
registered
uses.

2.2.2
Chronic
Reference
Dose
(
cRfD)

The
U.
S.
EPA
has
published
a
chronic
RfD
value
for
inorganic
chromium
(
USEPA
IRIS,
1998).
However,
as
with
the
acute
RfD,
there
are
no
exposure
scenarios
relevant
to
the
currently
registered
uses
of
inorganic
chromium,
and
specifically
the
registered
uses
in
CCA­
treated
lumber.
If
the
Agency
determines
in
the
future
that
an
aggregate
assessment
is
needed
for
calculation
of
risk
from
exposure
to
chromium
in
treated
lumber
and
exposure
in
drinking
water
and/
or
food,
the
chronic
RfD
value
can
be
utilized.

2.2.3
Short­
Term
(
1­
30
days)
and
Intemediate­
Term
(
30­
180
days)
Incidental
Oral
Exposure
Based
on
the
registered
use
of
CCA­
treated
lumber
for
fencing
and
decking
materials
in
residential
settings,
incidental
oral
exposure
to
chromium
is
expected,
based
on
potential
ingestion
of
soil
contaminated
with
chromium
as
a
result
of
leaching
from
wood,
and
from
ingestion
of
chromium
residues
from
the
palm
as
a
result
of
direct
dermal
contact
with
treated
wood.
The
study
selected
for
short­
and
intermediate­
term
incidental
oral
exposure
is
a
developmental
toxicity
study
in
the
rabbit
conducted
by
Tyl
and
submitted
to
the
Agency
under
MRID
#
42171201.
The
executive
summary
is
shown
below.

In
a
developmental
toxicity
study
[
MRID
421712­
01],
artificially
inseminated
New
Zealand
White
rabbits
(
16
females/
dose
group)
received
aqueous
chromic
acid
(
55.0%)
by
gavage
once
daily
on
gestation
days
7
through
19
at
dose
levels
of
0.0,
0.1,
0.5,
2.0,
or
5.0
mg/
kg/
day
in
deionized/
distilled
water.

Clinical
signs
of
toxicity
,
including
diarrhea,
and
slow,
audible
or
labored
breathing
were
observed
predominately
in
the
2.0
and
5.0
mg/
kg/
day
groups.
These
signs
were
observed
in
slightly
higher
incidence
at
the
2.0
mg/
kg/
day
dose
level
than
at
the
5.0
mg/
kg/
day
dose
level.
However,
the
incidence
and
temporal
occurrence
of
mortality
(
at
2.0
mg/
kg/
day,
one
doe
died
on
gestation
day
(
GD)
28;
at
5.0
mg/
kg/
day,
5
does
died
(
one
each
on
GD
10,
14,
and
two
on
GD
29
15)
and
the
magnitude
of
decreased
body
weight
gain
during
the
dosing
period
(
average
weight
loss
of
48
grams
at
2.0
mg/
kg/
day
and
average
weight
loss
of
140
grams
at
5.0
mg/
kg/
day
during
gestation
days
7­
19)
were
observed
to
occur
in
a
dose­
related
fashion
at
2.0
and
5.0
mg/
kg/
day.
Overall
weight
gain
was
decreased
24%
at
2.0
mg/
kg/
day
and
20%
at
5.0
mg/
kg/
day.
Food
efficiency
was
also
observed
to
be
significantly
lower
during
the
dosing
period
in
the
5.0
mg/
kg/
day
dose
group.
Cesarean
section
observations
were
unremarkable
in
this
study
at
any
dose
level
tested.
There
were
no
significant
treatment­
related
effects
on
the
incidence
of
external,
visceral,
or
skeletal
malformations
in
the
offspring
in
this
study.

The
Maternal
NOAEL
=
0.5
[
0.12]
mg/
kg/
day
and
LOAEL
=
2.0
[
0.48]
mg/
kg/
day
(
based
on
the
increased
incidence
of
maternal
mortality
and
decreased
body
weight
gain
).
The
Developmental
NOAEL
=
2.0
[
0.48]
mg/
kg/
day
and
LOAEL
>
2.0
[>
0.48]
mg/
kg/
day
based
on
the
lack
of
developmental
effects
at
any
dose
level
tested.

The
developmental
toxicity
study
in
the
rabbit
was
chosen
for
selection
of
the
short­
term
and
intermediate­
term
incidental
oral
exposure
endpoint.
This
study
and
endpoint
is
felt
to
be
appropriate
for
both
short­
and
intermediate­
term
incidental
oral
exposures,
based
on
the
occurrence
of
toxic
effects
after
short­
term
dosing
(
mortality,
clinical
signs,
weight
loss),
and
supporting
data
from
the
open
literature
showing
similar
effects
after
longer­
term
exposures
at
similar
dose
levels.
A
study
by
Zhang
and
Li
(
1987)
detailed
toxic
effects
observed
in
155
human
subjects
exposed
long­
term
to
chromium
in
drinking
water
at
a
concentration
of
approximately
20
mg/
L
(
USEPA
IRIS,
1998),
or
0.66
mg/
kg/
day.
These
effects
included
mouth
sores,
diarrhea,
stomach
ache,
indigestion,
vomiting,
and
elevated
white
cell
count.
Although
precise
concentrations
of
chromium
in
the
water,
exposure
durations,
and
confounding
factors
were
not
discussed
in
this
paper,
the
data
suggest
gastrointestinal
effects
at
a
level
of
approximately
0.66
mg/
kg/
day.
Thus,
the
choice
of
the
NOAEL
value
of
0.5
mg/
kg/
day
from
the
developmental
toxicity
study
in
rabbits
(
a
well­
conducted
multi­
dose
animal
study)
for
the
incidental
oral
endpoint
is
felt
to
be
protective
of
the
gastrointestinal
effects
observed
in
humans
at
a
similar
dose.
The
choice
of
this
endpoint
is
also
felt
to
be
protective
of
the
non­
lethal
effect
observed
in
humans
based
on
a
more
severe
effect
observed
in
animals
(
i.
e.
mortality).

2.2.4
Dermal
Absorption
For
inorganic
chromium,
a
dermal
absorption
value
of
1.3%
was
selected,
based
upon
the
data
of
Bagdon
(
1991).
The
executive
summary
of
this
study
is
presented
below.

Sodium
chromate
(
Cr(
VI))
was
applied
to
the
skin
of
guinea
pigs
and
the
skin
permeation
was
determined
by
assay
of
51Cr
content
present
in
the
excreta
(
1.11%)
and
organs
(
0.19%)
after
24
hours.
In
this
study
in
guinea
pigs,
skin
penetration
of
chromium
amounted
to
1.30%
of
the
applied
dose
after
24
hours.
Using
another
in
vivo
method,
a
weighed
amount
of
the
agent
was
patched
to
the
skin
of
guinea
pigs
and
the
concentration
followed
by
determination
of
the
remaining
agent
at
the
application
site
after
different
intervals.
Skin
penetration
was
concentration
dependent.
The
range
used
was
0.0048
to
1.689
M.
Dermal
penetration
for
hexavalent
chromium
amounted
to
2.6%
of
the
applied
dose
of
0.0175
M/
5
hours
and
4.0%
at
0.261
M/
5
hours.
At
0.261
M,
the
skin
permeation
rate
was
700
m
µ
M/
cm2/
hr.
This
procedure
may
overestimate
skin
30
penetration
because
chromium
present
in
the
skin
depot
would
be
calculated
as
part
of
the
residual
test
material
at
the
skin's
surface.

2.2.5
Short­,
Intermediate­,
and
Long­
term
Dermal
Exposure
The
1998
EPA
IRIS
document
on
chromium
(
VI)
states
that
"
chromium
is
one
of
the
most
common
contact
sensitizers
in
males
in
industrialized
countries
and
is
associated
with
occupational
exposures
to
numerous
materials
and
processes.."
In
addition,
it
is
stated
further
that
"
dermal
exposure
to
chromium
has
been
demonstrated
to
produce
irritant
and
allergic
contact
dermatitis."
The
relative
potency
of
this
effect
appears
to
differ
between
the
(
VI)
and
(
III)
species
of
chromium.
Bagdon
(
1991)
collected
skin
hypersensitivity
data
for
trivalent
chromium
compounds
in
human
subjects
and
concluded
that
the
threshold
level
for
evoking
hypersensitivity
reactions
from
trivalent
chromium
compounds
is
approximately
50­
fold
higher
than
for
hexavalent
chromium
compounds.
Nontheless,
it
is
apparent
that
both
forms
of
chromium
cause
hypersensitivity
reactions
in
humans.

It
was
determined
by
the
Hazard
Identification
Assessment
Review
Committee
(
HIARC)
of
the
Office
of
Pesticide
Programs
that
quantification
of
the
hazard
from
dermal
exposure
is
not
possible
for
chromium,
due
to
the
significant
dermal
irritation
and
sensitization
observed.
To
address
concern
from
occupational
dermal
exposure,
and
in
accordance
with
OPP
policy,
precautionary
label
statements
should
be
included
for
CCA
treatment
solution
used
in
treatment
facilities.

2.2.6
Inhalation
Exposure
(
all
durations)

Although
chromium
is
not
considered
a
volatile
agent
when
present
in
soil,
inhalation
of
soil
dust
contaminated
with
chromium
may
present
a
potential
inhalation
risk
given
the
significant
irritant
properties
of
chromium
and
the
potential
for
nasal
deposition
of
the
chemical
after
inhalation
of
contaminated
soil
dust.
Linberg,
1983
studied
respiratory
symptoms,
lung
function
and
changes
in
nasal
septum
in
104
workers
(
85
males,
19
females
exposed
in
chrome
plating
plants.
Workers
were
interviewed
using
a
standard
questionnaire
for
the
assessment
of
nose,
throat
and
chest
symptoms.
Nasal
inspections
and
pulmonary
function
testing
were
performed
as
part
of
the
study.

The
median
exposure
time
for
the
entire
group
of
exposed
subjects
(
104)
in
the
study
was
4.5
years
(
0.1­
36
years).
A
total
of
43
subjects
exposed
almost
exclusively
to
chromic
acid
experienced
a
mean
exposure
of
2.5
years
(
0.2­
23.6
years).
The
subjects
exposed
almost
exclusively
to
chromic
acid
were
divided
into
a
low
exposure
group
(
8­
hr
TWA
below
0.002
mg/
m3,
N=
19)
and
a
high­
exposure
group
(
8­
hr
TWA
above
0.002
mg/
m3,
N=
24).
Exposure
measurements
using
personal
air
samplers
were
performed
for
84
subjects
in
the
study
on
13
different
days.
Exposure
for
the
remaining
workers
20
workers
was
assumed
to
be
similar
to
that
measured
for
workers
in
the
same
area.
Nineteen
office
employees
were
used
as
controls
for
nose
and
throat
symptoms.
A
group
of
119
auto
mechanics
whose
lung
function
had
been
evaluated
by
similar
techniques
was
selected
as
controls
for
lung
function
measurements.
Smoking
habits
of
workers
were
evaluated
as
part
of
the
study.
31
At
mean
exposures
below
0.002
mg/
m3,
4/
19
workers
from
the
low­
exposure
group
experienced
subjective
nasal
symptoms.
Atrophied
nasal
mucosa
were
reported
in
4/
19
subjects
from
this
group
and
11/
19
had
smeary
and
crusty
and
septal
mucosa,
which
was
statistically
higher
than
the
controls.
No
one
exposed
to
levels
below
0.001
mg/
m3
complained
of
subjective
symptoms.
At
mean
concentrations
of
0.002
mg/
m3
or
above,
approximately
1/
3
of
the
subjects
had
reddened,
smeary
or
crusty
nasal
mucosa.
Atrophy
was
seen
in
8/
24
workers,
which
was
significantly
different
from
controls.
Eight
subjects
had
ulcerations
in
the
nasal
mucosa
and
5
had
perforations
of
the
nasal
septum.
Atrophied
nasal
mucosa
was
not
observed
in
any
of
the
19
controls,
but
smeary
and
crusty
septal
mucosa
occurred
in
5/
19
controls.

Short­
term
effects
on
pulmonary
function
were
evaluated
by
comparing
results
of
tests
taken
on
Monday
and
Thursday
among
exposed
groups
and
controls.
No
significant
changes
were
seen
in
the
low­
exposure
group
or
the
control
group.
Non­
smokers
in
the
high­
exposure
group
experienced
significant
differences
in
pulmonary
function
measurements
from
the
controls,
but
the
results
were
within
normal
limits.

The
authors
concluded
that
8
hour
exposure
to
chromic
acid
above
0.002
mg/
m3
may
cause
a
transient
decrease
in
lung
function,
and
that
short­
term
exposure
to
greater
than
0.002
mg/
m3
may
cause
ulceration
and
perforation.
Based
on
the
result
of
this
study,
a
LOAEL
of
0.002
mg/
m3
can
be
identified
for
incidence
of
nasal
septum
atrophy
following
exposure
to
chromic
acid
mists
in
chrome
plating
facilities.
Therefore,
the
LOAEL
of
continuous
exposure
of
0.002
mg/
m3
was
based
on
ulcerations,
perforations
of
the
nasal
septum
and
pulmonary
function
changes.
A
MOE
of
100
selected
(
3x
to
extrapolate
from
LOAEL
to
NOAEL,
3X
to
account
for
the
uncertainty
associated
with
using
an
epidemiological
study
and
10X
for
intraspecies
extrapolation).
The
100
mg/
m3
can
not
be
considered
as
NOAEL
because
it
is
just
a
level
reported
with
no
subjective
symptoms.

2.2.7
Carcinogenicity
The
cancer
endpoint
for
inhalation
exposure
is
classified
as
group
A
(
known
human
carcinogen)
with
an
inhalation
unit
risk
of
1.16x10­
2
(

g/
m3)­
1
(
Table
5).
The
24
hours
inhalation
unit
risk
is
1.16
x
10­
2
(
g/
m3)­
1
which
can
also
be
expressed
as
0.0116
m3/
g.
To
convert
the
air
concentration
to
a
dose
to
yield
units
of
kg­
day/
mg
or
(
mg/
kg/
day)­
1
the
unit
risk
is
expressed
mathematically
as
0.0116
m3/
g
x
day/
20
m3
x
1000
g/
mg
x
70
kg
=
40.6
(
mg/
kg/
day)­
1
.
For
workers
working
8
hour
per
day,
the
inhalation
potency
factor
is
derived
from
the
24
hour
inhalation
potency
factor
for
general
population.
CSF
=
40.6
(
mg/
kg/
day)­
1
x
(
8hrs/
24
hrs)
=
13.5
(
mg/
kg/
day)­
1.

Human
carcinogenicity
by
the
oral
route
of
exposure
cannot
be
determined
and
chromium
is
classified
as
group
D.
32
Table
5.
Toxicological
Endpoints
for
Assessing
Occupational
Exposures/
Risks
to
Chromium
(
VI)

EXPOSURE
SCENARIO
DOSE
(
mg/
kg/
day)
ENDPOINT
STUDY
Acute
Dietary
This
risk
assessment
is
not
required.

Chronic
Dietary
This
risk
assessment
is
not
required.

Incidental
Shortand
Intermediate­
Term
Oral
(
a)
NOAEL=
0.5
of
chromic
acid
[
0.12
of
Cr(
VI)]

MOE
=
100
based
on
the
increased
incidence
of
maternal
mortality
and
decreased
body
weight
gain
at
LOAEL
of
2.0
[
0.48
of
Cr
(
VI)]
Developmental/
Rabbit
Tyl,
1991
Dermal
Exposure
(
b)

(
All
Durations)
Because
dermal
irritation
and
dermal
sensitization
are
the
primary
concern
through
the
dermal
exposure
route,
no
toxicological
end­
point
is
selected
for
use
in
assessing
dermal
exposure
risks
to
chromium.

Inhalation
Exposure
(
All
Durations)
(
a)
LOAEL=
0.002
mg/
m3;
(
or
2.3
x
10­
4
mg/
kg/
day)
MOE
=
100
based
on
nose
and
throat
symptoms
observed
at
the
0.002
mg/
m3
level
Linberg
and
Hedenstierna,
1983.

Carcinogenicity
­
Inhalation
(
Inhalation
Risk)
CSF
=
40.6
(
c)(
mg/
kg/
day)­
1
(
For
general
Population)
Lung
tumors
IRIS
CSF
=
13.5
(
d)(
mg/
kg/
day)­
1
(
For
8
hour
working
day)

Note:
(
a).
MOE
=
Margin
of
Exposure;
NOAEL
=
No
observed
adverse
effect
level;
and
LOAEL
=
Lowest
observed
adverse
effect
level.
(
b).
The
dermal
absorption
factor
for
Cr(
VI)
=
1.3%
for
handler
dermal
contact
with
chromated
arsenical
pesticides.
(
c)
The
24
hours
inhalation
unit
risk
is
1.16
x
10­
2
(
µ
g/
m3)­
1
which
can
also
be
expressed
as
0.0116
m3/

g.
To
convert
the
air
concentration
to
a
dose
to
yield
units
of
kg­
day/
mg
or
(
mg/
kg/
day)­
1
the
unit
risk
is
expressed
mathematically
as
0.0116
m3/

g
x
day/
20
m3
x
1000

g/
mg
x
70
kg
=
40.6
(
mg/
kg/
day)­
1
(
EPA,
1989).
(
d)
For
workers
working
8
hour
per
day,
the
inhalation
cancer
slope
factor
(
CSF)
derived
from
the
24
hour
CSF
for
the
general
population,
is
adjusted
for
an
8
hour
work
day
.
CSF
for
8­
hr
work
day
=
general
population
CSF
of
40.6
(
mg/
kg/
day)­
1
x
(
8hrs/
24
hrs)
=
13.5
(
mg/
kg/
day)­
1.
33
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39
Attachment
1
US
EPA's
Risk
Assessment
for
Arsenic
in
Drinking
Water
40
41
42
43
Converting
from
ppb
and
(
ppb)­
1
to
µ
g/
kg/
d
and
(
µ
g/
kg/
d)­
1
Suppose
a
person
consumes
A
ppb
(
µ
g/
L)
of
arsenic
in
drinking
water.
They
weigh
K
kg
and
drink
C
L/
d
of
water.
Then
in
µ
g/
kg/
d,
their
exposure
is
A
C
K
AC
K
ug
L
L
d
kg
ug
kg
d
 
=
 
/

where
the
liters
have
cancelled
from
the
numerator
and
denominator.

On
the
risk
side,
suppose
that
the
risk
slope
is
S
per
ppb
(
ppb­
1).
For
the
same
person
as
above
drinking
C
L/
d
of
water
and
weighing
K
kg,
the
risk
per
µ
g/
kg/
d
is
S
K
C
SK
C
ug
L
kg
L
d
ug
kg
d
/
/
/
/
 
=

Again
the
liters
cancel.
