Document ID: EPA-HQ-OPP-2003-0072-0003
Agency: epa
Document Type: Supporting & Related Material
Title: 
Posted Date: 2003-02-13T05:00Z

January
31,
2003
MEMORANDUM
SUBJECT:
Atrazine:
Response
to
Public
Comments
on
the
EPA's
April
16,
2002
Revised
Human
Health
Risk
Assessment
and
Associated
Documents
for
the
Reregistration
Eligibility
Decision
(
RED).
PC
Code:
080803.
DP
Barcode:
284707.

FROM:
Catherine
Eiden,
Branch
Senior
Scientist
Reregistration
Branch
3
Health
Effects
Division
(
7509C)

THROUGH:
Donna
Davis,
Branch
Chief
Reregistration
Branch
3
Health
Effects
Division
(
7509C)

TO:
Kimberly
Lowe,
Chemical
Review
Manager
Special
Review
and
Reregistration
Division
(
7508C)

Please
find
attached
the
response
document
to
public
comments
on
the
EPA's
April
16,
2002,
"
Atrazine:
HED's
Revised
Human
Health
Risk
Assessment
(
and
Associated
Documents)
for
the
Reregistration
Eligibility
Decision
(
RED).
HED
responders
included:
Catherine
Eiden,
Vicki
Dellarco,
Jerry
Blondell,
and
Linda
Taylor.
2
Executive
Summary
This
memorandum
contains
HED's
responses
to
public
comments
submitted
during
the
60­
day
public
comment
period
for
"
Atrazine.
HED's
Revised
Human
Health
Risk
Assessment,
April
16,
2002".
The
HED
received
11
sets
of
comments
from
academia,,
and
groups
representing
the
agribusiness
and
the
farming
community
and
their
consultants,
non­
profit
organizations,
state
agencies,
and
water
quality
trade
associations.

HED
received
comments
from
the
American
Farm
Bureau
Federation,
Triazine
Network,
and
the
Louisiana
Farm
Bureau
Federation.

The
HED
also
received
comments
from
3
non­
profit
organizations
(
environmental
groups)
representing
public
concerns:
the
Natural
Resources
Defense
Council
(
NRDC),
Beyond
Pesticides/
NCAMP,
and
People
for
the
Ethical
Treatment
of
Animals
(
PETA).

HED
received
comments
from
the
State
of
New
York,
Office
of
the
Attorney
General,
the
California
Department
of
Pesticide
Regulation,
and
the
State
of
Connecticut,
Office
of
the
Attorney
General.

From
the
water
quality
community,
HED
received
comments
from
the
American
Water
Works
Association
(
AWWA).
From
the
general
public,
HED
received
comments
from
John
Wargo
of
Yale
University.

Agricultural
Community
Comments
Louisiana
Farm
Bureau
Federation
(
LFBF):

Comment
LFBF
provided
comment
on
the
ongoing
efforts
to
manage
pesticides
in
the
Iberville,
Jefferson
Parish,
and
Thibodaux
watersheds
to
minimize
the
impacts
of
atrazine
on
water
quality.
Cooperative
agreements
among
state
agencies,
university
programs,
and
grower
groups
are
cited
as
providing
the
best
framework
to
address
local
water
quality
issues
posed
by
agriculture.
Water
quality
monitoring
is
cited
as
providing
proof
that
cooperative
local
efforts
to
change
use
rates
3
and
use
best
management
practices
(
BMPs)
have
reduced
the
detections
and
levels
of
atrazine
in
the
managed
areas.
The
LFBF
notes
that
soil
erosion
is
reduced
and
soil
conservation
efforts
enhanced
as
a
result
of
the
use
of
atrazine
in
the
watersheds.
In
summary,
the
LFBF
supports
the
continued
use
of
atrazine
and
local
management
of
water
quality
impairment,
and
expresses
an
interest
that
EPA
review
available
water
monitoring
data
and
produce
a
timely
reregistration
decision
for
atrazine.

HED
Response
HED
fully
supports
the
idea
of
cooperative
efforts
involving
local
organizations
in
areas
with
impaired
water
quality
as
a
result
of
atrazine
use.
HED
understands
that
local
responses
can
be
the
best
approach
to
solving
a
localized
problem.
HED
has
reviewed
the
available
water
monitoring
data,
and
notes
that
in
finished
drinking
water
concentrations
of
atrazine
and
the
chlorinated
degradates
tended
to
be
below
the
MCL
of
3
ppb
in
Jefferson
Parish
and
did
not
exceed
levels
of
concern.
They
were
also
low
with
the
exception
of
a
few
spikes
in
May
and
June
of
some
years
in
the
Thibodaux
CWS,
but
did
not
exceed
levels
of
concern.
However,
the
community
water
system
(
CWS)
at
Iberville
has
exceeded
levels
of
concern
for
atrazine
and
the
chlorinated
degradates
as
recently
as
2001.
This
CWS
has
been
targeted
for
mitigation.
The
situation
at
the
Iberville
CWS
is
an
indication
that
there
are
CWS
impaired
by
atrazine
use
even
under
good
management
and
BMPs
that
need
additional
mitigation.

American
Farm
Bureau
Federation
(
AFBF):

Comment
AFBF
provided
comment
on
atrazine's
great
importance
to
agriculture.
It
is
an
inexpensive,
reliable,
and
effective
weed
control
preferred
by
farmers,
particularly,
those
growing
corn,
sorghum,
and
sugarcane.
It
is
a
critical
piece
of
"
no­
till"
or
conservation
tillage
practices
in
agriculture
that
helps
to
reduce
soil
erosion.
Regarding
science
and
the
risk
assessment,
AFBF
reiterates
the
designation
of
atrazine
as
"
not
likely
to
be
carcinogenic
to
humans".
Regarding
the
toxic
effects
of
atrazine,
AFBF
states,
"
Both
epidemiological
studies
of
the
population
in
areas
where
atrazine
has
been
manufactured
or
used
for
40
years
and
long­
term
dietary
studies
using
laboratory
animals,
show
that
atrazine
does
not
cause
adverse
effects
to
reproductive
systems,
affect
genetic
development,
cause
birth
defects,
affect
chromosome
structure
or
disrupt
endocrine
function,
(
i.
e.,
is
not
estrogenic)".
Regarding
spray
drift,
AFBF
makes
the
case
that
atrazine
is
non­
volatile
and
not
subject
to
drift
concerns.
As
to
drinking
water
concerns,
AFBF
states
that
atrazine
is
found
in
some
water
supplies
at
very
low
levels,
rarely
above
the
MCL
of
3
ppb,
and
that
short­
term
Health
Advisory
Levels
(
HALs)
have
not
been
exceeded.
AFBF
notes
that
through
local
management
detected
levels
of
atrazine
have
decreased
by
60%
between
1989
and
1998
in
Midwestern
streams
according
to
the
USGS.
Finally,
AFBF
notes
that
atrazine
is
not
4
found
in
foods
we
eat.

HED
Response
HED
acknowledges
the
importance
of
atrazine
in
agriculture
as
currently
practiced.
HED
concurs
with
AFBF's
designation
of
atrazine
as
not
likely
to
be
a
human
carcinogen.
This
position
is
reflected
in
the
human
health
risk
assessment.

Regarding
AFBF's
statement
as
to
atrazine's
toxicity,
HED
disagrees
with
AFBF's
statements
and
concludes
somewhat
differently
in
the
risk
assessment
that
atrazine
does
have
reproductive
consequences
and
does
alter
endocrine
function
in
test
animals
and
is
therefore
likely
to
do
so
in
humans.
Short­
and
intermediate­
term
exposures
to
atrazine
caused
fetal
"
resorptions"
(
abortions)
in
rabbits
and
delays
in
pubertal
development
of
young
rats,
as
well
as,
alterations
in
the
estrus
cycle
of
adult
rats
by
decreasing
the
luteinizing
hormone
surge,
which
affects
ovulation
(
both
a
reproductive
and
an
endocrine
effect).
HED
believes
the
results
of
the
animal
tests
indicate
that
atrazine
and
the
chlorinated
degradates
have
the
potential
to
disrupt
endocrine
function
and
have
adverse
developmental
and
reproductive
consequences
in
humans.
These
toxic
effects
form
the
basis
of
the
risk
assessment.

HED
has
received
comments
that
there
is
evidence
that
atrazine
is
present
in
rainwater
and
volatilization
may
be
a
source
of
exposure.
This
may
be
occurring
via
volatilization
from
lakes,
rivers,
and
bays
where
atrazine
is
present
in
dissolved
form.
HED
concludes
in
the
risk
assessment
that
exposure
to
atrazine
in
foods
humans
eat
is
minimal
and
not
a
significant
exposure
pathway.
HED
agrees
that
atrazine
is
a
non­
volatile
pesticide.
HED
does
not
consider
volatilization
and
spray
drift
to
be
major
contributors
to
exposure
to
atrazine
in
the
risk
assessment.
Even
so,
HED
did
conduct
inhalation
exposure
assessments
for
atrazine
as
a
routine
part
of
the
occupational
and
residential
risk
assessments.

HED
does
not
completely
agree
with
the
statement
that
atrazine
is
found
in
some
water
supplies
at
very
low
levels,
rarely
above
the
MCL.
HED
concluded
that
atrazine
is
widely
detected
in
the
nation's
streams,
rivers,
and
lakes
mostly
at
low
levels.
This
is
supported
by
USGS
monitoring
programs.
However,
to
date,
HED
has
reviewed
large
volumes
of
data
on
atrazine
and
the
chlorinated
degradates
in
finished
drinking
water
and
determined
there
are
197
CWS
with
annual
average
concentrations
of
atrazine
greater
than
or
equal
to
the
MCL
of
3.0
ppb.
Most
of
these
CWS
use
surface
waters.
These
CWS
represent
~
2%
of
CWS
in
the
US
using
surface
water.
This
occurrence
of
atrazine
above
the
MCL
may
not
be
considered
frequent
given
the
number
of
CWS
using
surface
water
in
the
US
(
~
10,000),
but
it
should
not
be
considered
rare,
either.

HED
defers
to
the
Environmental
Fate
and
Effects
Division
(
EFED)
to
discuss
the
decreasing
5
trend
of
atrazine
in
Midwestern
streams.

Triazine
Network:

Comment
The
Triazine
Network
submitted
comments
on
the
cancer
classification
of
atrazine,
the
toxicologic
endpoints
selected
for
use
in
the
human
health
risk
assessment,
and
on
the
10­
fold
FQPA
safety
factor
applied
to
dietary
risk
assessments
for
atrazine.
Specifically,
the
commenter
agrees
with
the
classification
of
atrazine
as
"
not
likely
to
be
a
human
carcinogen",
as
stated
in
the
risk
assessment.
They
do
disagree
with
the
selection
of
the
1.8
mg/
kg/
day
endpoint
based
on
disturbances
in
the
luteinizing
hormone
(
LH)
surge
in
adult
female
rats
as
the
basis
of
risk
assessments
for
infants
and
children,
and
the
application
of
this
endpoint
in
intermediate­
term
risk
assessments.
They
also
note
that
the
endpoint
comes
from
a
non­
guideline
study
and
this
practice
should
not
become
routine.
It
is
suggested
that
an
endpoint
from
a
rat
90­
day
(
subchronic)
study
be
used
to
assess
intermediate­
term
risks.
They
also
disagree
with
the
retention
of
the
10­
fold
FQPA
safety
factor
based
on
increased
sensitivity
in
the
young.
Specifically,
they
argue
that
the
decision
was
driven
by
data
on
DACT,
and
that
guideline
studies
in
the
young
have
not
produced
a
NOAEL
lower
than
1.8
mg/
kg/
day.
The
comment
concludes
that
the
assessment
uses
an
"
ultra
conservative"
approach.
6
HED
Response
Endpoint
selection:
The
endpoint
selected
for
use
in
intermediate­
term
and
chronic
risk
assessment
comes
from
a
6­
month
study
designed
to
elucidate
the
potential
mechanism
of
mammary
tumor
formation
in
the
female
Sprague­
Dawley
rat.
As
indicated,
the
study
was
not
a
guideline
study;
however,
the
endpoint
reflects
the
general
mechanism
by
which
atrazine
toxicity
is
believed
to
function,
i.
e.,
disruption
of
the
neuroendocrine
system.
It
also
represents
the
lowest
(
i.
e.,
most
conservative
and
protective)
endpoint
in
the
toxicity
database.
In
this
sense,
although
the
study
from
which
the
endpoint
was
taken
was
not
a
guideline
study,
it
nevertheless
was
determined
to
be
the
most
relevant
study
for
atrazine's
toxic
mode
of
action.
Available
guideline
studies
did
not
measure
the
hormonal
parameters
necessary
to
determine
endocrine
effects.

Regarding
the
use
of
the
endpoint
for
both
chronic
and
intermediate­
term
risk
assessments,
as
stated,
the
attenuation
of
the
LH
surge
is
deemed
to
be
indicative
of
atrazine's
general
toxic
mode
of
action
on
the
neuroendocrine
system.
A
six­
month
study
is
generally
considered
adequate
for
use
in
selecting
a
subchronic
endpoint
for
evaluation
of
intermediate­
term
exposures.
In
the
case
of
atrazine,
because
attenuation
of
the
LH
surge
is
deemed
to
be
a
critical
event
in
the
mode
of
action
of
atrazine­
associated
carcinogenesis
in
the
Sprague­
Dawley
strain
of
rat,
and
because
a
LH
surge
study
of
longer
duration
may
be
of
limited
value
given
that
the
attenuation
of
LH
surge
occurs
in
normally
aging
Sprague­
Dawley
rats
around
9
months
of
age,
the
6­
month
study
was
selected
as
the
basis
for
estimating
risks
associated
with
both
intermediate­
term
and
chronic
exposures.
An
additional
safety
factor
to
account
for
a
study
duration
of
less
than
12
months
was
not
deemed
necessary
since
attenuation
of
LH
surge
occurs
in
normally
aging
Sprague­
Dawley
rats
around
9
months
of
age.

As
to
the
application
of
this
endpoint
to
risk
assessments
for
infants
and
children,
though
this
specific
endpoint
(
LH
surge
attenuation
and
estrous
cycle
disruption)
is
directly
applicable
only
to
females
13­
50,
HED's
HIARC
noted
that
this
dose
is
the
lowest
NOAEL
available
in
the
toxicology
database
(
i.
e.,
the
most
sensitive
endpoint),
and
therefore
would
be
protective
of
other
adverse
effects,
including
those
occurring
in
males,
infants
and
children.
Further,
the
attenuation
of
the
LH
surge
is
considered
a
biomarker
indicative
of
atrazine's
ability
to
alter
hypothalamicpituitary
function
in
general.
Therefore,
a
separate
endpoint
was
not
selected
for
other
populations
(
i.
e.,
males,
infants
and
children).
As
discussed
in
the
Scientific
Advisory
Panel
(
SAP)
report
(
SAP
Report
No.
2000­
05;
Atrazine:
Hazard
and
Dose
Response
Assessment
and
Characterization).....
"
Because
of
the
rapid
developmental
brain
changes...
the
influence
of
Atrazine
on
neurotransmitters
in
the
hypothalamus
and
on
GnRH
may
well
have
a
differential,
permanent
effect
on
children.
This
phenomenon
is
the
basis
of
the
relatively
new
field
of
7
behavioral
teratology.
Atrazine
could
influence
the
migration
of
cells
and
the
connectivity
of
the
CNS.
The
influence
of
Atrazine
on
the
hypothalamus
and
on
GnRH
may
have
a
differential
effect
on
children.
This
effect
could
be
latent,
and
emerge
later
during
the
challenge
of
puberty,
or
during
senescence.
Behavioral
alterations
may
be
the
most
sensitive
outcome.
This
possibility
should
be
addressed...."
(
see
Part
A,
http://
www.
epa.
gov/
scipoly/
sap/
2000/
june27/
finalparta_
atz.
pdf
and
Part
B,
http://
www.
epa.
gov/
scipoly/
sap/
2000/
june27/
finalpartb_
atz.
pdf).

This
dose
and
endpoint
replaces
the
previous
dose
and
endpoint
of
3.5
mg/
kg/
day
based
on
decreased
body
weight
gain
and
food
consumption
in
a
two­
year
rat
bioassay
selected
by
HIARC
in
1998.
The
dose
of
1.8
mg/
kg/
day
for
use
in
risk
assessment
would
be
protective
of
effects
that
occur
at
the
higher
dose
of
3.5
mg/
kg/
day
as
well
as
protective
of
effects
such
as
LH
surge
attenuation
and
estrous
cycle
alterations,
and
any
effects
that
may
be
associated
with
alteration
of
these
parameters
such
as
prostatitis
in
developing
males
(
as
seen
from
pubertal
assays
on
rats).

This
endpoint
was
considered
particularly
appropriate
for
assessing
intermediate­
term
and
chronic
exposures
to
atrazine
in
drinking
water
(
the
main
exposure
route
of
atrazine),
as
these
exposures
occur
both
as
seasonal
pulses
from
weeks
to
months
in
duration,
and
chronically
from
months
to
years
in
duration,
reflective
of
atrazine's
use
patterns
and
occurrence
in
drinking
water.

An
endpoint
of
3.3
mg/
kg/
day
from
a
subchronic,
oral,
rat
study
was
considered,
but
deemed
inappropriate
because
the
effect
elicited
(
reduced
body
weight
gain)
is
not
reflective
of
the
general
toxic
mode
of
action
of
atrazine,
i.
e.,
in
that
study
there
was
no
assessment
of
endocrine
disruption
via
hormonal
measurements.

FQPA
Safety
Factor:
The
decision
reflected
in
the
April
16,
2002
human
health
risk
assessment
to
retain
the
10X
FQPA
safety
factor
was
not
based
solely
on
toxicity
considerations,
nor
on
a
rabbit
developmental
study
using
DACT.
The
decision
captured
in
the
document
dated
April
8,
2002,
Atrazine/
DACT
­
Reassessment
Report
of
the
FQPA
Safety
Factor
Committee,
establishes
that
residual
uncertainties
regarding
atrazine's
effects
on
the
developing
young,
and
evidence
of
increased
qualitative
susceptibility
from
the
rabbit
developmental
study
using
atrazine
were
noted.
The
rabbit
developmental
study
showed
increased
resorptions
of
fetuses
(
abortions)
at
the
same
dose
of
atrazine
in
which
the
mother
experienced
clinical
signs
and
reduced
body
weight
gain.
The
more
severe
effect
on
the
young
developing
fetuses
(
death)
is
considered
qualitative
evidence
of
the
young's
increased
sensitivity
to
atrazine.
In
addition,
the
committee
found
that
there
were
residual
concerns
and
uncertainties
regarding
the
extent
of
short­
8
and
intermediate­
term
exposure
to
atrazine
in
drinking
water.
Together,
these
two
sources
of
residual
uncertainty
led
the
committee
to
retain
the
10X
safety
factor
for
dietary
assessments,
only.
The
committee
decided
that
a
3X
safety
factor
was
adequately
protective
of
residential
exposures.
The
complete
rationale
for
the
FQPA
decisions
is
contained
in
the
FQPA
memorandum
cited
above
available
on
EPA's
website:
http://
www.
epa.
gov/
oppsrrd1/
reregistration/
atrazine/.

The
comment
indicates
that
only
the
developmental
rat
study
with
DACT
was
considered
in
the
FQPA
decision.
The
comment
states
that
there
is
no
evidence
that
the
developmental
study
using
DACT
shows
quantitative
susceptibility
in
the
young.
HED
reassessed
this
study
based
on
similar
comments
received
during
the
60­
day
public
comment
period
on
the
revised
preliminary
risk
assessment,
and
concluded
that
there
was
no
evidence
of
quantitative
susceptibility
in
the
young
in
the
DACT
developmental
study.
HED
concurs
with
the
comment
and
has
revised
the
FQPA
memorandum
and
toxicology
chapter
and
risk
assessment
accordingly.
Maternal
and
fetal
or
offspring
effects
occur
at
the
same
doses
(
25
mg/
kg/
day).
During
this
reassessment,
the
entire
toxicity
database
was
thoroughly
reexamined
and
the
resulting
conclusions
captured
in
the
April
5th
and
8th,
2002
HIARC
and
FQPA
documents,
respectively,
both
available
on
the
previously
cited
website.
That
reexamination
determined
there
was
no
evidence
of
quantitative
susceptibility,
but
there
was
evidence
of
"
qualitative"
susceptibility
in
the
rabbit
developmental
study
using
atrazine
(
not
DACT)
based
on
a
weight­
of­
the­
evidence
approach
using
the
entire
database.
This
increased
qualitative
susceptibility
is
based
on
reduced
body
weight
gain
in
the
mother
versus
fetal
resorptions
(
abortion/
death)
in
the
pups
at
equivalent
doses.

Regarding
comments
on
sensitivity
in
the
young
and
the
lack
of
any
indication
of
sensitivity
in
the
young
from
available
guideline
studies,
the
comment
states
that
all
evidence
indicates
that
young
rats
are
less
sensitive
to
the
neuroendocrine
effects
caused
by
atrazine
than
adult
rats.
The
basis
for
this
conclusion
stems
from
their
comparison
of
the
NOAEL/
LOAEL
from
studies
on
the
young
animal
[
those
where
the
young
were
not
directly
dosed,
two
pubertal
assays
and
two
recent
studies
in
which
young
rats
were
dosed
directly]
with
findings
in
the
available
database
on
the
adult
animal.

Although
the
NOAELs
in
some
of
the
adult
studies
are
lower
than
those
in
the
young,
this
apparent
difference
between
the
age
groups
may
be
attributed
to
dose
spacing
or
to
a
difference
in
dosing
duration.
For
example,
comparison
of
the
28­
day
LH
surge
study
in
the
female
adult
rat
[
NOAEL
of
5
mg/
kg/
day;
LOAEL
of
40
mg/
kg/
day]
with
the
published
pubertal
study
in
the
female
young
rat
[
delayed
vaginal
opening
(
VO)
NOAEL
of
25
mg/
kg/
day
;
LOAEL
of
50
mg/
kg/
day]
shows
rather
similar
LOAELs
[
40
vs
50]
for
similar
durations
of
dosing
[
young
9
female
20
days].
If
the
dose­
spacing
in
the
adult
study
were
similar
to
that
in
the
pubertal
study
[
2X],
the
NOAELs
might
have
been
similar
also
[
20
vs
25].
In
comparisons
made
by
Syngenta,
the
6­
month
study
duration
far
exceeds
any
study
performed
in
the
young
animal,
and
it
is
well
known
that
lower
doses
are
required
to
produce
an
effect
following
long­
duration
exposure
than
for
a
short­
duration
exposure.
A
comparison
of
the
adult
NOAELs/
LOAELs
obtained
in
the
6­
month
[
1.8/
3.65
mg/
kg/
day]
and
28­
day
[
5/
40
mg/
kg/
day]
studies
illustrates
this
also.

Based
on
one
of
the
recent
Syngenta
studies
[
described
above]
in
which
immature
female
rats
were
dosed
directly
[
21­
24
days],
the
lowest
NOAEL
was
10
mg/
kg/
day,
based
on
effects
[
delayed
vaginal
opening
and
reduced
uterine
weight]
at
30
mg/
kg/
day.
Comparison
of
this
study
with
the
NOAEL
observed
in
the
adult
female
28­
day
LH
surge
study
[
NOAEL
=
5/
mg/
kg/
day;
LOAEL
=
40
mg/
kg/
day]
also
does
not
support
the
conclusion
that
the
young
female
rat
is
less
sensitive
than
the
adult
female
rat.

Finally
regarding
speculation
about
atrazine's
effects
in
the
developing
young
throughout
critical
periods
of
development
and
the
use
of
non­
guideline
studies
in
assessing
atrazine,
HED
notes
that
endocrine
disruption
is
now
considered
the
main
toxic
mode
of
action
of
atrazine.
Residual
uncertainties
remain
at
this
time
regarding
that
mode
of
toxic
action,
and
the
timing
of
exposure
in
the
available
database.
Guideline
studies
currently
used
by
OPP
do
not
address
endocrine
disruption,
and
as
a
result
HED
responsibly
selected
endpoints
from
non­
guideline
studies
that
did
assess
changes
in
hormonal
parameters.
The
Agency
has
established
the
Endocrine
Disruptor
Screening
and
Testing
Advisory
Committee
(
EDSTAC)
to
develop
the
kinds
of
studies
needed
to
assess
neuroendocrine
disruption.
In
the
future,
atrazine
may
be
subject
to
further
testing
along
these
lines.
In
the
interim,
uncertainty
regarding
atrazine's
full
effects
on
the
endocrine
systems
of
adults
and
the
young,
and
the
consequences
of
those
effects
must
be
considered.
HED
acknowledges
that
because
of
these
remaining
toxicity
and
exposure
uncertainties,
the
human
health
risk
assessment
for
atrazine
and
its
chlorinated
degradates
is
conservative.

Environmental
Community
Comments
Natural
Resources
Defense
Council
(
NRDC):

The
Natural
Resources
Defense
Council
(
NRDC)
submitted
comments
covering
a
wide
range
of
issues
covering
drinking
water
exposures,
flaws
in
interpretation
of
toxicity
data
regarding
endpoint
selection
for
risk
assessment
and
cancer
classification
of
atrazine,
the
FQPA
safety
factor,
farm
children's
and
worker
exposures,
high­
end
exposures,
use
of
human
data,
percentcrop
treated
information
and
anticipated
residues,
and
inclusion
of
exposure
through
showering
in
the
aggregate
risk
assessment.
10
Drinking
Water
Issues
­

Comment
EPA
has
ignored
the
MCL
in
its
risk
assessment
for
atrazine.
The
use
of
the
concentration
figure
of
12.5
ppb
as
a
safe
upper
limit
in
drinking
water
is
wholly
unwarranted.
EPA
has
underestimated
drinking
water
exposures.

HED
Response
The
MCL
of
3
ppb
is
an
annual
average
concentration
of
atrazine
alone
that
is
based
on
a
NOAEL
of
0.5
mg/
kg/
day,
a
1000­
fold
safety
factor,
and
assumes
that
exposure
through
drinking
water
will
occupy
only
20%
of
the
reference
dose.
In
the
case
of
most
pesticides
OW
assumes
that
exposure
through
food
may
contribute
up
to
80%
of
the
exposure.
In
the
case
of
atrazine,
however,
dietary
exposure
through
food
is
minimal,
and
occupies
<
1%
of
the
reference
dose.
HED's
assessment
quantifies
and
takes
into
account
the
dietary
exposure
to
chlorotriazines
through
food
in
its
aggregate
exposure
assessment
rather
than
relying
on
assumptions
about
dietary
exposure.
Additionally,
the
12.5
ppb
DWLOC
that
OPP
has
identified
is
for
total
chlorotriazines
and
a
90­
day
rolling
average
concentration
in
contrast
to
an
annual
average
concentration
for
atrazine
alone.
Selection
of
a
90­
day
average
value
was
determined
to
be
the
most
appropriate
value
to
capture
seasonal
exposures
to
atrazine.
11
NRDC
discusses
the
endpoint
from
a
toxicity
study
considered
the
basis
of
the
MCL
for
atrazine.
HED's
risk
assessment
was
based
on
a
toxic
effect
and
endpoint
different
from
the
MCL.
The
MCL
is
based
on
several
studies,
one
of
which
is
a
2­
generation
reproduction
study
in
rats.
The
endpoint
from
the
2­
generation
reproduction
study
in
rats
is
reduced
body
weight
gain.
On
9/
28/
92
the
OPP
(
HED
RfD
Peer
Review
Committee)
in
conjunction
with
representatives
of
the
Office
of
Water
(
OW)
conducted
a
review
of
that
study
and
determined
that
the
endpoint
was
not
statistically
significant,
and
that
the
NOAEL
from
that
study
should
be
~
3.5
mg/
kg/
day,
not
the
0.5
mg/
kg/
day
currently
reflected
in
the
MCL.
This
decision
was
confirmed
by
the
Agency
Workgroup
on
12/
16/
92.
OPP
has
worked
closely
with
the
Office
of
Water
(
OW)
while
developing
the
risk
assessment
for
atrazine.
OW
has
indicated
that
they
will
review
the
MCL
for
atrazine
once
EPA
has
completed
its
risk
assessment.

The
volume
of
toxicity
data
on
atrazine
indicates
that
the
most
relevant
toxic
endpoints
for
risk
assessment
should
reflect
atrazine's
disruption
of
the
neuroendocrine
system
as
its
main
toxic
mode
of
action.
The
concentration
used
in
the
screening­
level
assessment
as
an
upper
limit
of
atrazine
and
its
chlorinated
degradates,
12.5
ppb,
is
based
on
attenuation
of
the
LH
surge
(
disruption
of
the
estrus
cycle)
a
biomarker
for
its
toxic
mode
of
action.
It
is
based
on
a
NOAEL
of
1.8
mg/
kg/
day,
which
translates
to
a
reference
dose
(
RfD)
of
0.018
mg/
kg/
day
reflecting
the
traditional
100X
safety
factor,
and
a
population
adjusted
dose
of
0.0018
mg/
kg/
day
reflecting
the
additional
10X
FQPA
safety
factor.
The
10X
FQPA
safety
factor
reflects
a
3X
safety
factor
for
residual
uncertainties
regarding
atrazine's
potential
effects
on
childrens'
development,
and
a
3X
safety
factor
for
residual
uncertainties
regarding
limitations
on
the
drinking
water
database.
The
residual
uncertainties
identified
by
the
FQPA
Committee
included
limited
monitoring
data
on
the
degradates
and
the
infrequency
of
monitoring
under
the
SDWA
at
specific
CWS.
It
represents
the
average
seasonal
concentration
over
a
90­
day
period
of
chlorotriazines
that
an
infant,
1
year
old
weighing
7
kg
and
consuming
1
liter
of
water
per
day,
may
safely
consume
in
drinking
water
as
a
part
of
its
aggregate
exposure
to
the
chlorotriazines
through
its
diet
(
i.
e.,
exposure
through
food
and
water).

It
should
also
be
noted
that
the
12.5
ppb
figure
was
used
to
screen
for
CWS
with
potential
exposures
of
concern.
Once
identified
through
the
screening
process,
probabilistic
assessments
for
specific
CWS
were
conducted.
The
toxic
endpoint
used
as
the
basis
for
these
probabilistic
assessments
was
the
same
as
that
used
to
calculate
the
12.5
ppb
figure.
However,
HED
does
not
intend
the
12.5
ppb
figure
to
serve
as
a
standard
but
as
a
screening
tool.
It
should
be
noted
that
the
12.5
ppb
figure
is
based
on
an
endpoint
considered
representative
of
atrazine's
main
toxic
mode
of
action
(
neuroendocrine
system
effects);
it
is
the
lowest/
most
protective
endpoint
in
the
toxicity
database,
and
it
comes
from
a
sub
chronic
study
well­
suited
to
assessing
risks
associated
with
seasonal
peaks
of
chlorotriazines
in
drinking
water
as
the
typical
high­
end
exposures
to
12
atrazine
occur
shortly
after
application
in
the
Spring.

For
those
specific
CWS
undergoing
or
preparing
to
undergo
intensive
monitoring,
residual
uncertainties
regarding
the
extent
and
magnitude
of
exposure
to
chlorotriazines
have
been
removed,
therefore
supporting
a
reduction
in
the
FQPA
safety
factor
to
3X.
Based
on
the
availability
of
reliable
drinking
water
exposure
data,
HED
has
recalculated
the
DWLOC
(
drinking
water
level
of
concern)
using
a
total
risk
assessment
300­
fold
uncertainty
factor
for
those
CWS
currently
undergoing
or
targeted
for
future
intensive
monitoring.
For
these
CWS,
the
DWLOC
for
a
90­
day
average
concentration
of
total
chlorotriazines
becomes
37.5
ppb
based
on
an
endpoint
of
1.8
mg/
kg/
day,
and
a
300­
fold
uncertainty
factor
reflecting
a
10­
fold
factor
for
interspecies
variation,
a
10­
fold
factor
for
intraspecies
variability,
and
a
3­
fold
safety
factor.
The
remaining
3­
fold
safety
factor
reflects
residual
uncertainties
associated
with
atrazine's
toxic
effects
on
the
developing
child
only.
For
CWS
without
intensive
monitoring
as
described
above,
the
screening
level
DWLOC
remains
12.5
ppb
for
total
chlorotriazines.

EPA
believes
that
we
have
not
underestimated
drinking
water
exposures
in
our
current
assessment.
The
Environmental
Fate
and
Effects
Division's
drinking
water
assessment
estimates
that
~
1
million
people
are
exposed
to
annual
average
concentrations
of
atrazine
above
the
MCL
of
3
ppb.
Based
on
all
available
compliance
monitoring
data
and
voluntary
monitoring
on
atrazine
in
finished
drinking
water
through
2001,
there
are
~
200
community
water
systems
(
CWS)
with
annual
average
concentrations
of
atrazine
above
3
ppb.
The
available
monitoring
data
used
in
the
risk
assessment
cover
~
99%
of
all
atrazine
use
in
the
US
and
represent
~
4000
CWS
using
surface
water
collecting
data
on
atrazine.

In
the
US,
there
are
~
55,
000
CWS
regulated
under
the
Safe
Drinking
Water
Act
(
SDWA).
Of
these
55,000
CWS,
10,000
use
surface
water
and
the
remaining
45,000
use
groundwater.
These
200
CWS
with
levels
of
atrazine
above
the
MCL
use
surface
water
and
represent
variously
0.036
%
of
all
the
CWS,
and
2%
of
the
~
10,000
CWS
using
surface
water.
HED
believes
that
these
200
CWS
represent
the
high­
end
of
atrazine
exposure
in
US
drinking
water
supplies.

Based
on
the
human
health
risk
assessment
and
analysis
of
compliance
monitoring
data
from
an
additional
10
states
with
atrazine
use
not
included
in
the
April
16,
2002
human
health
risk
assessment,
but
submitted
subsequently
to
the
public
release
of
the
assessment,
~
230,000
to
240,000
individuals
are
served
by
34
CWS
identified
as
having
aggregate
risk
estimates
of
concern
for
infants.
Altogether,
the
data
set
provides
information
on
~
4000
CWS
with
data
on
atrazine
monitored
under
the
SDWA
representing
99%
of
the
atrazine
use
in
the
US.
The
US
Bureau
of
Census
estimates
that
1.4%
of
the
US
population
is
infants
<
1
year
old.
Some
of
these
CWS
also
have
risks
of
concern
for
children
and
adults.
Although
not
precise
as
to
the
exact
number
of
13
individual
infants,
children,
or
adults
exposed,
the
assessment
does
provide
for
an
estimate
of
the
magnitude
of
the
population
of
concern.

An
additional
~
50
CWS
are
estimated
as
having
potential
risks
of
concern.
The
~
50
CWS
with
the
potential
for
risks
of
concern
were
not
identified
via
MCL
violations
of
an
annual
average
of
>
3ppb,
but
the
50
were
identified
as
having
a
single
maximum
concentration
of
>
12.5
ppb.
NRDC
points
out
that
there
may
be
a
hole
in
industry's
methodology
for
identifying
CWS
of
concern.
It
may
be
that
an
annual
average
of
3
ppb
is
too
high
to
identify
CWS
with
90­
day
average
concentrations
in
excess
of
12.5
ppb,
and
a
lower
"
trigger"
value
is
needed.
To
address
this
issue,
HED
and
EFED
considered
available
data
from
SDWA
compliance
monitoring
and
came
to
agreement
with
the
registrant
on
a
trigger
value
of
2.6
ppb
based
on
an
annual
average
concentration
in
finished
water
which
is
considered
predictive
of
the
likelihood
that
a
90­
day
average
during
peak
use
season
would
exceed
the
screening
DWLOC
of
12.5
ppb.
CWS
identified
in
the
future
with
potential
high­
end
seasonal
exposures
based
on
the
annual
average
trigger
of
2.6
ppb
will
receive
intensive
monitoring
under
the
Memorandum
of
Agreement
between
OPP
and
the
registrant.
It
should
be
noted
that
the
annual
average
trigger
of
2.6
ppb
is
for
total
chlorotriazines.
Therefore,
all
SDWA
compliance
monitoring
data
must
first
be
transformed
from
a
value
representing
atrazine
alone,
to
a
concentration
which
reflects
inclusion
of
degradates
of
concern
using
the
appropriate
seasonal
regression
equations
described
in
the
April
16,
2002
risk
assessment
document.

HED
believes
that
these
34
represent
CWS
with
high­
end
exposures,
but
not
all
of
them.
An
annual
average
concentration
value
for
atrazine
close
to
the
current
MCL
(
i.
e.,
the
2.6
ppb
total
chlorotriazine
trigger
value)
is
a
plausible
indicator
of
seasonal
exposures
of
concern.
In
this
way,
the
MCL
and
the
12.5
ppb
figure
may
work
together
constructively
to
identify
CWS
with
seasonal
exposures
of
potential
concern.

HED
examined
data
for
~
4000
CWS
using
surface
water
in
~
31
states
representing
99%
of
atrazine
use
in
the
US.
Although
there
are
~
10,000
CWS
using
surface
water
in
the
US,
not
all
of
them
collect
data
on
atrazine.
Under
the
SDWA,
CWS
may
apply
for
waivers
if
atrazine
is
not
used
in
the
area
and/
or
if
compliance
monitoring
for
3
consecutive
quarters
shows
no
detections
of
atrazine.
HED
has
assumed
that
these
other
CWS
have
received
data
waivers
under
the
SDWA.
Compliance
monitoring
for
the
SDWA
is
under
the
purview
of
EPA's
OW.
OPP
has
advised
OW
of
NRDC's
concern
and
must
defer
to
OW
on
the
issue
of
under
reporting
MCL
violations.

Toxicity
Issues
­
14
Comment
NRDC
believes
that
1.8
mg/
kg
bw
per
day
is
the
lowest
observable
adverse
effect
level
(
LOAEL)
rather
than
the
no
observable
adverse
effect
level
(
NOAEL)
for
suppression
of
the
LH
surge
in
the
6
month
LH
study
and
its
NOAEL
HED
Response
EPA's
position
is
that
1.8
mg/
kg
bw
per
day
is
a
NOAEL
in
the
6
month
LH
surge
study
by
Syngenta.
EPA
believes
it
is
justified
in
using
3.6
mg/
kg
bw
per
day
as
a
LOAEL
for
this
endpoint.
The
rationale
for
the
selection
of
3.6
mg/
kg
bw
per
day
as
a
LOAEL
and
1.8
mg/
kg
bw
per
day
as
a
NOAEL
for
suppression
of
the
LH
surge
is
based
on
a
weight
of
evidence
argument.
There
is
a
dose
response
trend
for
suppression
of
the
LH
surge.
While
the
3.6
mg/
kg
bw
per
day
dose
does
not
represent
a
statistically
significant
decrease
in
the
amount
of
LH,
the
dose
response
trend
is
supported
by
the
statistically
significant
difference
in
vaginal
cycling
at
3.6
mg/
kg
bw
per
day.
Vaginal
cycling
data
tends
to
be
less
variable
than
LH
data.
Thus,
EPA
acknowledges
that
selection
of
1.8
mg/
kg
bw
per
day
as
a
NOAEL
for
LH
suppression
is
conservative,
but
errs
on
the
side
of
health
protection.
Although
there
is
one
statistically
significant
response
for
suppression
of
the
LH
surge
in
the
1.8
mg/
kg
bw
per
day
dose
group
for
one
time
point,
this
is
not
sufficient
evidence
to
designate
1.8
mg/
kg
bw
per
day
as
a
LOAEL,
particularly
in
light
of
the
fact
there
were
no
statistically
significant
differences
found
for
vaginal
cycling
at
this
dose.

Cancer
Issues:

Comment
NRDC
believes
that
carcinogenicity
to
humans
must
be
reconsidered
and
"
new
data"
supporting
an
alternative
mode
of
action
and
"
new
data"
on
carcinogenicity
must
be
included
in
the
weight
of
evidence
determination.

HED
Response
It
is
to
be
noted
that
no
new
data
were
submitted
by
NRDC.
Additionally,
the
alternative
modes
of
action
discussed
by
NRDC
were
considered
and
discussed
previously,
both
by
the
Agency
and
by
the
FIFRA
Scientific
Advisory
Panel
[
SAP].

A)
mammary
tumors
­
estrogen
levels
Comment
NRDC
argues
that
the
failure
to
demonstrate
an
increase
in
serum
estradiol
levels
after
atrazine
exposure
refutes
the
hypothesis
that
a
hyper­
estrogenic
state
develops
in
SD
rats,
thereby
leading
to
mammary
tumors.
15
HED
Response
The
postulated
mode
of
action
is
that
atrazine
exacerbates
and
accelerates
reproductive
aging
in
the
SD
female
rat,
causing
an
earlier
onset
and
higher
incidence
of
mammary
gland
tumors.
The
key
events
in
this
process
include
suppressing
the
pituitary
LH
surge,
thereby
prolonging
estrous
and
attendant
peak
estrogen
levels
which
leads
to
mammary
gland
tumors.
This
postulated
mode
of
action
is
supported
by
the
LH
data
and
data
that
show
that
atrazine
treated
SD
rats
maintain
constant
estrous.
Thus,
it
is
not
hypothesized
that
there
is
an
increase
in
estrogen
levels
per
se
but
that
the
estrogen­
responsive
tissues
are
exposed
for
an
extended
period
of
time
to
estrogen
because
of
prolonged
estrous.
In
chronic
bioassays
on
natural
and
synthetic
estrogens,
it
has
been
established
that
prolong
stimulation
of
the
mammary
gland
with
estrogen
leads
to
development
of
adenocarcinomas.
NRDC
cites
3
studies
which
they
state
demonstrate
decreases
in
measured
estradiol
levels
following
atrazine
exposure
to
SD
female
rats.
However,
in
the
Eldridge
et
al.,
study
(
1993),
which
was
not
cited
by
NRDC,
estradiol
levels
were
elevated
at
3
months
in
the
atrazine­
treated
Sprague­
Dawley
female
rats
compared
to
the
control
rats
at
three
months.
Although
the
SAP
noted
that
there
is
a
lack
of
robust
data
on
hormones
in
the
atrazine
database,
the
SAP
stated
that
the
database
on
atrazine
strongly
supports
the
hypothesis
that
prolonged
exposure
to
estrogen
produced
by
the
ovary
is
requisite
for
development
of
the
mammary
tumors
observed.
16
B)
mammary
tumors
­
lengthening
of
estrous
Comment
NRDC
argues
that
EPA
fails
to
explain
the
discordant
finding
within
its
proposed
paradigm;
i.
e.,
Fischer
rat
shows
lengthening
of
estrus
but
no
mammary
tumors
[
Simic
(
1994)
­
J
Appl
Toxicol
14(
6):
401­
404].
Since
lengthening
of
estrus
is
part
of
the
mode
of
action,
this
finding
demonstrates,
according
to
NRDC,
that
the
hypothesized
MOA
is
not
the
only
[
or
even
the
most
important]
MOA.

HED
Response
In
the
paper
cited
by
NRDC,
the
prolonged
estrous
cycle
in
the
Fischer
344
rat
was
characterized
by
extended
diestrous,
in
contrast
to
prolonged
estrous
in
SD
rats.
In
another
paper
not
cited
by
NRDC
[
MRID
43598613],
the
effects
of
atrazine
exposure
[
100
and
300
mg/
kg/
day
for
2
weeks]
on
estrous
were
compared
in
SD
and
Fischer
344
rats.
The
SD
female
rats
exhibited
a
treatment­
related
lengthening
of
the
estrous
cycle
and
an
increased
number
of
days
characterized
by
cornified
epithelial
cells.
This
resulted
in
a
greater
percent
of
the
cycle
days
spent
in
estrous
and
reduction
in
the
percent
of
the
cycle
days
spent
in
diestrus.
Fischer
rats
also
exhibited
a
significant
trend
toward
cycle
lengthening,
but
this
was
due
to
reduction
in
the
percent
of
cycle
spent
in
estrus
and
a
concomitant
increase
in
diestrual
days.
According
to
the
authors,
these
findings
suggest
that
treatment
with
atrazine
at
the
dose
levels
used
may
result
in
prolonged
exposure
to
endogenous
estrogen
in
the
SD
but
not
the
Fischer
344
rat.

In
comparable
studies
in
the
Sprague­
Dawley
and
Fischer
344
rats,
atrazine
exposure
up
to
400
ppm
had
no
effect
on
the
percent
days
in
estrus
in
the
Fischer
rat
or
mammary
gland
tumor
incidence
[[
Thakur,
A.
K.
(
1991).
MRID
42146101]
whereas
the
SD
rats
[
Thakur,
A.
K.
(
1991),
MRID
42085001]
displayed
an
earlier
appearance
[
after
9
months
of
treatment]
of
altered
estrous
cycles
characterized
by
an
increase
in
the
percent
days
in
estrus.
Disrupted
estrus
cycles
in
SD
female
rats
precede
the
appearance
of
mammary
gland
tumors
in
both
control
and
treated
groups,
the
effect
of
atrazine
is
to
make
both
of
these
events
occur
earlier.
The
estrus
and
mammary
gland
tumor
results
reinforce
the
view
that
female
SD
rats
display
an
earlier
disruption
of
the
estrus
cycle
than
do
control
(
untreated)
animals
and
develop
mammary
gland
tumors
earlier.
Unlike
SD
rats,
control
Fischer­
344
female
rats
do
not
display
abnormal
estrous
cycles
until
late
in
life
and
do
not
develop
a
high
incidence
of
mammary
gland
tumors.
The
mode
of
action
for
SD
female
rats
is
further
confirmed
by
data
showing
that
Fischer
­
344
rats,
which
have
a
different
reproductive
senescence,
do
not
form
atrazine­
related
mammary
gland
tumors.

The
SAP
stated
that
tumorigenesis
in
female
F­
344
rats
may
have
been
obscured
by
the
decrease
17
in
body
weight
and
that
a
proper
statistical
test
should
be
employed.
EPA
performed
such
analyses
[
using
Gaylor
and
Kodell,
1999]
of
the
mammary
tumors
in
the
F­
344rats.
The
bodyweight
adjusted
analysis
of
the
data
indicates
that
there
is
no
statistically­
significant,
doseresponse
trend
in
tumor
incidence.

C)
mammary
tumors
­
male
mammary
tumors
in
F­
344
rats
Comment
NRDC
argues
that
although
the
mammary
tumors
observed
in
male
F344
rats
appeared
late
in
the
study
[
Pinter
(
1990)
­
Neoplasms
37:
533­
544],
they
add
to
the
weight­
of­
evidence.

HED
Response
As
discussed
previously
by
the
SAP,
a
proper
age­
adjusted
analysis
of
the
tumor
data
results
in
the
conclusion
that
the
tumors
appear
to
be
due
to
increased
survival
and
not
to
atrazine
exposure.

D)
mammary
tumors
­
ovarian
cycle
disruption
in
pigs
Comment
NRDC
believes
these
data
[
Gojermac
(
1996)
­
Toxicol
Lett
85(
1):
9­
15]
indicate
that
atrazine
disrupts
ovarian
cycling,
inhibits
estrus
at
low
doses,
and
causes
multiple
ovarian
cysts
in
the
pig,
and
these
data
should
not
be
ignored.

HED
Response
These
data
were
considered
previously.
It
was
determined
that
they
are
of
limited
value
with
respect
to
the
mode
of
action
assessment.
These
data
suggest
that
atrazine
may
affect
reproduction
in
pigs.
However,
there
are
several
aspects
of
the
study
that
hinder
interpretation
of
the
findings.
Although
the
authors
conclude
that
atrazine
prolonged
the
estrus
cycle,
this
endpoint
[
delayed
estrus]
was
not
adequately
examined.
There
is
no
information
regarding
the
frequency
of
the
checks
for
estrus
each
day
or
whether
the
checks
were
preformed
daily.
The
pigs
may
have
had
an
undetected
estrus
before
the
expected
estrus;
i.
e.,
short
cycles.
The
paper
states
that
the
duration
of
estrus
and
the
length
of
the
estrus
cycle
were
monitored
for
two
cycles
for
each
pig
prior
to
study
start,
but
no
data
were
provided.
It
is
not
apparent
whether
any
control
pigs
were
also
monitored
prior
to
the
start.
In
the
Methods
section
of
the
paper,
it
states
that
after
the
last
blood
sampling
[
day
24]
and
checking
the
next
expected
estrus,
the
animals
were
sacrificed
7
days
after
the
last
blood
sampling.
It
is
unclear
whether
the
pigs
were
monitored
for
the
next
expected
estrus
prior
to
day
24.
According
to
The
Merck
Veterinary
Manual,
the
18
estrous
cycle
is
18­
24
days
[
average
21]
in
sows
and
gilts.

No
hormone
data
were
provided
for
the
dosing
period
[
days
1­
19].
Blood
samples
[
for
hormone
assessment]
were
collected
three
times
in
6
hours
on
the
first
five
days
post
dose
[
estrus
cycle
days
20­
24].
It
is
noted
that
Figure
B
[
control]
of
the
paper
shows
estrus
day
22
to
be
estrus
day
0
also.
It
is
not
clear
whether
this
is
the
day
when
the
control
displayed
estrus
or
what
was
considered
to
be
the
next
expected
estrus.

The
estradiol
values
in
the
treated
pigs
did
not
fluctuate
much
over
the
5­
day
monitoring
period,
and
they
do
not
appear
to
be
elevated
compared
to
the
control
values.
The
progesterone
levels
were
low
[
atrazine
pigs]
in
the
first
sample,
which
might
be
expected
if
treatment
had
induced
early
luteolysis
or
the
pigs
were
experiencing
short
normal
cycles.
The
progesterone
levels
thereafter
increased
daily,
indicative
of
new
luteal
function,
not
persistence
of
corpora
lutea.
Although
the
profiles
of
these
hormones
appear
to
be
different
between
the
treated
and
control
pigs
[
Figures
A
and
B],
there
may
only
be
a
shift
in
time.
Also,
this
may
be
a
similar
situation
as
observed
in
the
Fischer
344
rat
[
prolonged
cycle
not
associated
with
increased
estrogen
exposure].
Interpretation
of
the
findings
in
the
pig
is
further
hindered
since
there
are
no
LH
data
to
determine
whether
the
pigs
failed
to
have
an
ovulatory
surge
of
LH.

Other
limitations
with
this
study
include
the
small
sample
size
[
4
animals]
and
the
lack
of
doseresponse
data
[
only
one
dose
evaluated].

E)
mammary
tumors
­
non­
estrogenic
mechanism/
increased
susceptibility/
tumor
promotion
Comment
NRDC
believes
there
is
new
evidence
[
references
Fenton,
2002]
that
demands
a
complete
reevaluation
of
cancer
risk.
The
Fenton
study
found
that
Long­
Evans
[
LE]
rats
prenatallyexposed
to
atrazine
and
subsequently
challenged
[
PND
45]
with
known
mammary
carcinogen
[
DMBA]
were
more
likely
to
develop
mammary
gland
tumors/
more
tumors/
larger
tumors
than
LE
rats
exposed
to
atrazine
or
DMBA
alone.
The
paper
also
reported
that
atrazine
exposure
alters
pubertal
mammary
gland
development
via
a
non­
estrogenic
mechanism,
thereby
supporting
a
mechanism
by
which
pubertal
alterations
may
predispose
individuals
to
tumor
development.

HED
Response
It
should
be
noted
that
the
Fenton
et
al.,
data
are
preliminary
and
have
not
been
fully
peer
reviewed.
The
preliminary
work
reported
in
an
abstract
by
Fenton
and
Davis
(
2002),
an
investigator
in
NHEERL's
Reproductive
Toxicology
Division,
suggests
that
gestational
exposure
to
atrazine
may
affect
the
developing
mammary
gland.
This
preliminary
work
indicates
that
19
atrazine
causes
a
developmental
delay
in
mammary
gland
maturation,
which
lengthens
the
window
of
susceptibility
to
the
carcinogen
DMBA.
In
another
abstract,
Greiner,
Youngblood,
and
Fenton
(
2002)
suggest
that
atrazine
decreases
puberty­
induced
mammary
gland
development
by
altering
normal
pituitary
functions.
The
Fenton
et
al.,
data
do
not
provide
evidence
of
a
direct
cancer
mode
of
action
that
may
be
operative
in
humans
given
these
studies
involve
co­
treatment
with
a
well
known
mutagenic
carcinogen.
This
work
is,
however,
consistent
with
the
other
reported
findings
from
Dr.
Ralph
Cooper's
laboratory
(
e.
g.,
Laws
et
al.,
2001,
Stoker
et
al.,
2001)
that
atrazine
affects/
causes
developmental
effects
or
delays
(
e.
g.,
delayed
puberty)
by
altering
hypothalamic­
pituitary
function.
EPA
agrees
that
atrazine's
ability
to
affect
pituitary
function
and
result
in
developmental
effects
should
be
assumed
to
be
relevant
to
humans.
The
NOAELs
and
safety
factors
used
in
the
atrazine
assessment
addresses
this
preliminary
study.
20
F)
Wilms
tumor
­
data
on
tadpoles
Comment
Reference
[
Tavera
Mendoza
Abstract
presented
at
SETAC
22nd
Annual
Meeting,
11/
13/
01]
is
made
to
a
recent
study
that
found
that
tadpoles
exposed
to
atrazine
during
gonadal
differentiation
developed
renal
embryonic
adenosarcoma
[
Wilms'
tumors].
It
is
stated
that
disruption
of
the
WT­
1
gene
can
occur
in
both
the
frog
and
human,
and
that
this
alteration
has
been
linked
to
Wilm's
tumor
in
both
species
[
referencing
the
above].
NRDC
believes
that
this
report
merits
careful
consideration.

Additionally,
NRDC
associates
studies
reporting
association
of
pesticide
exposure
of
the
parents
[
Sharpe,
et
al.,
Epidemiology
study
in
Brazil]
and
an
increase
in
this
tumor
in
children.
NRDC
wants
this
tumor
finding
as
part
of
the
weight
of
evidence
in
the
cancer
assessment.

HED
Response
The
potential
of
atrazine
to
alter
the
WT­
1
gene
is
not
based
on
data
and
is
speculation
at
this
time.
There
are
similarities
and
differences
in
development
and
regulation
by
hormones
among
vertebrates,
and
the
effects
of
atrazine
on
amphibians
and
how
they
may
relate
to
humans
is
under
review.
EPA
is
planning
to
convene
an
independent
scientific
peer
review
[
the
FIFRA
Science
Advisory
Panel
(
SAP)]
of
information
related
to
potential
effects
of
atrazine
on
amphibians
sometime
in
mid­
2003.

With
respect
to
the
other
cited
studies,
the
associations
described
in
humans
[
Sharpe,
et
al.]
were
with
pesticides
in
general
(
insecticides
and
herbicides]
used
in
farm
work.
Information
on
specific
pesticides
used
[
atrazine]
was
not
obtained.
Although
the
results
reported
in
some
studies
suggest
parental
exposure
to
pesticides
may
be
related
to
the
subsequent
development
of
cancer
in
the
offspring,
other
explanations
cannot
be
excluded.
Additionally,
there
are
numerous
other
studies
not
cited
by
NRDC
that
indicate
it
unlikely
that
environmental
exposures
play
a
major
role
in
the
etiology
of
Wilms
tumor.

In
a
case­
control
study
conducted
with
histologically
confirmed
neuroblastoma
cases
among
New
York
State
residents
[
Kerr,
M
.
A.,
et
al.
Cancer
Causes
Control
(
2000),
Aug.
11
(
7):
635­
643],
the
odds
ratios
were
significantly
elevated
for
maternal
and
paternal
occupational
exposure
to
various
substances,
including
insecticides;
herbicides
[
atrazine]
were
not
mentioned.
However,
the
authors
concluded
that
due
to
the
uncertainty
of
the
biologic
plausibility
of
these
associations
and
the
possibility
of
alternative
explanations,
the
results
should
be
interpreted
cautiously.

In
a
related
issue,
but
one
not
involving
cancer
per
se,
there
is
a
growing
concern
that
exposures
21
to
a
wide­
range
of
endocrine
disrupting
chemicals
(
EDCs)
are
associated
with
feminization
of
birds,
fish,
alligators,
and
other
animals
in
the
environment.
The
concern
has
been
raised
that
EDC
related
feminization
of
males
observed
in
the
ecosystem
is
also
occurring
in
humans.
This
is
an
emerging
area
of
concern,
and
the
scientific
community
and
other
interested
parties
are
engaging
in
discussions.
As
mentioned
above,
EPA
is
planning
to
convene
an
independent
scientific
peer
review
[
the
FIFRA
Science
Advisory
Panel
(
SAP)]
of
information
related
to
potential
effects
of
atrazine
on
amphibians
sometime
in
mid­
2003.

G)
lymphoma
­
several
studies
Comment
NRDC
states
that
Non­
Hodgkin's
lymphoma
has
been
on
the
rise
in
recent
decades,
and
several
studies
are
cited
and
discussed.

HED
Response
As
stated
by
the
SAP
previously,
"
To
summarize,
there
are
a
few
epidemiologic
studies
that
suggest
a
possible
association
between
atrazine
(
or
triazine)
exposure
and
NHL
and
ovarian
cancer.
However,
lack
of
multiple
studies
showing
an
association
and
internal
inconsistencies
in
the
studies
available
indicates
that
the
human
studies
by
themselves
do
not
make
a
strong
case
for
an
association."
Please
refer
to
the
Interim
Reregistration
Eligibility
Decision
(
IRED)
for
further
discussion.

H)
human
cancer
­
prostate
cancer,
ovarian
cancer,
testicular
cancer,
breast
cancer,
leukemias/
lymphomas
Comment
NRDC
discusses
Syngenta's
St.
Gabriel
facility
data
and
other
epidemiology
data
and
states
that
these
data
should
not
be
ignored.
NRDC
believes
the
epidemiology
results
are
"
not
likely
to
be
due
to
chance",
and
are
"
almost
certainly
related
to
herbicide
exposure".
Please
refer
to
the
memoradum
entitled,
"
Review
of
Additional
Data
on
Potential
Atrazine
Exposure
and
Review
Comments
Submitted
by
Syngenta
and
NRDC
on
Atrazine
Cancer
Epidemiology
Study:
"
Follow­
up
Study
of
Cancer
Incidence
Among
Workers
in
Triazine­
related
Operations
at
the
Vnovartis
St.
Gabriel
Plant"
by
E.
Delzell
et
al.
D287278,
J.
Blondell,
January
15,
2003
and
the
Interim
Reregistration
Eligibility
Decision
(
IRED)
for
further
discussion.

HED
Response
As
stated
above,
the
SAP
considered
the
available
epidemiology
data
and
concluded
that
there
are
22
a
few
epidemiologic
studies
that
suggest
a
possible
association
between
atrazine
(
or
triazine)
exposure
and
NHL
and
ovarian
cancer.
However,
lack
of
multiple
studies
showing
an
association
and
internal
inconsistencies
in
the
studies
available
indicates
that
the
human
studies
by
themselves
do
not
make
a
strong
case
for
an
association.

HED's
review
of
the
data
on
increased
incidences
of
prostate
cancer
at
the
St.
Gabriel
plant
in
Louisiana
is
as
follows
(
see
memorandum,
J.
Blondell,
1/
15/
03,
Review
of
Additional
on
Potential
Atrazine
Exposure
and
Review
Comments
Submitted
by
Syngenta
and
NRDC
on
Atrazine
Cancer
Epidemiology
Study:
"
Follow­
up
Study
of
Cancer
Incidence
Among
Workers
in
Triazinerelated
Operations
at
the
Novartis
St.
Gabriel
Plant
by
E.
Delzell
et
al."
DP
287278):

"
It
appears
that
most
of
the
increase
in
prostate
cancer
incidence
at
the
St.
Gabriel
plant
in
Louisiana
is
likely
due
to
intensive
PSA
screening.
The
study
was
insufficiently
large
and
suffered
from
other
limitations
which
prevent
ruling
out
atrazine
as
a
potential
contributor
to
the
increase
observed.
On
balance,
however,
a
role
for
atrazine
seems
unlikely
because
prostate
cancer
was
found
primarily
in
active
employees
who
received
intensive
PSA
screening,
there
was
no
increase
in
advanced
tumors
or
mortality,
and
proximity
to
atrazine
manufacturing
did
not
appear
to
be
correlated
with
risk.
Atrazine
has
been
tied
to
inflammation
of
the
prostate
in
laboratory
animals
and
changes
in
testosterone
levels
at
high
doses.
However,
neither
condition
has
been
tied
to
the
increased
risk
of
prostate
cancer
and
HED
concludes
the
animal
data
do
not
provide
biologically
plausible
evidence
to
support
atrazine
as
a
cause
of
prostate
cancer.

Other
cancers
besides
prostate
were
found
to
have
an
elevated,
though
not
statistically
significant,
increase
in
risk
at
the
St.
Gabriel
plant.
Other
studies
have
suggested
an
increased
risk
for
ovarian,
breast,
and
other
cancers,
including
non­
Hodgkin's
lymphoma.
However,
these
studies
are
at
best
preliminary
and
should
not
serve
as
a
basis
for
implicating
atrazine
as
a
human
carcinogen
due
to
their
methodological
limitations."

I)
other
modes
of
action
[
page
24]

Comment
NRDC
wants
EPA
to
fully
explore
other
modes
of
action
and
relevance
to
humans.
They
believe
that
EPA
has
failed
to
adequately
consider
other
modes
of
action.
Although
NRDC
states
that
it
is
clear
that
atrazine
acts
as
an
endocrine
disruptor
and
that
one
of
the
modes
of
action
involves
the
hypothalamic­
pituitary­
gonadal
axis,
they
are
not
convinced
that
this
is
the
only
mode
of
23
action.
NRDC
believes
there
is
evidence
of
at
least
three
other
modes
of
action.

(
1)
aromatase
activity
­
Aromatase
is
a
cytochrome
p450
enzyme
that
converts
steroids
or
androgens
to
estrogens,
thus
increasing
estrogen
levels
in
the
body.
It
is
found
in
different
species
(
both
mammalian
and
nonmammalian)
and
in
various
tissues
(
mammary
gland,
ovary,
bone,
brain,
etc).
Data
available
are
primarily
from
studies
in
frogs,
fish
and
alligators,
in
addition
to
data
on
human
adrenocortical
cells
[
in
vitro].
NRDC
says
EPA
has
not
explained
why
it
is
ignoring
this
critical
information
on
an
alternative
mode
of
action.

HED
Response
No
new
data
are
provided
by
NRDC
on
any
of
the
other
modes
of
action.
The
SAP
was
asked
to
comment
on
whether
alternative
modes
of
action
(
re:
mammary
tumors)
have
been
sufficiently
discussed
and
ruled
out
by
the
Agency.
The
SAP
stated
"
There
are
no
data
that
would
suggest
other
plausible
modes
of
action.
The
increased
level
of
hormones
and
the
increased
level
of
hormones
alone,
can
account
for
the
increased
incidence
of
mammary
tumors
in
Sprague
Dawley
female
rats.
The
proposed
mode
of
action
is
plausible
and
each
step
in
the
pathway
has
been
shown
to
be
affected
in
atrazine
treated
rats.

Previously,
OPP
concluded
that
it
is
plausible
that
enhanced
aromatase
activity
may
have
some
influence
on
the
development
of
mammary
tumors
in
SD
female
rats.
However,
whether
or
not
enhanced
aromatase
activity
is
a
significant
contribution
to
the
carcinogenicity,
or
other
effects,
of
atrazine
remains
to
be
determined.
EPA
acknowledged
the
fact
that
an
increase
in
aromatase
activity
would
be
consistent
with
dose­
response
increases
in
estradiol
and
estrone
and
decreases
in
testicular
testosterone
noted
in
a
study
that
examined
the
effects
of
atrazine
on
pubertal
development.
The
doses
that
resulted
in
effects
on
these
hormones
were
well
above
doses
that
led
to
reproductive/
developmental
effects.
Additionally,
it
was
acknowledged
that
it
is
plausible
that
enhanced
aromatase
activity
may
have
some
influence
on
the
development
of
mammary
tumors
in
SD
female
rats;
however,
there
are
no
data
to
date
on
whether
enhanced
aromatase
activity
significantly
contributes
to
the
carcinogenicity
observed.
The
effect
of
the
chlorotriazines
on
aromatase
remains
an
active
research
issue,
in
general.

The
EPA's
National
Health
and
Environmental
Research
Laboratory
(
Dr.
Ralph
Cooper's
laboratory)
have
recently
evaluated
the
effects
of
atrazine
and
DACT
on
aromatase
activity
in
the
rat.
Preliminary
results
show
that
DACT
does
not
effect
aromatase
activity
and
atrazine
actually
causes
a
decrease
in
aromatase,
but
only
at
high
doses.
Based
on
the
weight
of
evidence,
enhancing
aromatase
activity
does
not
appear
to
be
a
mode
of
carcinogenic
action,
particularly
given
the
recent
findings
of
Ralph
Cooper.
Further,
if
this
were
a
primary
mode
of
24
action,
a
more
consistent
finding
of
tumors
at
estrogen
sensitive
sites
would
be
anticipated
in
the
rodent
carcinogenicity
studies.
Lastly,
the
June
2000
FIFRA
Scientific
Advisory
Panel
was
specifically
asked
about
OPP's
assessment
of
other
possible
other
modes
of
carcinogenic
action,
and
the
SAP
agreed
that
there
is
an
insufficient
basis
to
link
effects
on
aromatase
to
the
mammary
gland
tumor
response
in
female
Sprague
Dawley
rats.

With
regard
to
research
data
relating
to
the
effects
of
atrazine
on
amphibians,
EPA
has
not
yet
reached
conclusions
on
these
data,
and
therefore
does
not
have
any
specific
comment
on
these
research
efforts.
EPA
is
planning
to
convene
an
independent
scientific
peer
review
[
the
FIFRA
Science
Advisory
Panel
(
SAP)]
of
information
related
to
potential
effects
of
atrazine
on
amphibians
sometime
in
mid­
2003.

2)
16­
alpha­
hydroxyestrone
­
NRDC
states
that
there
is
some
evidence
that
atrazine
may
affect
estrogen
metabolism,
resulting
in
a
greater
production
of
a
mutagenic
metabolite.

HED
Response
In
1993,
it
was
postulated
by
Davis
et
al.
that
the
16"­
hydroxyestrone
is
a
type
of
estrogen
which
results
in
the
formation
of
breast
cancer
in
women.
But,
this
hypothesis
is
in
contrast
to
the
work
of
Aldercreutz
et
al.,
1994
which
showed
through
epidemiologic
studies
that
involvement
of
estrogen
metabolites
as
a
risk
factor
for
breast
cancer,
is
at
best
circumstantial.
Furthermore,
more
recent
work
by
Ursin
et
al.,
1999
indicates
that
16"­/
2­
hydroxyestrone
ratios
are
not
predictive
of
breast
cancer
risk
in
patients.
In
1994,
Bradlow
et
al.,
reported
using
MCF­
7
cells
that
atrazine
might
increase
the
production
of
16"­
hydroxyestrone
by
altering
the
intracellular
metabolism
of
estrogens.
However,
more
recent
studies
by
Safe
and
coworkers
indicate
that
decreases
or
increases
in
16"­/
2­
hydroxyestrone
ratios
do
not
predict
mammary
gland
cancer
potential.
McDougal
et
al.,
1997
evaluated
the
effects
of
atrazine
and
the
effects
of
a
variety
of
chemicals
known
to
inhibit
or
induce
mammary
gland
tumors
in
rats
on
the
estradiol­
2­
hydroxylase
activity
in
the
MCF­
7
model
(
McDougal
et
al,
1997).
Atrazine
reduced
estradiol­
2­
hydroxylase
activity,
and
no
correlation
between
cancer
(
or
anticancer)
potential
and
estradiol­
2­
hydroxylase
activity
could
be
demonstrated.
McDougal
and
Safe,
1998
studied
the
effects
of
several
pesticides,
mammary
gland
carcinogens
and
anti­
estrogens
on
estradiol,
16"­
and
2­
hydroxylase
activities
and
16"­/
2­
hydroxylase
ratios
in
MCF­
7
cells.
These
results
also
indicated
that
in
MCF­
7
cells
treated
with
different
chemicals
both
increases
and
decreases
in
16"­/
2­
metabolite
ratios
were
found
and
thus
16"­/
2­
metabolite
ratios
were
not
predictive
mammary
gland
carcinogens.

This
issue
was
addressed
previously
[
in
Part
B
of
the
May
2000
EPA
atrazine
document],
and
NRDC
has
not
provided
any
new
data.
25
3)
metabolite
N­
nitrosoatrazine
­
NRDC
points
out
that
this
metabolite
is
mutagenic,
and
a
mutagenic
MOA
on
the
part
of
a
metabolite
would
imply
a
cancer
risk
in
humans
without
a
threshold.
NRDC
states
that
the
overall
scientific
evidence
indicates
that
atrazine
may
be
acting
both
as
an
initiator
and
as
a
promoter
of
cancers
in
hormonallysensitive
organs.

HED
Response
Again,
it
is
pointed
out
that
the
SAP
addressed
this
issue
in
2000.
The
role
nitrosoatrazine
may
play
in
cancer
development
in
humans,
is
questionable.
Although
the
mutagenic
compound
NNitrosoatrazine
(
NNAT)
can
be
formed
in
vitro
when
atrazine
and
nitrite
are
mixed
at
an
acid
pH,
and
because
nitrites
and
atrazine
can
be
found
together
in
drinking
water,
concern
has
been
raised
about
this
mutagenic
chemical.
Although
the
hypothesis
has
been
advanced
that
NNAT
can
be
formed
in
the
acid
pH
found
in
the
stomach,
the
formation
of
NNAT
in
the
stomach
in
vivo
has
yet
to
be
demonstrated.
If
indeed
the
mutagenic
compound
NNAT
could
act
as
an
initiator
of
the
cancer
process,
one
would
expect
NNAT
to
be
carcinogenic.
However,
the
cancer
bioassays
in
female
Swiss
mice
and
female
Wistar
rats
failed
to
show
a
carcinogenic
response
following
NNAT
exposure.
Since
the
June
2000
SAP,
there
have
been
no
new
data
on
NNAT
and
NRDC
has
not
provided
any
new
data
to
the
Agency.

FQPA
Safety
Factor
Issues
A.
2­
hydroxyatrazine
­
NRDC
considers
the
lack
of
a
FQPA
safety
factor
for
2­
hydroxyatrazine
to
be
a
mistake
since
it
shows
similar
toxicity
[
adverse
reproductive
endpoints]
as
atrazine
and
DACT.
NRDC
wants
a
10X
FQPA
safety
factor
on
this
metabolite
also.

HED
Response
Unlike
Atrazine,
2­
hydroxyatrazine,
did
not
cause
a
delay
in
vaginal
opening
but
did
cause
a
minimal
delay
in
preputial
separation
(
Laws
et
al.,
2002).
Furthermore,
there
was
no
increase
above
control
levels
in
the
incidence
of
mammary
gland
tumors
or
tumors
of
any
type
in
a
twoyear
chronic/
carcinogenicity
study
on
2­
hydroxyatrazine
(
Chow
and
Hart,
1995).
In
a
recent
registrant
sponsored
study
[
Eldridge,
J.
C.,
M
innema,
D.,
Breckenridge,
C.
B.
,
et
al.;
SOT,
March
2001],
2­
hydoxyatrazine
did
not
suppress
the
LH
surge.
However,
Dr.
Ralph
Cooper
at
the
EPA's
NHEERL
is
currently
evaluating
whether
this
metabolite
alters
the
LH
surge.
However,
based
on
available
data,
it
can
not
be
concluded
that
2­
hydroxyatrazine
shares
the
same
neuroendocrine
mode
of
action
with
atrazine.
Thus,
the
data
do
not
raise
the
same
issues
regarding
the
potential
susceptibility
of
the
young
due
to
its
neuroendocrine
mode
of
action.
Furthermore,
no
increase
in
sensitivity
was
observed
following
exposure
of
rats
during
gestation
26
days
6­
15.
Data
available
on
2­
OH
atrazine
include
a
subchronic
oral
toxicity
study
and
a
chronic
oral
toxicity
study
in
rats,
a
rat
developmental
toxicity
study,
and
mutagenicity
studies.
Reproductive
organ
toxicity
was
not
observed
in
any
of
these
studies.
In
a
recent
study
[
NHEERL],
pregnancy
loss
was
observed
at
300
and
500
mg/
kg/
day,
but
not
at
100
mg/
kg/
day,
following
2­
OH
atrazine
exposure
of
LE
dams
on
gestation
days
6­
10.

In
addition,
although
hydroxyatrazine
is
a
metabolite
of
atrazine,
it
is
structurally
dissimilar
to
atrazine
in
that
it
lacks
chlorine.
Plants
are
capable
of
metabolizing
atrazine
to
hydroxyatrazine.
In
plants
it
is
the
major
metabolite.
Bacteria
are
also
able
to
metabolize
atrazine
to
hydroxyatrazine.
However,
animals
do
not
metabolize
atrazine
to
hydroxyatrazine.
Ruminants
may
receive
hydroxyatrazine
in
their
diets
through
forages
and
fodders,
but
these
residues
are
not
anticipated
in
the
meat
and
milk
that
humans
eat.
Dietary
exposure
to
hydroxyatrazine
is
expected
to
be
minimal
(<
1%
of
the
cPAD).
Exposure
to
hydroxyatrazine
in
drinking
water
is
also
expected
to
be
insignificant.
The
EFED
has
determined
that
although
occasional
contamination
of
surface
waters
by
hydroxyatrazine
cannot
be
ruled
out,
in
general,
hydroxyatrazine
is
unlikely
to
contaminate
surface
water
to
the
same
degree
as
atrazine
and
some
of
the
chlorinated
metabolites.
This
qualitative
assessment
is
based
on
monitoring
data,
albeit
limited,
and
plant
metabolism
as
the
main
pathway
of
hydroxyatrazine
formation.

As
stated
in
the
April
16,
2002
risk
assessment,
..."
The
available
toxicity
database
for
hydroxy
atrazine
was
examined.
Toxicity
studies
submitted
under
Subdivision
F
Guideline
requirements
(
i.
e.,
subchronic,
chronic/
carcinogenicity,
and
developmental)
indicate
that
the
kidney
is
the
primary
target
organ
for
hydroxyatrazine
associated
toxicity.
Hydroxyatrazine
appears
to
crystallize
in
the
serum
leading
to
the
formation
in
the
blood
stream
of
hydroxyatrazine
crystals.
These
crystals
cause
direct
physical
damage
to
the
kidney.
This
crystallization
phenomenon
has
not
been
observed
with
atrazine
or
any
of
the
chlorinated
metabolites
of
atrazine.
Hydroxyatrazine
is
not
a
chlorinated
metabolite
of
atrazine,
and
is
not
considered
to
share
a
common
mechanism
of
toxicity
with
atrazine.

There
is
no
evidence
for
increased
susceptibility
of
rat
fetuses
following
in
utero
exposure
to
exposure
to
hydroxyatrazine
in
the
prenatal
developmental
toxicity
study
in
rats.
However,
neither
a
prenatal
developmental
study
in
the
rabbits
nor
a
two­
generation
reproductions
study
conducted
with
hydroxyatrazine
in
rats
is
available.
In
the
prenatal
developmental
toxicity
study
in
rats
there
was
a
statistically
significant
decrease
in
fetal
weights
and
an
increase
in
incompletely
ossified
interparietals
and
hyoid
bones
was
seen
in
the
presence
of
maternal
toxicity.
The
HIARC
determined
that
these
findings
lacked
toxicologic
significance.
While
special
studies
and
an
open
literature
study
indicate
a
neuroendocrine
toxicity
in
the
CNS
of
rats
following
atrazine
exposure,
overt
signs
of
27
neurotoxicity
were
not
seen
in
the
toxicology
studies
for
hydroxyatrazine.
The
neuroendocrine
alterations
mentioned
above
would
not
be
expected
to
be
seen
following
hydroxyatrazine
exposure.
Based
on
the
above
findings,
the
FQPA
Committee
made
the
following
determination:

The
FQPA
Safety
Factor
Committee
(
SFC)
following
review
of
the
hazard
and
exposure
(
food,
water
and
residential)
data
recommended
that
the
FQPA
safety
factor
be
removed
(
1x)
when
assessing
the
hydroxy­
metabolites
since:

1.
There
was
no
evidence
of
increased
susceptibility
in
the
prenatal
developmental
toxicity
study
in
rats
with
hydroxyatrazine;

2.
There
is
no
evidence
of
neurotoxicity
from
the
submitted
toxicity
studies;

3.
The
neuroendocrine
effects
described
for
atrazine
are
postulated
to
be
part
of
a
cancer
mode
of
action
for
atrazine.
Because
hydroxyatrazine
is
non­
carcinogenic,
the
current
belief
is
that
the
neuroendocrine
effects
described
for
atrazine
are
not
occurring
following
hydroxyatrazine
exposure;

4.
The
dietary
and
non­
dietary
exposure
assessments
do
not
underestimate
the
potential
exposures
for
infants
and
children;
and
5.
The
drinking
water
exposure
concerns
expressed
for
atrazine
and
the
chlorinated
metabolites
do
not
apply
to
hydroxyatrazine,
given
its
dissimilar
toxicological
profile
and
environmental
fate
properties
that
indicate
that
hydroxyatrazine
is
less
mobile
in
soil/
water
systems."

The
FQPA
decision
was
not
based
solely
on
toxicity,
but
also
on
exposure
concerns.
In
the
case
of
hydroxyatrazine,
exposure
concerns
are
minimal.
Although
hydroxyatrazine
has
shown
altered
pregnancy
maintenance
(
a
LOAEL
of
50
mg/
kg/
day
for
atrazine
and
91
mg/
kg/
day
for
hydroxyatrazine)
and
delayed
parturition
(
a
LOAEL
of
50
mg/
kg/
day
for
atrazine
and
91
mg/
kg/
day
for
hydroxyatrazine)
like
atrazine,
these
effects
occurred
at
higher
doses
than
for
atrazine.
28
B.
magnitude
of
safety
factor
­
NRDC
wants
a
larger
safety
factor
applied,
since
they
consider
the
FQPA
safety
factor
of
10X,
which
accounts
for
both
exposure
and
risk
uncertainty,
as
unlikely
to
sufficiently
capture
the
magnitude
of
uncertainty
within
this
assessment.

HED
Response
Retention
of
the
FQPA
safety
factor
of
10X
was
based
on
residual
concerns
for
both
developmental
effects
and
exposure.
For
all
the
reasons
listed
in
NRDC's
comment,
i.
e.,
lack
of
monitoring
data
on
degradates,
concern
over
peak
exposures
not
captured,
and
extent
of
exposure
not
captured
in
the
available
databases,
and
residual
concerns
regarding
toxicity,
the
FQPA
Committee
decided
to
retain
the
full
10X
FQPA
safety
factor.
The
Committee
met
twice
to
consider
the
FQPA
safety
factor
and
both
times
returned
a
decision
to
retain
the
10
X
for
dietary
assessments
because
of
these
residual
toxicity
and
exposure
concerns.
This
decision
was
made
in
light
of
the
fact
that
atrazine
has
the
most
extensive
drinking
water/
raw
water
monitoring
database
of
any
pesticide,
and
one
of
the
most
if
not
the
most
extensive
toxicity
database
for
a
pesticide.

The
HIARC
concluded
that
due
to
residual
concerns
[
concern
of
the
potential
neuroendocrine
effects
of
atrazine
exposure
throughout
all
critical
developmental
periods,
which
have
not
been
adequately
characterized],
the
hazard­
based
special
FQPA
safety
factor
was
required.
However,
the
HIARC
concluded
that
it
could
be
reduced
to
3X.
This
was
based
on
a
comparison
of
the
lowest
NOAEL
available
in
the
young
animal
[
6.25
mg/
kg/
day;
31­
day
pubertal
development
study]
with
the
lowest
NOAEL
in
the
adult
animal
[
1.8
mg/
kg/
day
;
6­
month
LH
surge
study].
This
comparison
suggests
that
the
young
would
not
be
expected
to
be
an
order
of
magnitude
more
sensitive
than
adults.
A
similar
comparison
using
studies
of
comparable
duration
also
indicates
that
the
young
would
not
be
expected
to
be
an
order
of
magnitude
more
sensitive
than
the
adult
animal.
For
example,
the
NOAEL
determined
for
delayed
sexual
maturation
[
20
days
exposure]
in
the
female
rat
is
25
mg/
kg/
day
compared
to
the
NOAEL
of
5
mg/
kg/
day
in
the
28­
day
exposure
study
in
adult
females
[
LH
surge
attenuation
and
estrous
cycle
alterations].
In
addition,
the
NOAELs
determined
for
delays
in
preputial
separation
and
delayed
sexual
maturation
are
6.25
mg/
kg/
day
[
males]/
25
mg/
kg/
day
[
females],
respectively.
These
endpoints,
which
are
indicators
of
pubertal
hypothalamic­
pituitary­
gonadal
related
effects,
show
NOAELs
that
are
3.5X
and
14X,
respectively,
greater
than
the
adult
NOAEL
for
LH
effects
[
1.8
mg/
kg/
day].

Regarding
exposure
based
uncertainty,
the
exposure
assessments
do
not
underestimate
exposure.
Data
collected
from
a
targeted
set
of
CWS
with
contamination
histories
or
MCL
violations
were
29
monitored
frequently
to
determine
maximum
exposures
in
these
most
highly
exposed
CWS.
CWS
with
compliance
monitoring
data
also
represent
a
targeted
data
set
because
these
CWS
are
the
ones
in
known
atrazine
use
areas.
Altogether,
as
explained
in
the
risk
assessment
documents,
the
data
set
used
was
biased
to
reflect
the
high­
end
exposures
occurring
in
the
US.
In
addition,
the
exposure
assessments
utilized
maximum
concentrations
for
one­
day,
90­
day,
and
annual
average
exposures
to
estimate
exposure
and
compared
these
exposures
to
the
most
sensitive
endpoint
(
lowest)
in
the
toxicity
database
to
which
a
1000­
fold
uncertainty
factor
has
been
applied.

Having
said
that,
it
is
likely
that
the
data
sets
used
may
not
have
identified
all
CWS
with
exposures
of
concern,
because
of
the
limitations
on
the
monitoring
data
previously
discussed
in
the
risk
assessment
and
at
the
technical
briefing.
However,
it
is
different
to
say
that
the
extent
of
exposure,
i.
e.,
the
exact
number
of
individuals
exposed
at
levels
of
concern,
is
not
known
versus
saying
the
high­
end
exposure
as
a
dose
(
in
mg/
kg/
day)
has
been
underestimated.
It
is
fair
to
say
that
the
CWS
identified
as
of
concern
represent
the
high­
end
exposures
(
doses
in
mg/
kg/
day)
for
the
US
population,
but
also
possible
that
not
all
CWS
with
high­
end
exposures
have
been
identified.

C.
underestimate
of
risk
­
NRDC
considers
the
lowest
dose
tested
in
the
6­
month
LH
surge
study
to
be
an
effect
dose
[
see
discussion
of
this
aspect
elsewhere].
Although
NRDC
supports
the
EPA
conclusions
that
the
neuroendocrine
effects
associated
with
atrazine
exposure
are
of
extreme
concern,
are
relevant
to
all
populations,
and
are
of
greatest
concern
to
fetuses,
infants,
and
children,
NRDC
states
that
the
demonstrated
ability
of
atrazine
and
its
metabolites
to
disrupt
normal
neuroendocrine
function
will
impact
growth,
development,
reproduction,
immune,
and
metabolic
functions.
NRDC
continues
by
pointing
out
that
"
human
exposures
to
abnormal
levels
of
LH
during
early
life
may
permanently
imprint
on
the
hypothalamic­
pituitary­
gonadal
pathway,
thereby
determining
the
ability
to
respond
normally
to
testosterone
and
other
gonadal
hormones
later
in
life.
The
response
of
the
central
nervous
system
to
the
gonadal
hormones
during
childhood
and
puberty
is
tightly
regulated
by
neurotransmitters
in
the
brain,
mainly
glutamate
and
GABA
(
gamma­
aminobutyric
acid).
Without
the
normal
hormonal
levels
during
development
of
the
fetal
and
infant
nervous
system,
the
ability
to
elicit
normal
responses
to
gonadal
hormones
later
in
life
may
be
compromised.
It
is
likely
that
exposure
of
the
infant
and
toddler
to
levels
of
atrazine
during
early
life,
at
levels
which
interfere
with
LH
activity,
may
have
adverse
effects
on
pubertal
development,
and
on
later
reproductive
function,
negatively
impacting
on
the
life­
long
health
of
an
exposed
person."
30
HED
Response
NRDC's
comments
are
essentially
what
was
stated
in
the
risk
assessment.
Atrazine
is
one
of
the
best
studied
pesticides,
and
there
is
an
extensive
toxicology
database
on
its
mechanism
of
toxicity.
The
perturbation
of
the
hypothalamic­
pituitary­
gonadal
axis
is
the
primary
and
only
established
mode
of
action
of
atrazine.
Based
on
the
nature
of
the
effect
of
concern
[
neuroendocrine
disruption]
and
uncertainties
with
respect
to
possible
effects
from
exposure
throughout
development,
which
have
not
been
thoroughly
examined,
a
potential
for
noncancer
effects
due
to
atrazine's
ability
to
disrupt
hypothalamic­
pituitary
function
could
not
be
discounted.
The
endpoint
selected
for
the
risk
assessments
[
LH
surge
attenuation
and
estrous
cycle
alterations]
serves
as
a
surrogate
for
the
effect
of
atrazine
on
the
hypothalamic­
pituitary
axis/
function,
and
the
NOAEL
selected
is
the
lowest
NOAEL
in
the
database
for
the
endpoint
of
concern
and
is
considered
protective
for
all
population
subgroups.

However,
as
previously
stated,
EPA's
position
is
that
1.8
mg/
kg/
d
is
a
NOAEL
in
the
6
month
LH
surge
study
by
Syngenta.
EPA
believes
it
is
justified
in
using
3.6
mg/
kg/
d
as
a
LOAEL
for
this
endpoint.
The
rationale
for
the
selection
of
3.6
mg/
kg/
d
as
a
LOAEL
and
1.8
mg/
kg/
d
as
a
NOAEL
for
suppression
of
the
LH
surge
is
based
on
a
weight
of
evidence
argument.
There
is
a
dose
response
trend
for
suppression
of
the
LH
surge.
While
the
3.6
mg/
kg/
d
dose
does
not
represent
a
statistically
significant
decrease
in
the
amount
of
LH,
this
dose
response
trend
is
supported
by
the
statistically
significant
difference
in
vaginal
cycling
at
3.6
mg/
kg/
d.
Vaginal
cycling
data
tend
to
be
less
variable
than
LH
data.
Thus,
EPA
acknowledges
that
selection
of
1.8
mg/
kg/
d
as
a
NOAEL
for
LH
suppression
is
conservative,
but
errs
on
the
side
of
health
protection.
Although
there
is
one
statistically
significant
response
for
suppression
of
the
LH
surge
in
the
1.8
mg/
kg/
d
dose
group
for
one
time
point,
this
is
not
sufficient
evidence
to
designate
1.8
mg/
kg
as
a
LOAEL,
particularly
in
light
of
the
fact
there
were
no
statistically
significant
differences
found
for
vaginal
cycling
at
this
dose.

Farm
Worker
Children
and
Worker
Risk
­

Comment
NRDC
believes
OPP
has
not
addressed
risks
to
farm
worker
and
their
children's
adequately
in
the
risk
assessment
under
FQPA.

HED
Response
HED
defers
to
the
IRED
for
further
discussion
and
response
to
this
comment.

High­
End
Exposures
­
31
Comment
EPA
cannot
willfully
ignore
high­
end
exposures.
EPA
does
not
quantify
the
risks
to
all
individuals.
The
assessment
does
not
address
the
top
0.1
percent
of
intermediate­
term
drinking
water
exposures.

HED
Response
HED
disagrees
with
the
NRDC
that
high­
end
exposures
were
ignored
in
the
risk
assessment.
The
CWS
targeted
for
probabilistic
assessment
represent
those
CWS
in
the
data
set
with
the
highest
exposures,
and
are
therefore
a
biased
set
of
CWS,
biased
towards
the
high­
end
of
known
exposures.
Therefore,
these
CWS
represent
the
high­
end
of
seasonal
drinking
water
exposures
anticipated
by
HED.
Average
90­
day
exposures
to
atrazine
in
drinking
water
at
the
99.9th
percentile
of
exposure
were
compared
to
the
selected
endpoint
for
intermediate­
term
effects
(
0.0018
mg/
kg/
day).
Because
these
CWS
represent
the
highest
exposures
anticipated
throughout
the
US,
the
99.9th
percentile
exposure
at
each
one
of
these
CWS
is
likely
to
represent
greater
than
the
99.9th
percentile
exposure
on
a
national
level.
Without
data
on
atrazine
for
all
CWS,
it
is
difficult
to
say
where
the
percentile
of
exposure
for
CWS
with
high­
end
exposures
would
fall
on
a
national
level
other
than
to
say,
it
would
fall
somewhere
between
the
99.9th
and
100th
percentiles.
However,
it
can
be
said
that
the
CWS
identified
with
risk
estimates
of
concern
represent
high­
end
exposures
and
serve
~
230,000
to
240,000
people.
For
these
CWS
risk
estimates
of
potential
concern
have
existed
at
each
of
these
CWS
at
some
point
between
1993
and
2001
for
infants
<
1
year
old.

In
general,
when
acute
food
exposures
are
estimated,
they
are
estimated
for
the
entire
US,
and
the
99.9th
percentile
of
exposure
represents
the
99.9th
percentile
exposure
for
the
entire
US
population.
Food
exposures
of
zero
are
included
in
the
probabilistic
assessments.
Unlike
food
exposure,
HED
considered
drinking
water
exposures
to
atrazine
on
a
system­
by­
system
basis,
rather
than
conducting
one
assessment
inclusive
of
exposures
at
all
community
water
systems
(
CWS).
The
drinking
water
exposure
assessment
was
based
on
those
CWS
for
which
data
on
atrazine
were
available,
located
in
the
high
use
areas
for
atrazine.
The
assessment
did
not
include
CWS
with
zero
exposure
because
of
a
lack
of
use
of
atrazine
in
the
vicinity.
Consequently,
by
definition,
the
drinking
water
exposure
assessments
are
biased
towards
the
high­
end
of
exposures
in
CWS
targeted
by
a
history
of
atrazine
use
or
contamination.

Percent
Crop­
Treated
and
Anticipated
Residues
­

Comment
The
EPA
may
only
use
percent
of
crop­
treated
data
for
dietary
chronic
risk
assessments,
and
before
using
the
data
must
show
the
data
are
reliable
and
do
not
underestimate
exposure.
Since
32
anticipated
residues
(
ARs)
were
used
in
the
dietary
assessment,
this
data
must
be
provided
within
5
years
of
establishing
a
tolerance
on
ARs
to
verify
that
the
tolerance
established
based
on
the
ARs
do
not
underestimate
actual
residue
levels.

HED
Response
The
issue
of
using
percent­
crop­
treated
data
in
acute
dietary
risk
assessments
has
been
addressed
by
OPP
before
in
a
variety
of
responses
to
public
comments,
SAP
reports,
and
policy
documents.
This
comment
was
addressed
in
a
previous
response
to
comment
document
but
is
reiterated
here.
OPP
believes
that
the
use
of
probabilistic
techniques
to
perform
acute
dietary
exposure
analyses
allows
a
more
realistic
evaluation
of
exposures
through
food
and
permit
the
risk
manager
to
make
decisions
which
reflect
a
truer
picture
of
risk.
Older
methods
used
by
OPP
for
acute
dietary
risk
assessments
were
limited
to
the
assumption
that
100%
of
the
crop
was
treated,
and
the
resulting
acute
risk
estimates
were
considered
"
high
end"
or
"
bounding";
these
provided
little
information
to
the
risk
manager
on
the
variability
or
uncertainty
associated
with
the
risk
estimate
nor
any
indication
of
how
probable
such
high­
end
exposures
were
or
what
might
be
more
expected
levels
of
exposure.
In
short,
then,
OPP
believes
that
its
use
of
probabilistic
techniques
in
acute
risk
assessments
are
entirely
appropriate
and
that
the
use
of
percent
crop
treated
is
an
important
consideration
that
is
a
critical
and
necessary
component
of
any
probabilistic
risk
assessment.
33
The
commentary
has
stated
that
"
acute
risk
assessments
should
never
include
any
averaging
of
exposures
over
time,
which
is
what
using
percent
crop
treated
data
does."
EPA's
position
is
that
using
percent
crop
treated
does
NOT
average
exposures
over
time,
but
rather
instead
accounts
for
the
probability
(
frequency)
of
an
exposure
occurring.
More
specifically,
this
percent
crop
treated
factor
determines
the
proportion
of
crop
that
is
assumed
to
have
zero
residues
(
calculated
as
1­
PCT).
Probabilistic
assessments
as
performed
by
OPP
do
not
"
adjust"
the
measured
residues
or
average
exposures
over
time,
but
rather
assign
a
probability
of
encountering
a
residue
in
any
individuals
daily
food
consumption.
The
difference
between
using
percent
crop
treated
as
an
adjustment
factor
(
an
invalid
approach)
and
using
it
as
an
assigned
probability
(
a
valid
approach)
is
illustrated
below:

Illustration
of
Valid
and
Invalid
Means
of
Incorporating
Percent
Crop
Treated
(%
CT)
Into
an
Acute
P
robabilistic
Assessment
Invalid
Valid
Available
Residue
Values
0.34
ppm
0.26
ppm
0.49
ppm
0.86
ppm
0.43
ppm
%
CT
10
Resulting
Residues
0.034
ppm
0.026
ppm
0.049
ppm
0.086
ppm
0.043
ppm
90%
P
robability
of
residue
being
"
zero"

and
10%
P
robability
of
residue
being
either
0.34
ppm,
0.26
ppm,
0.49
ppm,
0.86
ppm,
or
0.43
ppm
In
an
acute
probabilistic
exposure
assessment,
using
the
valid
approach
outlined
above,
a
distribution
of
residue
values
would
be
constructed
consisting
of
45
zeros
and
the
5
residue
values
shown.
This
provides
a
90%
chance
(
probability)
that
a
residue
concentration
of
zero
will
occur
and
a
10%
chance
that
a
residue
value
of
either
0.34
ppm,
0.26
ppm,
0.49
ppm,
0.86
ppm,

or
0.43
ppm
will
occur
in
the
assessment.
Each
of
the
5
residue
values
shown
have
an
equal
probability
relative
to
each
other
(
2%)
of
occurring
in
the
assessment.
OPP's
probabilistic
assessments
ensure
through
successive
iterations
that
all
residue
values
in
the
constructed
distribution
occur
in
the
assessment.
Therefore,
all
of
the
residue
values
available
will
be
represented
(
included)
in
the
probabilistic
assessment
with
the
appropriate
frequency
with
which
they
are
expected
to
occur
in
the
food
supply.
The
use
of
the
%
CT
factor
in
the
acute
probabilistic
assessment
ensures
that
the
available
residue
data
are
neither
over­
represented
nor
under­
represented
in
the
assessment.

Percent­
crop
treated
(
PCT)
data
are
updated
regularly
by
the
Benefits
and
Economic
Analysis
Division
(
BEAD).
The
original
EPA
estimate
was
based
on
the
years
1990­
1996.
The
34
Quantitative
Usage
Analysis
(
QUA)
dated
January
10,
2001
included
PCT
estimates
for
the
period
for
1990
to
1997.
Although
EPA's
most
recent
estimates
are
from
2000,
any
updated
PCT
analysis
would
include
data
from
a
broader
range
of
years
than
2000.
Since
the
data
from
a
period
of
1990
to
2000,
the
most
recent
decade
available,
were
used
in
the
assessment,
they
are
considered
current,
and
up
to
date.
BEAD
regularly
collects
these
data
from
a
variety
of
sources,
USDA
NASS,
the
registrant,
and
marketing
sources
(
DOANE's).
HED
believes
the
PCT
data
used
to
generate
ARs
in
the
atrazine
risk
assessment
are
current,
and
BEAD
regularly
collects
these
data
on
an
ongoing
basis
negating
the
need
to
require
any
data
from
the
registrant.

Anticipated
residues
(
ARs)
are
used
in
the
atrazine
dietary
risk
assessments
and
were
based
on
available
PDP
monitoring
data,
field
trial
residue
data,
plant
metabolism
study
data,
and
tolerances.
The
available
monitoring
and
field
trial
data
are
current
and
reflect
the
most
recent
use
patterns
and
rates
of
atrazine.
M
onitoring
data
generally
show
that
atrazine
residues
are
not
detected.
The
ARs
based
on
metabolism
data
are
very
conservative
in
that
they
are
based
on
levels
of
atrazine
not
normally
detected
in
field
trial
studies
or
monitoring
data
because
the
residues
are
radio­
labeled,
and
the
analytical
methods
used
to
detect
them
are
very
sensitive.
These
data
coupled
with
up
to
date
PCT
data
result
in
dietary
assessments
that
are
highly
refined
and
protective.
For
details,
HED
refers
the
reader
to
the
document
entitled,
"
Atrazine.
Anticipated
Residues
and
Acute
and
Chronic
Dietary
Exposure
Assessments
for
Atrazine,
Revised
January
2001,
January
18,
2001",
available
on
the
atrazine
website.

Atrazine
tolerances
are
not
based
on
ARs
.
Tolerances
for
atrazine
are
based
on
field
trial
data
submitted
by
the
registrant
under
OPPTS
guidelines.
Field
trial
data
reflecting
the
maximum
labeled
use
rate,
and
minimum
time
to
harvest,
show
for
most
foods
consumed
by
humans,
that
residues
of
atrazine
are
non­
detectable.
For
example,
the
corn
grain
tolerance
was
established
at
0.20
ppm
based
on
non­
detectable
levels
of
atrazine
and
its
3
chlorinated
metabolites
at
the
limit
of
quantitation
(
for
the
analytical
method
used)
0.05
ppm
for
atrazine
and
each
metabolite
(
4
x
0.05
=
0.20).
M
onitoring
data
collected
regularly
under
the
PDP
program
support
the
field
trial
data
and
provide
the
necessary
verification
check
on
actual
residue
levels
incurred
in
foods
to
ensure
that
tolerances
are
not
underestimated.
ARs
are
based
on
this
monitoring
data
as
well
as
field
trial
and
metabolism
data.
ARs
are
used
for
the
purposes
of
assessing
dietary
exposure,
not
for
establishing
tolerances.

Human
Testing
­

Comment
EPA
used
a
flawed
human
study
for
dermal
absorption.
The
dermal
absorption
study
EPA
considered
is
"
poorly
designed
and
non­
probative
from
a
scientific
standpoint".
The
study
in
35
question
used
too
few
subjects
(
10)
to
account
for
variability
in
the
population.
Consideration
of
the
dermal
absorption
study
is
inconsistent
with
EPA's
policy
"
not
to
use
human
studies
while
their
propriety
is
under
review."
The
comment
further
urges
EPA
not
to
use
results
from
human
tests,
and
expresses
concerns
about
the
ethics
of
human
testing
under
the
Nuremberg
Code.

HED
Response
Because
toxicity
testing
overall
involves
too
few
subjects
(
animal)
to
account
for
interspecies
variability,
OPP
routinely
applies
a
10
uncertainty
factor
to
all
risk
assessments
to
account
for
this
uncertainty.
The
atrazine
risk
assessment
includes
the
10X
uncertainty
factor
for
interspecies
variability.
Therefore,
it
is
EPA's
position
that
the
number
of
subjects
in
the
dermal
study
does
not
preclude
its
usefulness
in
the
risk
assessment.

OPP
is
interested
in
reducing
uncertainty
where
possible
in
its
risk
assessments.
The
statement
that
use
of
this
study
is
inconsistent
with
EPA
policy
is
over­
broad
and
mischaracterizes
EPA
policy.
EPA's
December
14,
2001
policy
announced
that
until
we
have
a
policy
in
place,
we
will
not
use
third
party
human
studies
involving
intentional
exposure
to
toxicants
for
the
purpose
of
defining
or
quantifying
their
toxic
effects.
Although
the
dermal
absorption
study
is
a
third­
party
study
and
it
did
involve
intentional
exposure,
its
purpose
was
not
to
define
or
quantify
toxic
effects.
Therefore
we
are
not
prohibited
by
the
Agency's
policy
from
considering
or
relying
on
this
study.

Dermal
Absorption
while
Showering
­

Comment
Atrazine
may
be
inhaled
in
water
in
the
shower,
and
absorbed
through
the
skin
and
mucous
membranes.

HED
Response
Previously,
NRDC
noted
that
exposure
to
atrazine
in
the
shower
was
excluded
from
the
risk
assessment
and
that
ignoring
such
exposures
may
underestimate
risk.
They
gave
examples
of
volatile
organic
compounds
like
benzene
and
chloroform
for
which
inhalation
of
vapors
account
for
50%
of
exposure.
HED
provided
the
following
response,
"
Atrazine
is
not
a
volatile
chemical.
Inhalation
exposures
are
not
anticipated
as
a
major
exposure
pathway.
Atrazine
has
a
vapor
pressure
of
2.89
x
10­
7
mm
Hg
at
25
C.
The
vapor
pressure
of
benzene
is
94.8
mm
Hg
at
25
C,
and
for
chloroform
is
197
mm
Hg
at
25
C.
The
comparison
of
vapor
pressures
of
atrazine
to
compounds
like
benzene
and
chloroform
shows
that
benzene
is
333,333,333
times
more
volatile
than
atrazine,
and
chloroform
is
666,666,667
times
more
volatile
than
atrazine.
Clearly,
inhalation
through
volatilization
is
the
most
significant
exposure
pathway
for
benzene
and
36
chloroform.
To
exclude
exposure
via
inhalation
in
the
shower
for
compounds
like
benzene
and
chloroform
present
in
tap
water
would
clearly
be
an
error.
It
is
not
surprising
that
exposure
via
showering
for
these
compounds
accounts
for
50%
of
total
exposure
to
these
compounds
because
of
their
high
volatility.
Equally
clearly,
however,
given
the
low
volatility
of
atrazine
that
is
nine
orders
of
magnitude
less
than
organic
solvents
like
benzene
and
chloroform,
it
can
be
seen
that
inhalation
through
volatilization
is
not
a
significant
exposure
pathway
for
a
non­
volatile,
water
soluble
compound
like
atrazine."

Regarding
absorption
of
dissolved
atrazine
through
the
skin
and
mucous
membranes,
given
that
exposure
to
atrazine
in
drinking
water
and
food
assumes
a
gut
absorption
rate
of
100%,
the
oral
exposure
route
is
considered
to
be
the
dominant
exposure
pathway.
Given
atrazine's
dermal
absorption
rate
of
6%,
atrazine
dissolved
in
water
and
absorbed
through
the
skin
and
mucous
membranes
is
not
expected
to
be
a
dominant
exposure
pathway.
HED
did
consider
dermal
absorption
and
inhalation
of
atrazine
in
its
aggregate
exposure
assessments.
The
aggregate
risk
assessments
combine
oral
(
dietary:
food
+
drinking
water)
and
non­
dietary
(
toddler
hand­
tomouth
exposures,
with
dermal
and
inhalation
exposures
as
appropriate.
These
assessments
consider
dermal
and
inhalation
exposure
to
the
actual
liquid
products
as
applied
by
homeowners,
which
is
expected
to
be
in
a
much
more
concentrated
form
than
atrazine
dissolved
in
shower
water
after
being
diffused
and
dissipated
in
the
environment.
These
estimates
show
that
dermal
exposures
are
greater
than
inhalation
exposures
for
atrazine.
Before
risk
mitigation,
dermal
exposures
from
use
of
atrazine
products
in
and
around
the
home
are
estimated
to
be
1.6
to
0.0034
mg/
kg/
day.
Inhalation
exposures
for
atrazine
(
0.00023
and
0.00002
mg/
kg/
day)
are
3
to
4
orders
of
magnitude
lower
than
dermal
exposures
to
liquid
formulations
(
0.16
to
0.0034
mg/
kg/
day).
Therefore,
HED
expects
inhalation
exposure
to
be
insignificant
relative
to
oral
and
dermal
exposures.
Given
the
conservative
assumptions
resulting
in
high­
end
estimates
for
the
dermal
and
inhalation
exposures
used
in
the
aggregate
risk
assessments,
and
the
belief
that
exposure
to
atrazine
through
showering
and
swimming
will
be
insignificant
in
comparison,
HED
believes
any
potential
exposures
through
showering
and
swimming
have
been
adequately
covered.
Finally,
HED
believes
that
the
1000­
fold
uncertainty
factor
used
for
dietary
exposure
and
the
300­
fold
uncertainty
factor
used
for
residential
exposure
used
in
conjunction
with
the
conservative
assumptions
regarding
residential
exposure
used
in
the
atrazine
human
health
risk
assessment
is
adequately
protective
of
aggregate
exposures
to
atrazine.

American
Water
Works
Association
(
AWWA):

The
AWWA
in
association
with
Dr.
Douglas
Crawford­
Brown
of
UNC
and
McGuire
Environmental
Consultants,
Inc.
submitted
comments
on
the
human
health
risk
assessment.
These
comments
and
HED
responses
are
summarized
below.
In
general,
they
request
37
clarification
on
how
the
common
mechanism
of
toxicity
and
the
risk
assessment
will
affect
regulatory
development
in
OPP
and
OW.
AWWA
expresses
concern
that
the
risk
assessment
has
underestimated
the
number
of
CWS
"
at
risk".
They
request
clarification
on
the
rationale
underlying
the
application
of
the
10X
FQPA
safety
factor,
citing
their
belief
that
at
most
a
3X
is
warranted.
They
cite
a
number
of
data
needs,
including:
treatment
and
analytical
methodologies
and
occurrence
data
for
the
chlorinated
degradates,
and
reliably
predicting
90­
day
average
concentrations.
They
provide
several
mitigation
proposals.

Comment
Common
Mechanism
of
Toxicity
­
AWWA
and
consultants
request
clarification
on
how
the
common
mechanism
of
toxicity
and
the
risk
assessment
will
affect
regulatory
development
in
OPP
and
OW.

HED
Response
HED
cannot
comment
on
how
the
common
mechanism
of
toxicity
for
the
triazines
will
affect
OPP
or
OW
regulations
regarding
this
class
of
pesticides
until
the
OPP
has
completed
the
cumulative
risk
assessment
for
the
triazines
sharing
a
common
mechanism
of
toxicity.
Regulatory
developments
based
on
the
atrazine
risk
assessment
are
in
process,
and
stakeholder
meetings
will
be
held
to
ensure
involvement
of
stakeholders
in
the
process.
As
to
any
specific
regulatory
actions,
HED
must
defer
to
SRRD.

Comment
CWS
@
Risk
­
AWWA
expresses
concern
that
the
risk
assessment
has
underestimated
the
number
of
CWS
"
at
risk".

HED
Response
HED
believes
the
CWS
identified
in
the
risk
assessment
represent
the
high
end
of
exposures
to
atrazine
and
the
chlorinated
degradates;
however,
HED
agrees
with
the
AWWA
in
that
the
risk
assessment
probably
did
not
identify
all
CWS
"
at
risk".
There
are
several
reasons
for
this
of
which
the
most
obvious
is
the
limited
database
used
in
the
assessment.
Although
the
drinking
water
monitoring
database
for
atrazine
is
the
most
complete
for
any
pesticide
to
date,
it
is
still
lacking
regarding
degradates
for
which
very
limited
data
were
available,
and
the
frequency
of
sampling
under
the
SDWA.
Also
of
concern
is
the
sporadic
pattern
with
which
concentrations
of
concern
occur
at
CWS.
Even
if
a
CWS
has
no
exposures
of
concern
for
several
years,
it
does
not
necessarily
mean
that
it
never
will.
HED
believes
that
a
continuing
process
to
identify
CWS
@
risk
now
and
in
the
future,
and
that
continued
monitoring
at
CWS
identified
as
of
potential
concern
is
a
necessary
part
of
any
mitigation
plan.
The
OW
is
currently
assessing
the
available
38
databases
for
atrazine
in
drinking
water
statistically
to
estimate
the
extent
of
exposures
of
concern
(
i.
e.,
the
total
number
of
CWS
with
90­
day
average
concentrations
likely
to
exceed
>
12.5
ppb).
HED
defers
to
OW
for
details
on
the
results
of
this
assessment.

Comment
FQPA
Safety
Factor
(
SF)
­
AWWA
notes
that
the
rationale
for
the
10X
FQPA
SF
is
not
clear
and
states
that
a
3X
would
have
been
sufficient.
HED
provides
the
following
clarification
as
to
why
a
10X
FQPA
safety
factor
was
applied
to
dietary
risk
assessments.
The
rationale
can
also
be
found
in
the
April
2002
FQPA
and
HIARC
memoranda
posted
to
the
atrazine
website.

HED
Response
FQPA
directs
EPA
to
use
an
additional
10­
fold
safety
factor
in
assessing
risks
to
infants
and
children
to
take
into
account
the
potential
for
pre­
and
post­
natal
toxicity
and
the
completeness
of
the
toxicity
and
exposure
databases.
The
default
10X
factor
can
only
be
reduced
if
the
different
margin
of
safety
based
on
reliable
data
would
be
safe
for
infants
and
children.
This
is
referred
to
as
the
FQPA
safety
factor
provision.
Under
this
provision
OPP
used
a
weight­
ofevidence
approach
wherein
all
data
on
toxicity
and
exposure
are
considered
together
for
atrazine.
Under
this
approach,
the
level
of
confidence
associated
with
the
hazard
and
exposure
assessments
and
any
residual
uncertainties
regarding
either
toxicity
or
exposure
are
evaluated.
The
10X
FQPA
safety
factor
was
applied
to
dietary
risk
assessments
for
atrazine
based
on
residual
uncertainties
regarding
atrazine's
toxicity
and
the
extent
of
exposure
to
atrazine
and
the
chlorotriazines.

Specifically,
the
HIARC
(
HED's
Hazard
Identification
Assessment
and
Review
Committee)
determined
that
the
toxicity
database
was
complete
and
there
was
evidence
of
increased
qualitative
susceptibility
of
the
young
following
exposure
to
atrazine
in
the
rabbit
developmental
study.
The
HIARC
then
performed
a
Degree
of
Concern
Analysis
to:
1)
determine
the
level
of
concern
for
the
effects
observed
when
considered
in
the
context
of
all
available
toxicity
data;
and
2)
identify
any
residual
concerns
after
establishing
toxicity
endpoints
and
traditional
uncertainty
factors
to
be
used
in
the
risk
assessment
of
this
chemical.
If
residual
concerns
are
identified,
HIARC
examines
whether
these
residual
concerns
can
be
addressed
by
a
special
FQPA
safety
factor
and,
if
so,
the
size
of
the
factor
needed.
For
atrazine,
the
HIARC
concluded
that
there
is
low
degree
of
concern
for
the
qualitative
increased
susceptibility
(
increased
fetal
resorptions
at
a
dose
level
that
resulted
in
decreased
body­
weight
gain
and
clinical
signs
in
the
maternal
animal)
because:
1)
the
NOAELs
in
the
study
are
well
characterized;
and
2.)
the
fetal
effects
seen
occurred
at
a
high
dose
level
(
75
mg/
kg/
day).
The
HIARC
also
concluded
that
there
are
no
residual
concerns
for
these
effects
considering
that
the
Acute
RfD
established
for
Atrazine/
DACT
is
based
on
a
NOAEL
of
10
mg/
kg
which
is
1SAP
Report
No.
2000­
05;
Atrazine:
Hazard
and
Dose
Response
Assessment
and
Characterization.
"
Because
of
the
rapid
developmental
brain
changes...
the
influence
of
Atrazine
on
neurotransmitters
in
the
hypothalamus
and
on
GnRH
may
well
have
a
differential,
permanent
effect
on
children.
This
phenomenon
is
the
basis
of
the
relatively
new
field
of
behavioral
teratology.
Atrazine
could
influence
the
migration
of
cells
and
the
connectivity
of
the
CNS.
The
influence
of
Atrazine
on
the
hypothalamus
and
on
GnRH
may
have
a
differential
effect
on
children.
This
effect
could
be
latent,
and
emerge
later
during
the
challenge
of
puberty,
or
during
senescence.
Behavioral
alterations
may
be
the
most
sensitive
outcome.
This
possibility
should
be
addressed...."

39
protective
of
the
fetal
effects
observed
at
75
mg/
kg/
day
in
the
developmental
rabbit
study.

After
considering
the
effects
observed
in
the
special
developmental
studies
with
atrazine
in
the
context
of
establishing
toxicity
endpoints
for
risk
assessment,
the
HIARC
identified
the
following
residual
concerns:

"
Since
the
focus
of
the
testing
with
Atrazine
in
the
young
rat
has
been
limited
to
short
periods
of
dosing
to
specific
developmental
periods,
uncertainties
are
raised
for
susceptibility
during
earlier
developmental
periods
as
well
as
for
consequences
of
earlier
developmental
exposure
with
longer
duration
of
dosing
throughout
development.
The
effects
of
neurotransmitters/
peptides
(
known
to
be
critical
for
normal
development
and
which
could
potentially
translate
into
severe
effects
in
children
that
may
not
be
manifested
until
later
in
life)
have
not
been
fully
characterized.
And
as
the
FIFRA
Scientific
Advisory
Panel
noted,
there
are
concerns
for
behavioral
effects
in
the
young
resulting
from
Atrazine's
CNS
mode
of
action
and
the
dose
level
at
which
these
effects
might
occur
compared
to
reproductive/
developmental
effects1."

Considering
the
existing
data
used
for
toxicity
endpoint
selection,
the
HIARC
used
the
following
rationale
to
conclude
that
an
additional
Special
FQPA
Safety
Factor
of
3X
would
be
adequate
to
account
for
these
hazard­
based
(
toxicity)
residual
uncertainties
described
above:

"
The
toxicology
endpoints
selected
for
risk
assessment
are
all
consistent
with
Atrazine's
mode
of
toxicity
using
the
most
sensitive
endpoint
with
the
lowest
NOAEL
(
1.8
mg/
kg/
day).
When
comparing
the
effects
observed
in
adults
to
those
observed
in
the
young,
the
HIARC
considered
the
results
of
the
pubertal
assay.
It
is
noted
that
delayed
puberty
was
observed
in
both
male
and
female
offspring
exposed
to
Atrazine
during
the
pubertal
period
(
30
days
for
the
males
and
20
days
for
the
females)
and
that
clear
NOAELs
were
established
for
this
endpoint
in
both
sexes
(
6.25
mg/
kg/
day
in
males;
12.5
mg/
kg/
day
in
females).
If
the
lowest
offspring
NOAEL
from
this
study
is
protected
by
a
factor
of
3X,
the
extrapolated
NOAEL
is
2
mg/
kg/
day.
Comparing
this
value
to
the
adult
NOAEL
of
1.8
mg/
kg/
day
from
the
6­
month
LH
Surge
study
(
used
to
establish
the
Chronic
RfD
and
for
the
intermediate
and
chronic
oral,
dermal,
and
inhalation
exposure
40
scenarios)
indicates
that
the
young
are
not
likely
to
be
an
order
of
magnitude
more
sensitive
than
the
adult.
Therefore,
the
HIARC
concluded
that
a
half­
log
reduction
in
the
default
Special
FQPA
Safety
Factor
is
considered
to
be
sufficiently
protective
of
the
concerns
for
this
CNS
mode
of
action
in
the
young."

Once
the
HIARC
makes
its
determination
as
to
the
necessary
"
hazard­
based"
(
toxicity)
FQPA
safety
factor,
the
FQPA
Safety
Factor
Committee
(
FQPA
SFC)
determined
the
overall
FQPA
SF
by
considering
the
HIARC's
determination
and
evaluation
regarding
increased
susceptibility/
sensitivity,
degree
of
concern
analysis,
completeness
of
the
toxicity
database,
and
any
residual
hazard­
based
uncertainties
in
conjunction
with
the
completeness
of
the
exposure
database,
and
any
residual
uncertainties
associated
with
the
exposure
database
and
the
exposure
assessments
based
on
it.

After
careful
deliberation,
the
FQPA
SFC
"
concluded
that,
as
to
dietary
risk,
the
default
10X
FQPA
safety
factor
is
statutorily
required
because
of
the
absence
of
reliable
evidence
showing
that
an
additional
safety
factor
different
than
the
statutory
10X
default
would
be
protective
of
infants
and
children.
The
principal
grounds
for
this
conclusion
are:
1.)
the
HIARC
identified
residual
concerns
for
the
effects
of
the
neuroendocrine
mode
of
action
described
for
Atrazine
on
the
development
of
the
young
(
Refer
to
Section
I.
3.
B.).
These
concerns
could
not
be
accounted
for
in
the
determination
of
toxicity
endpoints
and
traditional
uncertainty
factors
to
be
used
in
risk
assessment;
and
2.)
residual
concerns
were
also
identified
with
regard
to
the
drinking
water
exposure
assessment.
The
various
water
monitoring
data
sources
which
exist
for
Atrazine
and
its
chlorinated
metabolites
indicate
that
exposure
via
drinking
water
sources
is
high
in
some
of
the
systems
that
have
been
monitored
and
widespread
low
levels
are
commonly
detected.
Although
it
is
known
that
there
is
significant,
widespread
exposure
to
Atrazine
and
its
metabolites
in
drinking
water,
limitations
in
the
extent,
frequency,
and
compounds
tested
for
in
the
monitoring
data
raise
significant
uncertainties
regarding
the
level
of
exposure
to
Atrazine
and
its
metabolites.
Because
of
these
uncertainties,
the
Committee
concluded
there
is
not
reliable
data
to
assign
an
additional
safety
factor
that
would
adequately
protect
the
safety
of
children
by
insuring
that
exposure
in
drinking
water
is
not
underestimated.
The
FQPA
specifies
that
in
the
absence
of
such
reliable
data
a
default
value
of
10X
is
to
be
used
as
an
additional
safety
factor
for
the
protection
of
infants
and
children.
As
discussed
below,
the
Committee
believes
there
is
reliable
data
to
address
the
residual
uncertainties
regarding
the
neuroendocrine
mode
of
action;
however,
because
reliable
data
is
not
available
as
to
all
of
the
issues
raising
residual
uncertainties,
use
of
the
default
10X
factor
is
appropriate."
41
Comment
Data
Needs
­
Treatment
technologies,
and
analytical
methodologies,
occurrence
data
and
the
frequency
of
monitoring
for
atrazine
and
the
chlorinated
degradates.

HED
Response
The
data
needs
listed
are
mostly
under
the
purview
of
the
OW
and
HED
defers
to
OW
regarding
treatment
technologies,
and
analytical
methodologies
for
chlorinated
metabolites
of
atrazine
in
drinking
water.
HED
must
also
defer
to
OW
regarding
occurrence
data
and
the
frequency
of
monitoring
for
atrazine
and
the
chlorinated
degradates
in
a
way
that
will
adequately
capture
90­
day
average
concentrations
of
concern
under
any
compliance
monitoring
scheme.
However,
weekly
to
biweekly
monitoring
during
application
season
were
used
for
the
VMS
and
ARP
databases,
and
appear
adequate
to
capture
the
seasonal
pulses
(
spikes)
in
atrazine
concentrations
otherwise
missed
with
the
quarterly
sampling
schemes
currently
used
under
the
SDWA.

Comment
Mitigation
Options
­
AWWA
included
a
section
discussing
options
to
mitigate
the
risk
from
atrazine
use
including
use
restrictions,
best
management
practices,
use
bans
in
certain
watersheds,
a
complete
ban
on
use,
and
several
programs
to
defer
the
costs
of
atrazine
contamination
of
water
to
the
registrant.

HED
Response
OPP
is
currently
working
on
mitigation
strategies
and
is
including
AWWA
in
these
discussions
as
a
stakeholder.
During
these
meetings,
AWWA
should
have
ample
opportunity
to
discuss
their
suggestions
and
concerns
regarding
mitigation
options.

AWWA
Consultants
(
Dr.
Douglas
Crawford­
Brown
and
McGuire
Environmental,
Inc.):
Dr.
Douglas
Crawford­
Brown
stated
that
overall
the
risk
assessment
document
presented
a
reasonable
set
of
conservative
calculations
for
assessing
exposures
to
atrazine
and
the
chlorinated
metabolites
in
food,
water,
and
residential
settings.
He
further
noted
that
a
reasonable
set
of
toxic
endpoints
were
selected
and
correctly
used
to
establish
reference
doses.
The
conclusions
of
the
document
were
generally
reasonable
and
well
documented.
He
offers
the
following
comments:

Comment
Probabilistic
component
of
acute
exposures
­
Dr
Crawford­
Brown
notes
that
in
the
acute
assessment
for
food
exposures,
food
intake
and
body
weight
are
correlated
for
each
individual
considered
in
the
assessment.
These
data
come
from
records
contained
in
the
Continuing
Survey
of
Food
Intake
by
Individuals
(
CSFII),
and
are
used
as
distributions
representing
an
individual's
daily
food
intake/
body
weight
on
a
single
day.
He
also
notes
that
to
estimate
acute
drinking
42
water
exposures
in
a
single
day,
drinking
water
intake
and
body
weights
are
not
correlated
for
individuals.

HED
Response
HED
agrees
with
the
comment
that
data
on
body
weight
and
drinking
water
consumption
linked
are
available
and
should
be
used.
However,
HED
used
a
different
approach
in
assessing
acute
food
versus
drinking
water
exposures.
The
acute
food
exposure
assessment
was
conducted
probabilistically
using
distributions
of
individuals'
food
intake
linked
to
their
reported
body
weights
along
with
distributions
of
food
residues,
while
the
acute
drinking
water
exposure
assessment
used
a
screening­
level
approach.
The
screening­
level
approach
assumes
default
body
weights
and
consumption
values
currently
in
use
by
the
OW
in
setting
drinking
water
standards
rather
than
body
weight/
consumption
values
from
the
CSFII
or
the
Exposure
Factors
Handbook.
Under
the
acute
assessment,
the
simpler
screening­
level
approach
for
drinking
water
indicated
that
acute
risks
through
drinking
water
were
below
levels
of
concern,
and
therefore,
more
refined
probabilistic
assessments
for
acute
exposures
in
drinking
water
were
not
needed.
However,
for
CWS
showing
intermediate­
term
risks
of
concern
under
the
screening­
level
approach,
probabilistic
drinking
water
exposure
assessments
were
conducted
using
distributions
of
linked
body
weight
and
consumption
per
individual.

Comment
FQPA
Safety
Factor
­
The
application
of
the
10X
FQPA
safety
factor
is
not
explained
satisfactorily.

HED
Response
See
response
under
FQPA
Safety
Factor
above.

HIARC
and
FQPA
documents
can
be
found
at
the
following
URLs:

http://
www.
epa.
gov/
oppsrrd1/
reregistration/
atrazine/
hed_
fqpasfreport_
8apr02.
pdf
http://
www.
epa.
gov/
oppsrrd1/
reregistration/
atrazine/
hed_
hiarc_
atrazine_
5april02.
PDF
Comment
Document
organization
and
clarity
­
The
PAD
should
be
explained
earlier
in
the
document.

HED
Response
HED
acknowledges
that
the
programs
use
of
varying
terms
as
risk
metrics
is
confusing
and
should
be
explained
early
and
often.
43
Comment
The
document
needs
an
example
of
how
quarterly
average
concentrations
were
calculated.

HED
Response
HED
initially
calculated
simple
arithmetic
quarterly
average
concentrations
of
chlorotriazines
for
those
CWS
in
VMS
and
ARP.
Typically
these
CWS
may
have
had
a
total
of
30
samples
per
year,
and
up
to
10­
12
samples
in
the
spring
quarter.
Samples
within
a
given
quarter
tended
to
be
evenly
spaced
in
time,
but
not
exactly.
Therefore,
time­
weighted
mean
concentrations
(
TWMC)
were
calculated
and
compared
to
the
simple
arithmetic
values.

The
TWMC
was
calculated
by
the
following:

TWMC
=
(
C
1
x
T
1
/
T
T)
+
(
C
2
x
T
2
/
T
T)
+
(
C
3
x
T
3
/
T
T)
................(
C
n
x
T
n
/
T
T)
where,
C
1
is
concentration
value
in
the
first
time
period
of
interest
(
weekly
sample),
T
1
is
the
first
time
period
of
interest
(
7
days),
and
T
T
is
the
total
time
period
of
interest
(
90
days).

Comment
The
document
should
explain
the
equations
and
assumptions
used
to
estimate
the
chlorinated
degradates
in
exposure
assessments.

HED
Response
The
details
of
this
process
are
quite
lengthy
and
involved.
Consequently,
to
keep
the
length
of
the
risk
assessment
document
down,
the
details
are
contained
in
supporting
documents.
The
equations
used
to
estimate
the
chlorinated
degradates
in
drinking
water
are
contained
in
the
EFED
chapter
dated
October
16,
2000,
"
Drinking
water
exposure
assessment
for
atrazine
and
various
chlorotriazine
and
hydroxy
triazine
degradates",
H.
Nelson,
J.
Lin,
M.
Frankenberry,
posted
to
the
website
under
Preliminary
Risk
Assessment
at
the
following
URL:
http://
www.
epa.
gov/
oppsrrd1/
reregistration/
atrazine/
drinkingwater.
pdf
The
chlorinated
degradates
were
estimated
in
food
based
on
field
trial
studies
and
plant
and
animal
metabolism
studies.
Foods
were
analyzed
for
atrazine
and
the
chlorinated
degradates
in
these
studies.
The
details
are
contained
in
the
document
dated
January
18,
2000,
"
Atrazine.
Anticipated
Residues
and
Acute
and
Chronic
Dietary
Exposure
Assessments
for
Atrazine
",
D.
Soderberg,
C.
Eiden,
posted
to
the
website
under
Preliminary
Risk
Assessment
at
the
following
URL:
http://
www.
epa.
gov/
oppsrrd1/
reregistration/
atrazine/
antici_
residues.
pdf
Comment
44
Parameters
regarding
the
residential
risks
for
children
were
not
clear
in
the
text
of
the
document,
but
contained
in
tables.

HED
Response
Again,
the
reader
is
referred
to
the
supporting
documents
on
the
website
for
details.
All
equations
and
assumptions
are
clearly
spelled
out
but
excluded
from
the
risk
assessment
because
of
length
considerations.
The
document
can
be
found
at
the
following
URL:
http://
www.
epa.
gov/
oppsrrd1/
reregistration/
atrazine/
hed_
ore_
25april02.
pdf.

Comment
Carcinogenic
Potential
of
Atrazine
­
The
document
only
briefly
discusses
atrazine's
cancer
classification,
more
is
needed.
A
discussion
of
the
MCL
versus
the
12.5
ppb
figure
used
in
the
document.

HED
Response
The
cancer
issue
was
brought
before
a
SAP
in
June
2000.
The
details
of
that
assessment
are
also
quite
lengthy
and
discussed
only
briefly
in
the
risk
assessment
in
the
interest
of
brevity.
For
those
interested
in
the
details
the
reader
is
referred
to
the
following
website:
May
22,
2000
document
atrazine
to
the
FIFRA
Scientific
Advisory
Panel
(
SAP)
(
see
Part
A,
http://
www.
epa.
gov/
scipoly/
sap/
2000/
june27/
finalparta_
atz.
pdf
and
Part
B,
http://
www.
epa.
gov/
scipoly/
sap/
2000/
june27/
finalpartb_
atz.
pdf).
Please
see
the
response
to
NRDC's
comment
on
the
MCL
versus
the
12.5
ppb
DWLOC
on
p.
8.

Comment
Uncertainty
­
Dr.
Crawford­
Brown
correctly
notes
that
the
discussions
around
the
titles
of
"
Uncertainty"
are
not
quantitative
and
are
more
correctly
called
discussions
of
levels
of
confidence.

HED
Response
HED
agrees
with
this
comment.

Comment
Probabilistic
assessments
­
They
are
not
clearly
explained
in
the
risk
assessment
document.
The
reader
cannot
determine
the
underlying
probability
distributions,
the
quality
of
the
distributions,
how
samples
were
selected......
etc.
Dr.
Crawford­
Brown
expresses
concern
that
the
distributions
are
not
representative
but
biased
towards
sites
with
atrazine.
McGuire
Environmental,
Inc.
consultants
also
expressed
concern
that
the
data
used
were
inappropriate
for
a
national
assessment.
45
HED
Response
HED
can
refer
the
reader
to
Appendix
III
of
the
revised
risk
assessment,
and
the
memorandum
entitled,
"
Review
of
Probabilistic
Exposure
Assessment
for
Drinking
Water
from
28
community
Water
Systems,
dated
April
23,
2002,
C.
Eiden,
posted
to
the
website
under
Revised
Risk
Assessment
at
the
following
URL:

http://
www.
epa.
gov/
oppsrrd1/
reregistration/
atrazine/
probabilisticreview_
23apr02.
pdf.

Although
the
actual
distributions
of
water
concentrations
are
not
given
there,
the
methodology
used
to
create
them
is
described
in
some
detail.
The
document
refers
to
submitted
probabilistic
assessments
conducted
by
Novigen
Sciences,
Inc.
using
the
Calandex
 
model,
and
methodology
and
procedures
approved
by
OPP
and
used
for
the
cumulative
risk
assessment
for
the
organophosphate
pesticides.
If
need
be
the
actual
distributions
of
drinking
water
intake
and
body
weight
are
available
from
the
CSFII,
and
the
actual
distributions
of
water
concentrations
may
be
requested
under
the
FOIA.

The
concern
regarding
the
representativeness
of
the
probabilistic
exposure
assessments
correctly
notes
that
the
data
used
to
develop
the
water
concentration
distributions
used
are
from
CWS
with
high
atrazine
exposures
and
the
data
set
is
itself
conservatively
biased.
However,
it
should
be
noted
that
the
probabilistic
assessments
were
conducted
for
specific
CWS
only,
therefore,
this
is
not
a
problem.
Had
the
results
of
the
risk
assessment
been
extrapolated
from
these
CWS
with
high­
end
exposures
to
the
entire
US
population,
then
the
concern
would
have
been
well­
founded.
However,
as
stated
in
the
risk
assessment
document,
the
probabilistic
assessments
were
conducted
for
a
small
number
of
CWS
~
30
for
which
screening­
level
assessments
indicated
risk
of
concern,
and
for
which
enough
high
quality
monitoring
data
were
available
to
conduct
a
probabilistic
exposure
assessments.
A
separate
probabilistic
assessment
was
conducted
for
each
of
the
~
30
CWS.
The
results
were
not
extrapolated
beyond
the
specific
CWS
for
which
they
are
representative.

The
risk
assessment
did
not
attempt
to
conduct
a
national
assessment
because
of
the
lack
of
data,
i.
e.,
roughly
33­
40%
of
the
CWS
using
surface
water
in
the
US
have
data
on
atrazine.
Screeninglevel
assessments
were
conducted
with
the
available
data
for
these
CWS,
only,
and
probabilistic
assessments
only
for
those
CWS
with
risk
of
concern
based
on
the
screen.
In
effect,
the
risk
assessment
included
only
those
CWS
with
data
on
atrazine,
and
was
indeed
a
biased
assessment
looking
at
high­
end
exposures
only.
The
remaining
60+%
of
CWS
using
surface
water
in
the
US
either
do
not
collect
data
on
atrazine
because
of
lack
of
use
or
detection
under
the
SDWA
waiver
program.
The
risk
for
these
CWS
could
be
assumed
to
be
zero,
but
the
risk
assessment
document
did
not
conclude
that
because
of
a
lack
of
verification
that
the
data
waivers
were
current
and
46
appropriate.
Prompted
by
comments
from
the
NRDC,
OPP
has
been
in
discussion
with
the
OW
about
the
waiver
program.

Comment
DWLOC
Issues
­
How
should
the
reader
interpret
the
results
on
residential
exposures
and
their
effect
on
the
DWLOC?
Is
it
suggested
that
the
DWLOC
be
reduced
for
policy
purposes?

HED
Response
Under
OPP's
aggregate
screening­
level
exposure
assessment,
the
DWLOC
value
varies
according
to
what
is
left
over
in
the
risk
cup
once
estimates
of
food
and
residential
exposures
(
if
warranted)
are
considered.
DWLOC
values
vary
with
risk
assessment
type,
i.
e.,
acute,
short­
term,
intermediate­
term,
and
chronic)
as
each
risk
assessment
varies
by
toxic
endpoints,
uncertainty
factors,
food
and
residential
exposures.
Consequently,
under
any
given
exposure
scenario
the
greater
the
exposure
through
food
and
residential
uses
the
lower
the
DWLOC
values
will
be.
The
DWLOC
is
not
a
standard
but
a
way
of
measuring
aggregate
risk
in
the
form
of
a
theoretical
upper
limit
on
what
is
allowable
in
drinking
water
in
light
of
other
exposures.
The
DWLOC
is
simply
based
on
the
portion
of
the
allowable
exposure
(
NOAEL/
UF
or
PAD)
left
after
subtracting
food
and
residential
exposures.
The
relationship
of
the
PAD
to
the
DWLOC
is
directly
proportional.
The
reader
is
referred
to
the
following
URL
for
details:
http://
www.
epa.
gov/
pesticides/
trac/
science/
screeningsop.
pdf
HED
first
estimates
dietary
and
residential
exposures
separately,
and
then
in
aggregate.
If
the
residential
exposure
is
above
levels
of
concern
independent
of
the
food
or
water
exposures,
then
by
default,
the
DWLOC
value
for
the
residential
exposure
scenario
exceeding
levels
of
concern
is
zero,
i.
e.,
because
there
is
an
exposure
pathway
by
itself
exceeding
levels
of
concern,
there
is
no
room
for
aggregate
exposures
through
water
and
food.
For
any
individual
residential
exposure
scenario
with
risk
estimates
of
concern,
an
aggregate
exposure
assessment
in
theory
is
not
possible.
It
is
HED
policy
that
when
residential
exposure
scenarios
exceed
levels
of
concern,
the
DWLOC
value
is
set
at
zero
indicating
no
more
room
in
the
risk
cup
until
that
residential
exposure
is
mitigated.

In
the
case
of
atrazine,
OPP
does
not
anticipate
intermediate­
term
exposures
to
atrazine
in
residential
settings
because
of
residential
uses.
Residential
exposures
do
not
impact
the
intermediate­
term
DWLOC
value
at
all.
Therefore,
the
aggregate
exposure
assessment
for
intermediate­
term
exposures
only
includes
exposures
through
food
and
drinking
water
as
these
are
the
pathways
contributing
the
most
to
exposure
to
atrazine
and
the
chlorinated
degradates
with
reliable,
available
data.
Under
the
aggregate
intermediate­
term
exposure
assessment
(
90
days),
the
lowest
DWLOC
of
concern
is
12.5
ppb
for
infants
and
is
based
on
a
NOAEL
of
1.8
47
mg/
kg/
day,
a
1000­
fold
uncertainty
factor,
and
chronic
food
exposures
of
0.000008
mg/
kg/
day.

However,
OPP
does
anticipate
short­
term
exposures
to
atrazine
in
residential
settings
because
of
residential
uses.
Residential
exposures
do
impact
the
DWLOC
value.
Therefore,
the
aggregate
exposure
assessment
for
short­
term
exposures
includes
exposures
through
food,
drinking
water,
and
residential
uses
as
these
are
the
pathways
contributing
the
most
to
exposure
to
atrazine
and
the
chlorinated
degradates
with
reliable,
available
data.
Under
the
short­
term
drinking
water
exposure
assessment,
the
lowest
DWLOC
of
concern
is
zero
for
toddlers
based
on
short­
term
exposures
(<
30
days),
a
NOAEL
of
6.25
mg/
kg/
day
and
a
300­
fold
uncertainty
factor,
chronic
food
exposures
of
0.000008
mg/
kg/
day,
and
high­
end
residential
exposures.
A
DWLOC
of
zero
simply
indicates
that
short­
term
exposure
through
the
residential
pathway
alone
exceeds
the
level
of
concern.

For
example,
the
DWLOC
values
for
intermediate­
term
and
chronic
exposures
are
less
than
the
DWLOC
values
for
short­
term
exposures
even
though
aggregate
short­
term
exposures
include
food,
water,
and
high­
end
residential
exposures
while
the
aggregate
intermediate­
term
and
chronic
exposures
include
food
and
water
only
because
intermediate­
term
and
chronic
residential
exposures
are
not
anticipated.
This
is
largely
because
the
short­
term
exposure
scenarios
are
based
on
and
driven
by
an
endpoint
of
6.25
mg/
kg/
day
and
an
UF
of
300,
whereas
the
intermediate­
term
and
chronic
exposure
scenarios
are
based
on
an
endpoint
of
1.8
mg/
kg/
day
and
an
UF
of
1000.
The
greater
the
endpoint
and
lower
the
UFs,
the
greater
the
allowable
dose
upon
which
the
DWLOC
is
based.
Again,
the
DWLOC
is
directly
proportional
to
the
endpoint
and
UFs.

Comment
Tolerance
Reassessment
Impacts
on
Water
Quality
­
Dr.
Crawford­
Brown
expresses
concern
that
increases
in
tolerances
may
lead
to
a
situation
where
increased
tolerances
lead
to
higher
allowable
levels
of
atrazine
in
drinking
water
under
the
aggregate
risk
assessment.

HED
Response
Increases
in
tolerances
do
not
translate
directly
into
increases
in
allowable
exposure
to
a
given
pesticide.
The
tolerance
represents
a
legal
limit
on
a
pesticide
residue
that
may
be
on
a
given
crop
that
has
been
treated
at
the
maximum
labeled
rate
and
harvested
at
the
shortest
post­
harvest
interval.
That
is,
the
tolerance
represents
the
maximum
residue
expected
at
the
farm
gate
prior
to
any
storage
and
processing,
which
may
include
washing,
peeling,
and
cooking.
The
tolerance's
main
function
is
to
control
for
any
illegal/
misuse
of
a
pesticide
product
on
a
crop
as
the
crop
moves
through
the
channels
of
commerce.
The
tolerance
does
not
represent
the
pesticide
residues
expected
(
anticipated)
on
foods
that
humans
or
animals
eat.
Although
tolerance
level
residues
may
be
used
in
dietary
risk
assessments,
these
assessments
are
considered
crude
and
for
48
more
refined
assessments
OPP
uses
monitoring
data
collected
on
crops
and
foods
closer
to
the
point
of
consumption
for
exposure
and
risk
assessment
purposes.
The
allowable
dose
of
atrazine
and
the
chlorinated
degradates
in
food,
drinking
water,
and
the
home
under
an
aggregate
risk
assessment
is
based
on
the
chronic
PAD
(
0.0018
mg/
kg/
day)
or
acute
PAD
(
0.01
mg/
kg/
day)
that
has
no
relationship
to
the
actual
tolerance.

In
the
case
of
atrazine,
the
tolerances
were
increased
for
several
commodities
including
meats
and
milk.
This
increase
is
a
reflection
of
the
addition
of
the
chlorinated
degradates
of
atrazine
in
the
tolerance
expression,
not
any
increase
in
the
allowable
dose
of
atrazine
and
the
chlorinated
degradates.
It
means
the
legal
limit
for
atrazine
must
now
include
its
three
degradates,
as
well,
and
that
USDA
and
FDA
should
be
monitoring
for
all
the
degradates
as
well
as
the
parent.
Most
tolerances
for
atrazine
on
crops
were
decreased
because
of
decreases
in
the
use
rates
of
atrazine
on
grains
such
as
corn
and
sorghum.

New
York
and
Connecticut
State
Attorney
General's
Offices
(
NYSAGO):

Comment
The
revised
human
health
risk
assessment
fails
to
assess
adequately
the
endocrine
disruption,
reproductive,
and
carcinogenic
effects
of
atrazine.

HED
Response
HED
disagrees
with
the
NYSAGO's
comment.
Atrazine
is
one
of
the
best
studied
pesticides
with
an
extensive
data
base
on
its
mechanism
of
toxicity.
The
perturbation
of
the
hypothalamicpituitary
gonadal
axis
is
the
primary
and
only
established
mode
of
action
for
atrazine.
The
June
2000
SAP
agreed
with
this
conclusion.
As
part
of
the
cancer
mode
of
action
evaluation,
however,
EPA
fully
considered
other
modes
of
action,
and
included
discussion
of
these
alternative
pathways
in
its
May
22,
2000
document
atrazine
to
the
FIFRA
Scientific
Advisory
Panel
(
SAP)
(
see
Part
A,
http://
www.
epa.
gov/
scipoly/
sap/
2000/
june27/
finalparta_
atz.
pdf
and
Part
B,
http://
www.
epa.
gov/
scipoly/
sap/
2000/
june27/
finalpartb_
atz.
pdf).
Furthermore,
EPA
asked
the
June
27,
2000
FIFRA
SAP
"
Have
other
modes
of
carcinogenic
action
been
sufficiently
discussed
and
ruled
out?".
The
SAP
concluded
that
"
Alternative
modes
of
action
have
been
thoroughly
discussed
and
ruled
out."
in
the
May
2000
EPA
document.
Below
are
more
specific
responses
to
the
other
mechanistic
pathways
raised
by
NRDC.
The
Scientific
Advisory
Panel
(
SAP)
report
convened
in
June
of
2000
and
all
of
the
supporting
documentation
that
went
into
that
SAP
are
available
for
review
at
the
above
website.
Also
see
response
to
NRDC
comment
on
pages
13
­
14.

As
to
reproductive
and
developmental
effects,
HED
based
all
aspects
of
the
human
health
risk
2SAP
Report
No.
2000­
05;
Atrazine:
Hazard
and
Dose
Response
Assessment
and
Characterization.
"
Because
of
the
rapid
developmental
brain
changes...
the
influence
of
Atrazine
on
neurotransmitters
in
the
hypothalamus
and
on
GnRH
may
well
have
a
differential,
permanent
effect
on
children.
This
phenomenon
is
the
basis
of
the
relatively
new
field
of
behavioral
teratology.
Atrazine
could
influence
the
migration
of
cells
and
the
connectivity
of
the
CNS.
The
influence
of
Atrazine
on
the
hypothalamus
and
on
GnRH
may
have
a
differential
effect
on
children.
This
effect
could
be
latent,
and
emerge
later
during
the
challenge
of
puberty,
or
during
senescence.
Behavioral
alterations
may
be
the
most
sensitive
outcome.
This
possibility
should
be
addressed...."

49
assessment
on
either
reproductive
or
developmental
effects,
i.
e.,
the
acute
risk
assessment
was
based
on
delayed
ossification
and
prostatitis
effects
in
fetuses
and
developing
offspring,
respectively;
the
short­
term
risk
assessment
was
based
on
pubertal
delays;
the
intermediate­
term
and
chronic
risk
assessments
were
based
on
disruptions
to
the
estrus
cycle
and
hormonemediated
ovulation
effects.
In
addition,
the
10X
FQPA
SF
was
based
in
part
on
the
uncertainties
surrounding
the
critical
periods
of
development
in
the
young
versus
the
timing
of
atrazine
administration.
The
following
excerpt
is
taken
from
the
HIARC
document
for
atrazine
(
April
5,
2002).
It
provides
the
basis
for
the
rationale
as
to
why
residual
uncertainties
regarding
atrazine's
toxicity
with
regards
to
developmental
consequences
in
the
young
exist.
(
Also
see
response
on
page
31.)

"
Since
the
focus
of
the
testing
with
Atrazine
in
the
young
rat
has
been
limited
to
short
periods
of
dosing
to
specific
developmental
periods,
uncertainties
are
raised
for
susceptibility
during
earlier
developmental
periods
as
well
as
for
consequences
of
earlier
developmental
exposure
with
longer
duration
of
dosing
throughout
development.
The
effects
of
neurotransmitters/
peptides
(
known
to
be
critical
for
normal
development
and
which
could
potentially
translate
into
severe
effects
in
children
that
may
not
be
manifested
until
later
in
life)
have
not
been
fully
characterized.
And
as
the
FIFRA
Scientific
Advisory
Panel
noted,
there
are
concerns
for
behavioral
effects
in
the
young
resulting
from
Atrazine's
CNS
mode
of
action
and
the
dose
level
at
which
these
effects
might
occur
compared
to
reproductive/
developmental
effects2."

The
NYSAGO's
comment
that
the
risk
assessment
states,
"...
there
was
no
evidence
of
increased
sensitivity
following
exposure
to
atrazine",
with
respect
to
NHEERL
studies
is
correct.
The
statement
in
the
risk
assessment
should
have
been
clearer
by
stating,
"....
there
was
no
evidence
of
increased
"
quantitative"
sensitivity
following
exposure
to
atrazine",
with
respect
to
NHEERL
studies.
[
The
specifics
are
given
in
the
HIARC
and
FQPA
memoranda
previously
cited.]
The
endpoints
(
LOAELs)
at
which
these
pubertal
(
endocrine)
effects
from
the
NHEERL
studies
were
seen
in
young
rats
were
greater
than
or
equal
to
12.5
mg/
kg/
day
and
were
all
above
the
lowest
endpoint
(
LOAEL)
identified
for
endocrine
effects
in
the
adult
rat
(
3.65
mg/
kg/
day)
indicating
no
increased
quantitative
sensitivity.
However,
the
HIARC
document
actually
states
the
following
50
regarding
sensitivity
of
the
young
to
atrazine
exposure
of
which
only
a
portion
was
captured
in
the
risk
assessment:

"
The
HIARC
concluded
that
there
is
a
concern
for
pre­
and/
or
postnatal
toxicity
resulting
from
exposure
to
Atrazine.

Determination
of
Susceptibility
The
HIARC
concluded
that
there
was
no
increased
quantitative
or
qualitative
susceptibility
in
any
of
the
guideline
studies
on
atrazine
in
the
rat,
and
there
was
no
increased
quantitative
susceptibility
in
the
rabbit
study.
However,
there
was
increased
qualitative
susceptibility
in
the
rabbit
study
[
increased
resorptions
(
deaths)
at
a
dose
level
that
resulted
in
decreased
body­
weight
gain
and
clinical
signs
in
the
maternal
animal].
There
are
other
non­
guideline
studies
on
atrazine
that
show
evidence
of
endocrine
disruption
[
prostatitis
study,
delayed
puberty
study,
and
data
on
LH
surge
attenuation,
and
estrous
cycle
alterations].
The
primary
underlying
events
that
lead
to
mammary
and
pituitary
tumor
formation
following
atrazine
exposure
of
Sprague­
Dawley
female
rats
involve
disruption
of
the
hypothalamic­
pituitary­
ovarian
axis.
Since
aspects
related
to
this
axis
are
involved
in
reproductive
and
developmental
competency,
there
is
a
concern
for
adverse
reproductive
and
developmental
effects
in
maternal
animals
and
their
offspring.
Several
special
studies
have
been
performed
that
show
that
treatment
of
pregnant
rats
with
atrazine
can
lead
to
reproductive
and
developmental
effects
that
may
be
associated
with
endocrine
alterations.
Additionally,
the
neurotoxicity
seen
in
the
non­
guideline
studies
with
atrazine
is
a
central
nervous
system
(
CNS)
toxicity
­
specifically,
neurotransmitter
and
neuropeptide
alterations
at
the
level
of
the
hypothalamus.

Studies
in
the
open
literature
indicate
increased
qualitative
susceptibility.
Dosing
of
dams
immediately
following
parturition
[
postnatal
days
1­
4]
resulted
in
prostatitis
in
male
offspring,
and
dosing
of
the
young
following
weaning
resulted
in
delayed
puberty
in
both
sexes.
The
mode
of
action
for
these
two
effects
(
prostate
inflammation
and
delayed
puberty)
is
believed
to
be
similar
to
the
mode
of
action
described
for
atrazine­
associated
cancer
and
involves
the
CNS
neuroendocrine
alterations,
specifically,
neuroendocrine
alterations
at
the
hypothalamus.

In
the
previous
HIARC
assessment
of
DACT,
it
was
determined
that
increased
quantitative
susceptibility
of
the
young
was
observed
in
the
rat
developmental
toxicity
study
on
DACT.
A
re­
examination
of
the
maternal
body­
weight
gain
data
from
that
study
was
performed
subsequently,
and
it
was
determined
that
decreased
body­
weight
gain
was
evident
during
the
initial
dosing
period
[
gestation
days
6­
8]
at
25
mg/
kg/
day,
and
the
magnitude
of
the
decrease
[
32%]
is
considered
to
be
evidence
of
maternal
toxicity.
Therefore,
the
NOAEL
51
for
maternal
toxicity
has
been
changed
to
2.5
mg/
kg/
day,
and
the
LOAEL
for
maternal
toxicity
is
25
mg/
kg/
day.
The
developmental
NOAEL
was
2.5
mg/
kg/
day
based
on
increase
incidences
of
incompletely
ossified
parietals,
interparietals
and
unossified
hyoids
at
25
mg/
kg/
day
(
LOAEL).
Therefore,
developmental
toxicity
and
maternal
toxicity
occurred
at
the
same
dose
level
[
25
mg/
kg/
day],
and
there
is
no
apparent
increased
quantitative
susceptibility
following
DACT
exposure
in
this
study.
Additionally,
it
was
determined
that
a
2­
generation
reproduction
study
on
DACT
is
not
required.

Degree
of
Concern
Analysis
and
Residual
Uncertainties
Since
there
is
evidence
of
increased
susceptibility
of
the
young
following
exposure
to
Atrazine
in
the
rabbit
developmental
study
and
in
several
special
studies
conducted
to
evaluate
endocrine
effects,
HIARC
performed
a
Degree
of
Concern
Analysis
to:
1)
determine
the
level
of
concern
for
the
effects
observed
when
considered
in
the
context
of
all
available
toxicity
data;
and
2)
identify
any
residual
concerns
after
establishing
toxicity
endpoints
and
traditional
uncertainty
factors
to
be
used
in
the
risk
assessment
of
this
chemical.
If
residual
concerns
are
identified,
HIARC
examines
whether
these
residual
concerns
can
be
addressed
by
a
special
FQPA
safety
factor
and,
if
so,
the
size
of
the
factor
needed.
The
results
of
the
HIARC
Degree
of
Concern
analyses
for
Atrazine
(
and
DACT)
follow.

Prenatal
Developmental
Study
with
Atrazine
in
Rabbits
The
HIARC
concluded
that
there
is
low
concern
for
the
qualitative
increased
susceptibility
(
increased
fetal
resorptions
at
a
dose
level
that
resulted
in
decreased
body­
weight
gain
and
clinical
signs
in
the
maternal
animal)
because:
1)
the
NOAELs
in
the
study
are
well
characterized;
and
2.)
the
fetal
effects
seen
occurred
at
a
high
dose
level
(
75
mg/
kg/
day).

The
HIARC
also
concluded
that
there
are
no
residual
concerns
for
these
effects
considering
that
the
Acute
RfD
established
for
Atrazine/
DACT
is
based
on
a
NOAEL
of
10
mg/
kg
which
is
protective
of
the
fetal
effects
observed
at
75
mg/
kg/
day
in
the
developmental
rabbit
study."

It
is
fair
to
say
that
this
distinction
between
quantitative
and
qualitative
sensitivity
could
have
been
made
clearer
and
captured
more
fully
in
the
risk
assessment.
It
is
reasonable
to
say
that
all
aspects
of
atrazine's
toxicity
have
neither
been
fully
studied
nor
understood.
However,
these
residual
uncertainties
surrounding
atrazine's
toxic
effects
on
development
and
reproductive
consequences
for
the
young
were
clearly
considered
and
ultimately
formed
the
basis
for
52
maintaining
the
full
10X
FQPA
SF
along
with
residual
uncertainties
regarding
exposure.

The
portions
of
the
comment
referring
to
the
endocrine
effects
in
frogs
has
not
been
fully
explored
at
this
time
as
those
results
were
just
emerging
at
the
time
of
the
atrazine
public
technical
briefing.
HED
must
defer
to
the
Environmental
Fate
and
Effects
Division
(
EFED)
as
to
the
validity
of
these
emerging
findings.
EPA
expects
to
convene
a
Scientific
Advisory
Panel
in
the
Summer
2003
to
discuss
the
frog
issue.

Comment
Pesticides
in
general,
and
atrazine
in
particular
occur
widely
in
surface
and
drinking
water.
The
risk
assessment
fails
to
include
an
analysis
of
the
aggregate
risk
posed
by
atrazine
and
its
metabolites,
as
well
as
an
analysis
of
multiple
pesticides
in
drinking
water.
The
human
health
risk
assessment
does
not
adequately
consider
exposures
to
atrazine
through
drinking
water
and
air.

HED
Response
HED
agrees
with
the
case
made
by
the
NYSAGO
that
atrazine
contamination
in
US
surface
waters
is
widespread
as
seen
from
the
USGS'
variety
of
databases
on
water
quality.
Atrazine
is
present
in
surface
waters
in
the
US
typically
at
low
levels
between
0.1
and
1
ppb.
However,
the
kinds
of
data
collected
by
the
USGS
to
determine
the
quality
of
US
waters,
i.
e.,
raw
water
in
streams,
lakes,
creeks,
rivers,
ditches
is
applicable
to
ecological
risk
assessments
rather
than
risk
assessments
for
human
health.
These
data
do
not
represent
pesticide
concentrations
in
raw
water
at
intake
points
into
drinking
water
facilities
but
may
be
miles
upstream,
and
consequently
do
not
reflect
the
influence
of
dilution,
treatment,
and
distribution
effects
within
the
treatment
facility
that
all
may
affect
pesticide
concentrations
in
finished
drinking
water.
These
data
were
used
appropriately
by
OPP
in
the
ecological
risk
assessment,
but
should
not
be
used
in
human
health
assessments.
OPP's
human
health
risk
assessments
are
necessarily
health­
based,
quantitative,
and
linked
to
a
toxic
endpoint
for
health
effects
rather
than
qualitative
and
based
on
general
occurrence
information.

OPP's
human
health
risk
assessment
was
based
on
finished
drinking
water
from
a
variety
of
sources
including
compliance
monitoring
under
the
SDWA
and
more
intensive
monitoring
programs
of
drinking
water
in
CWS
in
areas
with
known
high
use
of
and
exposures
to
atrazine.
The
data
used
reflect
a
database
biased
towards
CWS
with
atrazine
exposure.
The
exposure
assessment
considered
each
of
~
4000
CWS
using
surface
water
with
data
on
atrazine
serving
55
million
+
people
and
representing
~
40%
of
all
CWS
in
the
US
using
surface
water,
and
is
believed
to
reflect
all
CWS
reporting
data
on
atrazine.
Data
on
418
CWS
using
groundwater
(
50%
of
which
were
the
CWS
using
groundwater
with
prior
detections
of
atrazine
reported
under
the
SDWA)
representing
14,115
CWSs
serving
20.5
million
people
were
assessed.
In
addition
to
53
these
data
sets,
2
programs
of
intensive
monitoring
in
CWS
using
surface
water
were
used
to
estimate
90­
day
average
exposures.
One
program
included
~
100
CWS
and
the
other
~
175
CWS.
These
CWS
are
believed
to
contain
CWS
with
exposures
to
atrazine
and
the
chlorinated
metabolites
that
represent
high­
end
exposures.
Although
incomplete,
these
data
sets
represent
the
most
robust
data
set
for
a
pesticide
in
finished
drinking
water.
OPP
intentionally
conducted
a
drinking
water
assessment
using
targeted
monitoring
data
CWS
by
CWS
in
the
interest
of
identifying
specific
CWS
at
risk.
Although
it
is
unlikely
that
all
CWS
with
high
atrazine
exposures
were
identified,
this
assessment
is
believed
to
highlight
not
the
entire
extent
of
exposure
but
the
likely
high­
end
of
exposures.
The
OW
is
currently
assessing
the
extent
of
these
high­
end
exposures.

HED
agrees
that
the
metabolites
are
formed
and
exposures
to
them
must
be
included
in
the
risk
assessments.
However,
HED
disagrees
with
the
statement
that
the
risk
assessment
fails
to
include
aggregate
exposures
to
atrazine
and
its
metabolites.
The
human
health
risk
assessment
for
atrazine
included
estimates
of
exposures
to
atrazine,
desethyl
atrazine
(
DEA),
des
isopropyl
atrazine
(
DIA),
and
diaminochlorotriazine
(
DACT)
in
food
and
drinking
water.
These
four
compounds
are
considered
to
have
a
common
mechanism
of
toxicity
and
believed
to
have
equivalent
toxicity
to
the
parent
compound.
A
separate
assessment
for
the
hydroxy
metabolites
was
also
included
in
the
risk
assessment
Exposure
to
the
hydroxy
metabolites
were
not
aggregated
with
the
exposure
to
atrazine
and
the
chlorinated
metabolites,
as
the
hydroxy
compounds
are
not
believed
to
share
a
common
mechanism
of
toxicity
with
the
chlorotriazine
compounds.

Concern
was
expressed
that
the
real
exposure
to
humans
in
the
diet
cannot
be
ignored.
The
details
of
the
dietary
assessments
for
atrazine
and
the
chlorinated
metabolites,
as
well
as,
the
hydroxy
atrazine
dietary
assessment
showing
that
dietary
(
food)
exposures
to
chlorotriazines
and
hydroxy
metabolites
are
insignificant
(<
1%
of
the
a
PAD
and
cPADs)
can
be
found
at
the
following
URL:
http://
www.
epa.
gov/
oppsrrd1/
reregistration/
atrazine/
antici_
residues.
pdf.

The
comment
expresses
concern
that
the
risk
assessment
did
not
include
atmospheric
deposition
contributions
to
exposure
or
multiple
pesticide
exposures
in
the
risk
assessment.
Because
HED
used
monitoring
data
for
surface
water,
the
contribution
of
atrazine
to
water
supplies
as
deposited
by
atmospheric
transport
and
rain
is
captured,
i.
e.,
is
inherent
in
the
database.
There
was
no
need
to
estimate
this
contribution
from
drift
with
computer
models,
etc.
Any
contribution
to
the
dietary
exposure
from
rainwater
is
also
reflected
in
the
monitoring
data
used
to
assess
dietary
exposures.
For
a
further
discussion
of
atrazine
in
rain
water
and
fog
and
multiple
pesticides
see
HED
Response
to
Dr.
John
Wargo
on
these
issues
on
pp.
48
­
49.
As
to
the
chemical
mixtures
issue,
HED
acknowledges
that
pesticides
co­
occur,
but
OPP
has
no
54
statutory
authority
to
regulate
or
methodology
to
assess
risks
associated
with
chemical
mixtures
not
based
on
a
common
mechanism
of
toxicity.
OPP
will
conduct
a
risk
assessment
in
the
future
for
triazines
with
a
common
mechanism
of
toxicity.

Comment
The
human
health
risk
assessment
improperly
applies
a
3­
fold
uncertainty
factor
under
the
FQPA
for
residential
exposures.
The
use
of
a
3­
fold
safety
factor
for
residential
exposures
is
wholly
unjustified
given
the
uncertainties
associated
with
exposure.

HED
Response
The
following
excerpt
is
from
the
FQPA
SFC
memorandum
dated
April
8,
2002.

"
The
FQPA
Safety
Factor
Committee
concluded
that
an
additional
Special
FQPA
safety
factor
of
3X
is
adequate
for
assessing
residential
exposures
to
Atrazine
/
DACT
because
the
concerns
for
drinking
water
(
described
above)
would
have
little
or
no
impact
on
the
residential
exposure
scenarios.
The
concerns
for
the
effect
of
the
neuroendocrine
mode
of
action
on
the
development
of
the
young
remain
and
the
Committee
concluded
that
there
are
reliable
data
to
address
these
concerns
through
use
of
an
additional
Special
FQPA
Safety
Factor
of
3X
(
Refer
to
Section
I.
3.
B
for
the
rationale
that
this
factor
would
be
adequate
to
account
for
these
hazard­
based
residual
uncertainties)."

In
considering
residential
exposures
under
FQPA,
the
SFC
determined
that
although
there
are
residual
hazard­
based
uncertainties
for
atrazine
that
apply
to
the
young,
residual
concerns
for
exposure
uncertainties
would
be
adequately
covered
by
the
3X
SF
for
hazard­
based
concerns
because
of
the
conservative
assumptions
used
to
estimate
children's
residential
exposure.
These
assumptions
are
based
on
the
OPP's
Standard
Operating
Procedures
for
Residential
Exposure
(
revised
2001),
and
can
be
reviewed
in
HED's
occupational
residential
exposure
chapter
for
the
reregistration
eligibility
decision.

The
risk
estimates
for
residential
exposures
are
considered
to
be
conservative.
A
variety
of
data
were
used
to
estimate
exposures,
some
of
it
chemical­
specific
for
atrazine.
Residential
handler
exposure
and
risk
estimates
were
conducted
using
two
sets
of
surrogate
chemical
data:
the
Occupational
and
Residential
Exposure
Task
Force
(
ORETF)
study
data
and
the
Residential
Standard
Operating
Procedures
(
SOPs).
Generally,
the
Residential
SOP
data
(
default
assumptions)
are
more
conservative
than
ORETF
data.
Both
data
sets
show
wide
variations
in
exposure
depending
on
individual
behaviors.
Dermal
postapplication
exposures
to
atrazine
were
based
on
the
higher
average
daily
residues
from
the
chemical­
specific
turf
transferable
residues
(
TTR)
study
data,
but
also
used
standard
assumptions
for
transfer
coefficients.
Oral
ingestion
55
scenarios
for
liquid
formulations
are
based
on
standard
assumptions
and
formulae
(
Residential
SOPs)
which
are
designed
to
be
screening
level.
Oral
ingestion
scenarios
for
hand­
to­
mouth
exposures
from
granular
formulations
are
based
on
a
chemical­
specific
study
designed
to
determine
the
residue
and/
or
granules
adhering
to
a
wet
hand
after
being
repeatedly
pressed
onto
turf
treated
with
a
granular
formulation
and
are
considered
more
refined.
The
risk
estimates
for
children's
residential
exposures
inclusive
of
a
3X
hazard­
based
FQPA
SF
are
considered
adequately
protective.

Environment
and
Human
Health,
Inc.
(
Dr.
John
Wargo):

Comment
Dr.
Wargo
recommends
that
atrazine
be
cancelled
based
on
the
following
points.
The
burden
of
proof
should
be
shifted
to
the
registrants
to
show
the
absence
of
hormonal
effects
especially
in
early
life.
Millions
of
Americans
are
routinely
exposed
to
atrazine
without
their
knowledge
or
consent.
EPA
has
no
capacity
to
continue
registration
while
preventing
human
exposure.
The
Agency
has
not
demonstrated
that
there
is
a
reasonable
certainty
of
no
harm
to
children
from
atrazine
exposure.
EPA
is
only
now
beginning
a
cumulative
assessment
to
include
other
triazines
found
to
have
a
common
mechanism
of
toxicity.
Why
should
the
public
bear
the
burden
of
water
testing
and
filtraiton?
The
registrant
should.

HED
Response
The
evidence
that
atrazine
disrupts
normal
endocrine
function
is
clear.
Atrazine's
documented
neuroendocrine
effects
have
become
the
main
mechanism
of
toxicity,
replacing
the
previous
emphasis
on
carcinogenicity.
Indeed,
all
of
the
toxic
endpoints
used
in
the
atrazine
human
health
risk
assessment
are
based
on
this
mechanism
of
toxicity.
The
registrant
has
devoted
time
and
effort
to
researching
the
toxic
mode
of
action
in
Sprague­
Dawley
rats
leading
to
early
onset
of
mammary
adenomas
and
carcinomas.
It
has
been
suggested
that
the
registrant
conduct
special
studies
to
assess
the
endocrine
effects
of
atrazine
on
early
life
and
development.

Dr.
Wargo
comments
that
contamination
and
exposure
to
atrazine
is
widespread.
HED
agrees
that
atrazine
is
commonly
found
in
water
in
USGS
surveys
and
is
relatively
ubiquitous
in
streams,
creeks,
rivers,
and
lakes
located
in
atrazine
use
areas.
However,
OPP
does
not
base
risk
assessments
on
the
kinds
of
data
routinely
collected
by
the
USGS
because
it
is
not
indicative
of
human
exposure
through
drinking
water.
Although
filtration
typically
used
by
community
water
systems
(
CWS)
does
not
remove
atrazine,
raw
water
samples
collected
by
USGS
do
not
reflect
treatment
effects
that
do
impact
atrazine
concentrations,
i.
e.,
activated
carbon,
nor
do
they
reflect
the
effects
of
dilution
and
distribution
systems
at
CWS.
As
mentioned,
available
drinking
water
monitoring
data
used
in
the
risk
assessment
are
limited,
but
are
more
reliable
to
estimate
human
56
exposures
than
available
ambient
water
quality
monitoring
data.

HED
also
agrees
with
the
comment
that
people
are
routinely
exposed
to
atrazine
without
their
consent
and
knowledge.
However,
this
can
be
said
of
pesticides
in
general
as
they
are
detected
in
foods
that
we
eat
as
seen
through
the
USDA's
Pesticide
Data
Program
(
PDP).
In
risk
assessment,
the
key
point
is
whether
or
not
the
levels
of
pesticides
to
which
people
are
exposed
result
in
hazardous
impacts
on
their
health.
OPP's
risk
assessments
are
quantitative
and
are
based
on
No
Observed
Adverse
Effects
Levels
(
NOAELs)
of
toxic
endpoints
modified
by
uncertainty/
safety
factors
that
are
compared
to
estimates
of
exposures.
OPP
does
not
base
its
risk
assessments
on
zero
exposure
as
the
comment
seems
to
suggest
it
should.

HED's
risk
assessments
for
aggregate
exposures
of
children
to
atrazine
and
its
chlorinated
degradates,
as
well
as,
hydroxy
atrazine
compounds
indicate
that
although
exposures
through
food
are
minimal
(
insignificant),
exposures
via
certain
lawn
use
products
and
in
specific
CWS
are
above
levels
of
concern.
That
is,
in
general,
OPP
could
not
demonstrate
reasonable
certainty
of
no
harm
for
certain
lawn
uses
of
atrazine
products.
However,
the
converse
is
suggested
for
drinking
water
exposures,
i.
e.,
in
general
OPP
could
demonstrate
reasonable
certainty
of
no
harm
for
drinking
water
exposures
except
in
specific
CWS.
Although
the
rigor
of
this
finding
is
subject
to
limitations
and
uncertainties
in
the
database,
these
residual
concerns
about
uncertainty
in
the
exposure
database
were
taken
into
account
in
applying
the
10X
FQPA
safety
factor
to
the
drinking
water
assessments.

However,
for
those
specific
CWS
undergoing
or
preparing
to
undergo
intensive
monitoring,
residual
uncertainties
regarding
the
extent
and
magnitude
of
exposure
to
chlorotriazines
have
been
removed,
therefore
supporting
a
reduction
in
the
FQPA
safety
factor
to
3X.
Based
on
the
availability
of
reliable
drinking
water
exposure
data,
HED
has
recalculated
the
DWLOC
(
drinking
water
level
of
concern)
using
a
total
risk
assessment
300­
fold
uncertainty
factor
for
those
CWS
currently
undergoing
or
targeted
for
future
intensive
monitoring.
For
these
CWS,
the
DWLOC
for
a
90­
day
average
exposure
becomes
37.5
ppb
for
total
chlorotriazines.
This
value
is
based
on
an
endpoint
of
1.8
mg/
kg/
day,
and
a
300­
fold
uncertainty
factor
reflecting
a
10­
fold
factor
for
interspecies
variation,
a
10­
fold
factor
for
intraspecies
variability,
and
a
3­
fold
safety
factor.
The
3­
fold
safety
factor
reflects
residual
uncertainties
associated
with
atrazine's
toxic
effects
on
the
developing
child
only.
For
CWS
without
intensive
monitoring
as
described
above,
the
screening
level
DWLOC
remains
12.5
ppb
for
total
chlorotriazines.

In
short,
for
those
CWS
with
intensive
monitoring,
such
that
sufficient
accuracy
in
the
exposure
assessments
could
be
achieved,
the
portion
of
the
FQPA
safety
factor
reflecting
residual
uncertainties
in
the
drinking
water
exposure
database
could
be
removed.
Short
of
cancellation,
57
OPP
does
have
options
to
mitigate
these
specific
residential
uses
that
are
of
concern
for
children,
and
to
mitigate
impacts
of
atrazine
on
drinking
water
in
general
via
rate
reductions,
and
on
CWS
in
specific
via
rate
reductions,
and
local
restrictions
on
use
followed
up
by
intensive
monitoring.

As
noted,
the
cumulative
assessment
for
the
triazines
has
not
been
completed.
Aggregate
risk
assessments
for
simazine
and
propazine
are
required
first.

Comment
Dr.
Wargo
brings
up
additional
points
regarding
widespread
atrazine
contamination
of
water.

HED
Response
Regarding
atrazine's
use,
OPP
is
aware
of
the
large
volume
of
atrazine
use
in
the
US
and
the
resultant
impact
of
atrazine
on
the
nation's
water
supplies.
OPP
recognizes
that
part
of
any
mitigation
proposal
should
emphasize
reducing
this
environmental
loading.
HED
is
also
aware
that
countries
in
Europe
have
banned
atrazine
because
of
widespread
occurrence
at
greater
than
0.1
ppb.
These
bans
are
not
based
however
on
risk
assessments
but
are
related
to
policies
in
those
countries.

Comment
Dr.
Wargo
brings
up
additional
points
regarding
atrazine's
widespread
contamination
of
water,
averaging
obscures
peak
concentrations,
and
degradates
that
are
unregulated.

HED
Response
HED
agrees
that
the
current
monitoring
scheme
under
the
SDWA
obscures
peaks
of
atrazine
that
may
be
occurring
seasonally.
To
address
this
issue,
HED
has
based
its
drinking
water
risk
assessment
on
intermediate­
term
exposures
to
90­
day
average
concentrations
of
atrazine
and
the
chlorinated
degradates
rather
than
annual
average
concentrations.
This
assessment
shows
that
seasonal
peaks
occur
and
are
of
greater
concern
for
atrazine
exposures
than
annual
average
exposures.
HED
defers
to
the
Office
of
Water
on
the
unregulated
degradates
comment.

Comment
Dr.
Wargo
brings
up
additional
points
regarding
exposures
to
atrazine
is
in
fog
and
rainwater.

HED
Response
The
comment
expresses
concern
that
the
risk
assessment
did
not
include
exposure
to
atrazine
through
fog
and
atmospheric
deposition.
Because
HED
used
monitoring
data
for
surface
water
to
assess
drinking
water
exposures,
the
contribution
of
atrazine
to
water
supplies
as
deposited
by
atmospheric
transport
and
rain
is
captured,
i.
e.,
is
inherent
in
the
database.
There
was
no
need
to
3
Cooter,
EJ,
and
WT
Hutzell,
USEPA,
National
Exposure
Research
Laboratory,"
A
Regional
Atmospheric
Fate
and
Transport
Model
for
Atrazine.
1.
Development
and
Implementation",
Environmental
Science
and
Technology
,
Vol.
36,
No.
19,
2002.

4
Cooter,
EJ,
and
WT
Hutzell,
USEPA,
National
Exposure
Research
Laboratory,"
A
Regional
Atmospheric
Fate
and
Transport
Model
for
Atrazine.
1.
Development
and
Implementation",
Environmental
Science
and
Technology
,
Vol.
36,
No.
19,
2002.

58
estimate
this
contribution
from
drift
with
computer
models,
etc.
Any
contribution
to
the
dietary
exposure
from
rainwater
is
also
reflected
in
the
monitoring
data
used
to
assess
dietary
exposures.
Based
on
the
data
available,
dietary
exposure
estimates
ranged
up
to
0.000017
mg/
kg/
day
for
food
and
up
to
0.012
mg/
kg/
day
for
drinking
water.
The
highest
exposure
estimates
for
food
are
approximately
twice
the
maximum
exposure
estimate
for
air/
fog
concentrations
of
atrazine,
and
drinking
water
exposures
are
at
least
3
orders
of
magnitude
higher
than
food
or
air/
fog
exposures.
Published
literature
indicates
that
atrazine
has
been
detected
and
modeled
in
the
atmosphere
(
air/
fog)
ranging
from
10­
9
up
to
0.00001
mg/
kg/
day
3.

Although
relative
to
drinking
water
and
residential
dermal
exposures,
exposures
to
atrazine
through
fog
are
expected
to
be
minimal
and
not
contribute
significantly
to
risk,
HED
did
consider
inhalation
of
atrazine
in
its
aggregate
exposure
assessments.
These
assessments
consider
inhalation
exposure
to
the
actual
liquid
and
granular
products
containing
atrazine
as
applied
by
the
homeowner,
which
is
expected
to
be
in
a
much
more
concentrated
form
than
atrazine
dissolved
in
fog
after
being
diffused
and
dissipated
in
the
environment.
HED
estimates
show
that
dermal
exposures
are
greater
than
inhalation
exposures
for
atrazine.
Dermal
exposures
from
use
of
atrazine
products
in
and
around
the
home
are
estimated
to
be
1.6
to
0.0034
mg/
kg/
day.
Inhalation
exposures
for
atrazine
are
estimated
to
be
0.00089
to
0.00001
mg/
kg/
day
(
1
to
5
orders
of
magnitude
lower
than
dermal
exposures).
Published
literature
indicates
that
atrazine
has
been
detected
and
modeled
in
the
atmosphere
(
air/
fog)
ranging
from
10­
9
up
to
0.00001
mg/
kg/
day
4.
The
maximum
exposure
estimate
is
for
locations
within
200
km
of
the
point
of
application.
These
estimated
exposures
are
5
to
9
orders
of
magnitude
lower
than
the
maximum
estimated
dermal
exposures
and
at
most
equal
to
the
lowest
estimated
inhalation
exposures
for
homeowners
handling
concentrated
liquid
or
granular
atrazine
products
as
well
as
several
orders
of
magnitude
less
than
drinking
water
exposures.

Therefore,
HED
expects
inhalation
exposure
through
fog
to
be
insignificant
relative
to
drinking
water,
dermal
and
inhalation
exposures
from
handling
liquid
atrazine
products,
which
have
been
included
in
the
risk
assessment.
Given
the
conservative
assumptions
resulting
in
high­
end
estimates
for
the
dermal
and
inhalation
exposures
used
in
the
aggregate
risk
assessments,
and
the
belief
that
exposure
to
atrazine
through
fog
will
be
insignificant
in
comparison,
HED
believes
any
59
potential
exposures
through
fog
have
been
adequately
covered.
Finally,
HED
believes
that
the
1000­
fold
uncertainty
factor
used
for
dietary
exposure
and
the
300­
fold
uncertainty
factor
used
for
residential
exposure
used
in
conjunction
with
the
conservative
assumptions
regarding
residential
exposure
used
in
the
atrazine
human
health
risk
assessment
is
adequately
protective
of
aggregate
exposures
to
atrazine.

Comment
Dr.
Wargo
brings
up
additional
points
regarding
atrazine
in
breast
milk
and
fetal
exposure.

HED
Response
Dr.
Wargo
expresses
concern
that
atrazine
may
be
transferred
through
breast
milk
and
that
this
has
not
been
considered
in
the
risk
assessment.
However,
HED
points
out
that
the
human
health
risk
assessment
did
consider
both
exposure
and
toxic
effects
associated
with
1)
the
transfer
of
atrazine
residues
through
milk
via
lactation,
and
2)
fetal
exposures.
The
acute
dietary
risk
assessment
for
food
and
drinking
water
is
based
on
several
developmental
effects
in
offsrping
and
fetuses.
One
of
these
studies
focused
on
the
effects
of
exposure
of
the
mother
to
atrazine
on
her
suckling
pups
through
lactation.
This
study
showed
prostatitis
effects
in
the
male
pups
exposed
to
atrazine
through
the
mother's
milk.
The
acute
PAD
is
0.01
mg/
kg/
day.
This
endpoint
in
conjunction
with
other
developmental
endpoints
relevant
to
fetal
effects
formed
the
basis
of
the
acute
reference
dose.
The
acute
reference
dose
was
determined
through
a
weight­
of­
the­
evidence
analysis
of
three
developmental
studies
and
this
fourth
study
on
exposure
through
lactation.
HED's
intermediate­
term
and
chronic
risk
assessments
are
based
on
an
endpoint
more
than
5
times
lower
than
the
acute
PAD
or
0.0018
mg/
kg/
day.
HED
did
not
attempt
to
measure
human
breast
milk
for
atrazine,
but
used
instead
used
available
information
from
animal
feeding
studies
to
estimate
exposure.
Since
animals
receive
more
atrazine
in
their
diets
than
humans,
this
estimate
of
exposure
through
animal
milk
included
in
the
dietary
assessments
should
be
conservative
and
protective
of
this
type
of
exposure.
HED
therefore
contends
that
not
only
exposure
to
atrazine
through
breast
milk
has
been
considered,
but
that
relevant
toxic
endpoints
regarding
offspring
and
fetal
effects
have
also
been
included
in
the
human
health
risk
assessments.

Comment
Dr.
Wargo
brings
up
additional
points
regarding
the
inadequacy
of
filtration
to
remove
atrazine
from
drinking
water,
and
environmental
justice
issues.

HED
Response
Dr.
Wargo
states
that
conventional
water
treatment
does
not
remove
atrazine,
but
that
atrazine
must
be
removed
by
powdered
activated
carbon
(
PAC).
This
means
the
wealthier
communities
60
will
treat
while
poor
ones
will
not.
HED
agrees
that
conventional
treatment
will
not
remove
atrazine
and
that
PAC
is
required.
As
to
the
issue
relating
to
the
benefits
of
PAC
only
going
to
wealthier
communities,
HED
must
defer
to
the
Office
of
Environmental
Justice
(
OEJ).

Comment
Dr.
Wargo
expresses
concern
that
the
PLEX
database
is
registrant
generated
and
that
the
data
are
limited
because
too
few
samples
are
taken
per
year
for
a
given
community
water
system.
This
database
will
underestimate
high
seasonal
exposures.

HED
Response
HED
agrees
that
there
are
limitations
in
the
database
used
to
estimate
drinking
water
exposures.
However,
although
the
data
in
the
PLEX
database
were
complied
by
the
registrant,
these
data
were
not
generated
by
the
registrant
as
the
comment
states.
These
data
are
in
fact
generated
under
the
SDWA;
they
are
compliance
monitoring
data.
The
registrant
organized,
collected,
and
compiled
these
data
by
going
to
the
individual
CWS
operators.
HED
agrees
that
some
CWS
with
monitoring
data
under
the
SDWA
may
have
been
missed
out
of
PLEX
contributing
to
uncertainties
in
the
exposure
database.
HED
agrees
that
sampling
under
the
SDWA
is
too
infrequent
to
capture
short­
term
peaks,
like
seasonal
pulses,
of
atrazine.
Because
of
just
these
residual
the
uncertainties
regarding
the
drinking
water
exposure
database,
along
with
residual
uncertainties
regarding
developmental
toxicity,
HED
determined
that
the
full
10X
FQPA
safety
factor
should
be
applied
to
dietary
risk
assessments.
As
to
increasing
the
frequency
of
compliance
monitoring
under
the
SDWA,
HED
must
defer
to
OW
on
this
issue.

Comment
Dr.
Wargo
brings
up
additional
points
regarding
health
effects
at
high
doses
including
mammary
tumors
resulting
from
lifetime
exposures.

HED
Response
HED
agrees
that
atrazine
at
high
doses
has
been
associated
with
a
variety
of
health
consequences
in
test
animals,
some
but
not
all
being
relevant
to
humans.
HED
believes
that
the
most
important/
dominant
health
consequences
known
to
date
have
been
reflected
in
the
human
health
risk
assessment.

Comment
Dr.
Wargo
states
that
the
risk
assessment
document
concludes
that
the
atrazine
toxicity
database
is
complete,
in
spite
of
a
lack
of
acute,
sub
chronic,
and
DNT
studies.
61
HED
Response
The
HIARC
document
dated
April
5,
2002
states
that
the
toxicity
database
for
atrazine
is
complete
and
adequate
to
evaluate
potential
adverse
health
consequences
to
infants
and
children
under
FQPA.
Atrazine
has
one
of
the
most
extensive
databases
of
any
pesticide.
The
toxicity
database
is
complete
as
per
OPPTS
Guideline
requirements
for
atrazine.
The
DNT
is
not
a
guideline
study,
and
the
DNT
is
not
appropriate
to
assess
pituitary/
endocrine
function
effects.
For
this
reason,
a
DNT
study
has
not
been
required.
Similarly,
acute
and
sub
chronic
neurotoxicity
studies
were
not
required
for
atrazine
because
the
kinds
of
effects
these
studies
test
for
(
functional
battery
tests)
are
not
expected
for
atrazine.
Rather,
the
HIARC
recommended
special
studies
designed
to
examine
atrazne's
specific
neuroendocrine
mode
of
action
as
more
useful.

Comment
Dr.
Wargo
expresses
concerns
regarding
atrazine's
effects
on
growth
and
development,
and
its
potential
as
a
carcinogen.
He
cites
previously
reviewed
epidemiology
studies
and
a
case
study
in
Louisiana
at
an
atrazine
manufacturing
plant
as
evidence
for
continued
concern
regarding
atrazine's
carcinogenic
potential.
He
notes
the
many
alarming
hormonal
effects
of
atrazine,
particularly
for
children.

HED
Response
HED
shares
Dr.
Wargo's
concern
for
atrazine's
effects
on
development
and
growth
in
the
young.
The
risk
assessment
is
based
on
toxic
endpoints
that
are
all
related
to
either
developmental
or
reproductive
effects
in
keeping
with
atrazine's
main
mode
of
toxic
action,
i.
e,
neuroendocrine
effects.
Based
on
this
concern,
HED's
HIARC
and
FQPA
committees
determined
that
a
10X
safety
factor
for
children
was
warranted
based
in
part
on
residual
uncertainties
regarding
atrazine's
effects
on
growth
and
development
along
with
uncertainties
in
the
exposure
database.
On
this
point
the
HIARC
concluded...

"
Since
the
focus
of
the
testing
with
Atrazine
in
the
young
rat
has
been
limited
to
short
periods
of
dosing
to
specific
developmental
periods,
uncertainties
are
raised
for
susceptibility
during
earlier
developmental
periods
as
well
as
for
consequences
of
earlier
developmental
exposure
with
longer
duration
of
dosing
throughout
development.
The
effects
of
neurotransmitters/
peptides
(
known
to
be
critical
for
normal
development
and
which
could
potentially
translate
into
severe
effects
in
children
that
may
not
be
manifested
until
later
in
life)
have
not
been
fully
characterized.
And
as
the
FIFRA
Scientific
Advisory
Panel
noted,
there
are
concerns
for
behavioral
effects
in
the
young
resulting
from
Atrazine's
CNS
mode
of
action
and
the
dose
level
at
which
these
effects
might
occur
5SAP
Report
No.
2000­
05;
Atrazine:
Hazard
and
Dose
Response
Assessment
and
Characterization.
"
Because
of
the
rapid
developmental
brain
changes...
the
influence
of
Atrazine
on
neurotransmitters
in
the
hypothalamus
and
on
GnRH
may
well
have
a
differential,
permanent
effect
on
children.
This
phenomenon
is
the
basis
of
the
relatively
new
field
of
behavioral
teratology.
Atrazine
could
influence
the
migration
of
cells
and
the
connectivity
of
the
CNS.
The
influence
of
Atrazine
on
the
hypothalamus
and
on
GnRH
may
have
a
differential
effect
on
children.
This
effect
could
be
latent,
and
emerge
later
during
the
challenge
of
puberty,
or
during
senescence.
Behavioral
alterations
may
be
the
most
sensitive
outcome.
This
possibility
should
be
addressed...."

62
compared
to
reproductive/
developmental
effects5."

Therefore,
HED
believes
its
risk
assessment,
which
incorporates
this
safety
factor,
is
protective
of
children.

Epidemiological
evidence
linking
atrazine
to
cancer
does
not
show
a
direct
causal
effect.
HED
cannot
quantitate
a
cancer
risk
in
the
absence
of
a
toxic
endpoint
linking
atrazine
exposure
directly
to
cancer.
Since
mammary
tumors
in
the
Sprague­
Dawley
rat
have
been
the
only
tumors
identified
in
association
with
atrazine
exposure
in
test
animals,
and
the
toxic
mechanism
leading
to
these
mammary
tumors
has
been
determined
not
to
be
operative
in
humans,
HED
has
no
toxic
endpoint
upon
which
to
base
a
cancer
assessment.
However,
the
National
Cancer
Institute
(
NCI)
is
currently
conducting
a
study
on
cancer
and
pesticide
exposures
among
the
agricultural
community
of
which
atrazine
is
a
part.
These
data
and
additional
information
on
the
incidence
of
prostate
cancer
at
a
Louisiana
atrazine
production
facility
were
requested
and
reviewed.
This
review
indicates
that
it
appears
that
most
of
the
increase
in
prostate
cancer
incidence
at
the
St.
Gabriel
plant
is
likely
due
to
intensive
prostate
specific
antigen
(
PSA)
screening
of
employees
conducted
as
part
of
the
company's
"
Wellness
Program."
The
study
was
insufficiently
large
and
has
limitations
that
prevent
ruling
out
atrazine
as
a
potential
contributor
to
the
increase
observed.
On
balance,
however,
a
role
for
atrazine
seems
unlikely
because
prostate
cancer
was
found
primarily
in
active
employees
who
received
intensive
PSA
screening;
there
was
no
increase
in
advanced
tumors
or
mortality;
and
proximity
to
atrazine
manufacturing
did
not
appear
to
be
correlated
with
risk.

Atrazine
has
also
been
tied
to
inflammation
of
the
prostate
in
laboratory
animals
and
changes
in
testosterone
levels
at
high
doses.
However,
neither
condition
has
been
tied
to
the
increased
risk
of
prostate
cancer
and
the
Agency
concludes
the
animal
data
do
not
provide
biologically
plausible
evidence
to
support
atrazine
as
a
cause
of
prostate
cancer.

Other
cancers
besides
prostate
were
found
to
have
an
elevated,
though
not
statistically
significant,
increase
in
risk
at
the
St.
Gabriel
plant.
Other
studies
have
suggested
an
increased
risk
for
ovarian,
breast,
and
other
cancers,
including
non­
Hodgkin's
lymphoma.
However,
these
63
studies
are
at
best
preliminary
and
should
not
serve
as
a
basis
for
implicating
atrazine
as
a
human
carcinogen
due
to
their
methodological
limitations.
See
the
IRED
for
further
discussion.

Comment
Dr.
Wargo
brings
up
the
triazine
common
mechanism
decision
and
the
chemical
mixture
issue
as
a
potential
problem
for
atrazine
as
USGS
studies
have
found
that
it
co­
occurs
with
other
pesticides.

HED
Response
HED
expects
to
begin
work
on
the
triazine
cumulative
risk
assessment
after
completing
work
on
the
aggregate
simazine
and
aggregate
propazine
risk
assessments.
Until
these
single
chemical
risk
assessments
are
completed,
HED
cannot
comment
on
the
outcome
of
the
cumulative
risk
assessment
for
the
triazine
common
mechanism
group.
As
to
the
chemical
mixtures
issue,
HED
acknowledges
that
pesticides
co­
occur,
but
OPP
has
no
statutory
authority
to
regulate
or
methodology
to
assess
risks
associated
with
chemical
mixtures
not
based
on
a
common
mechanism
of
toxicity.

Beyond
Pesticides/
NCAMP:

Comment
NCAMP
expresses
concern
that
atrazine
is
widespread
in
water
supplies
and
is
a
powerful
endocrine
disruptor.
It
cites
several
examples
of
endocrine
effects
in
wildlife
and
test
animals.
They
express
concern
for
mammary
tumors
in
rats
exposed
to
atrazine
and
cite
epidemiological
studies'
results
to
bolster
this
concern
including
the
prostate
cancer
study
at
the
St.
Gabriel
facility.
NCAMP
also
provides
mitigation
measures
for
atrazine
including:
strengthening
and
enforcing
the
drinking
water
standard,
banning
all
residential
uses,
and
switching
to
widely
available
alternatives.

HED
Response
HED
agrees
with
NCAMP
that
atrazine
is
an
endocrine
disruptor.
The
human
health
risk
assessment
has
been
based
entirely
on
developmental
and
reproductive
effects
believed
to
be
driven
by
a
neuroendocrine
mode
of
action
believed
to
common
to
atrazine,
its
chlorinated
degradates,
and
simazine
and
propazine.
However,
HED
must
defer
to
the
EFED
for
a
response
on
the
specific
wildlife
effects
noted.

The
mammary
tumors
in
the
female
Sprague­
Dawley
rat
have
been
attributed
to
atrazine's
ability
to
affect
the
neuroendocrine
system
in
the
rat.
However,
the
actual
mechanism
by
which
tumor
formation
occurs
was
determined
by
a
June
2000
SAP
to
be
"
unlikely
to
be
operative
in
64
humans".
Although
the
tumor
formation
in
the
rat
and
consequently
the
cancer
endpoint
are
no
longer
considered
relevant
to
human
health,
atrazine's
ability
to
alter
hypothalamic/
pituitary
function
in
test
animals
is
considered
to
be
relevant
to
humans,
and
consequently,
the
entire
human
health
risk
assessment
was
based
on
toxic
endpoints
reflecting
a
neuroendocrine
mode
of
action.

As
to
the
epidemiological
evidence
for
cancer
in
humans,
the
available
epidemiologic
data
on
atrazine
do
not
make
a
direct
causal
link
between
atrazine
and
cancer.
See
the
response
to
Dr.
Wargo
on
the
cancer
issue
on
p.
51
and
the
IRED
for
further
discussion.

By
way
of
history,
OPP
has
reviewed
the
many
epidemiological
studies
on
atrazine
cited
by
NCAMP.
These
studies
deal
with
various
cancers
of
the
ovary,
prostate,
colon,
breast,
leukemia,
non­
Hodgkin's
lymphoma.
The
results
of
these
reviews
can
be
found
in
their
entirety
in
the
following
memoranda:
"
Review
of
Atrazine
Incident
Reports",
DP
Barcode:
D270014,
"
Review
of
five
epidemiological
published
articles
for
SAP",
DP
Barcode:
D262405,
and
"
A
Follow­
up
Study
of
Mortality
Among
Workers
at
the
Novartis
St.
Gabriel
Plant
&
Follow­
up
Study
of
Cancer
Incidence
Among
Workers
in
Triazine­
Related
Operations
at
the
St.
Gabriel
Plant,
DP
Barcode:
D281568
&
D278933.
The
studies
reviewed
are:
IARC
Overall
Evaluation
of
Carcinogenicity
to
Humans,
"
A
Follow­
up
Study
of
Workers
at
the
Ciba­
Geigy
St.
Gabriel
Plant",
E.
Delzell,
et
al,
April
8,
1996,
"
Atrazine,
An
Epidemiological
Study
at
the
Schweizerhalle
Plant",
R.
Gass
et
al.,
January
15,
1993,
Ciba
Geigy
Herbicide
Mortality
Study,
"
Ovarian
Mesothelial
Tumors
and
Herbicides:
A
Case­
Control
Study",
Donna,
et
al.,
1984,
"
Triazine
Herbicides
and
Ovarian
Epithelial
Neoplasms,
Donna,
et
al.,
1989,
"
Agricultural
Herbicide
Use
and
Risk
of
Lymphoma
and
Soft­
Tissue
Sarcoma",
Hoar,
et
al.,
1986,
"
Pesticide
Exposures
and
Other
Agricultural
Risk
Factors
for
Leukemia
Among
Men
in
Iowa
and
Minnesota",
Brown,
et
al.,
1990,
"
Herbicides
and
Colon
Cancer,
Hoar,
et
al.,
1985,
"
A
Case­
Control
Study
of
Non­
Hodgkin's
Lymphoma
and
Agricultural
Factors
in
Eastern
Nebraska,
Zahm,
et
al.,
1988,
"
Farming
and
Non­
Hodgkin's
Lymphoma,
Cantor,
et
al.,
1985,
"
Role
of
the
Herbicide
Atrazine
in
the
Development
of
Non­
Hodgkin's
Lymphoma
",
Zahm,
et
al.,
1993,
"
Triazine
Herbicide
Exposure
and
Breast
Cancer
Incidence:
An
Ecological
Study
of
Kentucky
Counties",
Kettles,
et
al.,
1997,
and
"
Correlation
Analysis
of
Pesticide
use
Data
and
Cancer
Incidence
Rates
in
California
Counties",
Mills,
et
al.,
1998.

In
summary,
reviews
of
the
epidemiological
studies
dealing
with
prostate
cancers
and
exposure
to
atrazine
conclude
that
the
increases
in
prostate
cancers
among
workers
manufacturing
atrazine
are
attributable
to
the
increased
PSA
screening
conducted
at
the
plants
as
a
part
of
routine
checkups
at
the
plants,
and
could
not
be
conclusively
linked
to
atrazine
exposure.
The
reviews
of
studies
dealing
with
non­
Hodgkin's
lymphoma
(
NHL)
concluded
that
there
was
little
to
no
65
increase
in
the
risk
of
NHL
attributable
to
the
agricultural
use
of
atrazine
after
adjustment
for
the
use
of
other
pesticides,
specifically
2,4­
D
and
organophosphates.
Or
put
another
way,
there
is
little
evidence
that
atrazine
exposure
explains
any
appreciable
increase
in
NHL
over
the
last
15
years
in
the
US.
Reviews
of
studies
dealing
with
ovarian
cancers
conclude
that
definite
exposure
to
triazines
was
associated
with
a
2
to
3­
fold
increase
of
borderline
significance
in
the
risk
for
ovarian
cancer,
but
that
confirmatory
studies
were
needed
as
this
study
was
small
and
potentially
confounded
by
exposure
to
other
herbicides,
which
was
not
controlled
for
in
this
study.
Reviews
of
studies
for
leukemia
conclude
that
the
results
for
an
association
between
leukemia
and
atrazine
are
unremarkable.
Reviews
of
studies
on
breast
cancers
show
only
modest
increases
in
risk
that
are
in
the
same
range
as
non­
chemical
risk
factors
not
measured.
The
reviews
conclude
that
in
general,
epidemiological
studies
containing
information
on
atrazine
exposures
and
cancer
either
indicate
no
significant
increases
in
cancer
risk
that
is
directly
associated
with
atrazine
exposure,
or
raise
more
questions
than
they
answer.

OPP
concludes
that
"
the
results
of
the
human
epidemiology
studies
do
not
provide
clear
evidence
of
an
association
between
triazines
and
cancer.
Some
of
the
studies,
particularly
those
in
which
hormone­
responsive
cancers
such
as
breast,
ovary
and
prostate,
were
examined,
are
suggestive
of
a
possible
association.
There
is
also
suggestive
evidence
of
a
possible
association
of
triazine
exposure
and
NHL.
Further
epidemiologic
research
is
needed
­
especially
in
the
area
of
hormone­
responsive
cancers"
(
Final
Report
­
Atrazine:
Hazard
and
Dose­
Response
Assessment
and
Characterization,
Part
B­
Hazard
Assessment
and
Review
of
Available
Studies,
report
prepared
for
June
2000
SAP
or
www.
epa.
gov/
scipoly/
sap/
2000/
index.
htm#
June
27).

Regarding
strengthening
and
enforcing
the
atrazine
drinking
water
standard
in
general,
HED
must
defer
to
the
OW.
However,
HED
recognizes
that
atrazine
is
widespread
in
the
Midwest.
The
majority
of
community
water
systems
(
CWS)
with
risk
estimates
exceeding
levels
of
concern
are
located
in
the
Midwest.
As
to
the
CWS
identified
in
the
OPP
human
health
risk
assessment,
mitigation
to
reduce
the
impacts
of
atrazine
on
those
CWS
is
currently
being
discussed
and
will
be
negotiated
with
the
registrant
as
part
of
a
reregistration
eligibility
decision.
HED
agrees
that
residential
uses
of
atrazine
show
risk
estimates
of
concern
for
children,
particularly
for
children
playing
on
lawns
shortly
after
application
of
liquid
products.
Mitigation
for
those
uses
and
exposure
patterns
will
be
discussed
as
a
part
of
the
reregistration
eligibility
decision.

HED
must
defer
to
the
BEAD
regarding
the
availability
of
atrazine
alternatives.
66
People
for
the
Ethical
Treatment
of
Animals
(
PETA):

Comment
PETA,
believing
the
current
MCL
for
atrazine
is
based
on
the
rat
study
in
which
mammary
female
tumors
in
Sprague­
Dawley
rats
were
noted,
states
that
the
mode
of
action
behind
the
formation
of
these
tumors
is
"
not
relevant
to
humans
because
there
are
considerable
differences
between
the
hypothalmic­
pituitary
ovarian
functions
in
humans
and
rats".
Given
this
finding,
they
question
how
EPA
can
go
forward
with
animal
testing
under
the
endocrine
disruptor
screening
program
if
it
has
been
decided
that
these
tests
don't
apply
to
humans.

HED
Response
PETA
correctly
notes
that
the
tumors
associated
with
the
Sprague­
Dawley
rat
are
based
on
a
specific
toxic
mechanism
"
not
likely
to
be
operative
in
humans"
(
June
2000
SAP
report).
However,
the
same
SAP
noted
that
although
the
mechanism
resulting
in
mammary
tumor
formation
in
the
Sprague­
Dawley
rat
is
not
relevant
to
humans,
the
potential
for
atrazine
to
alter
the
function
of
the
hypothalamus/
pituitary
in
a
generic
neuroendocrine
mode
of
action
is.
To
complete
the
SAP's
thoughts
on
the
subject,
the
following
is
an
excerpt
from
the
human
health
risk
assessment
for
atrazine,

"
Atrazine
alters
hypothalamic
gonadotrophin
releasing
hormone
(
GnRH)
release
in
rats.

There
are
also
some
data
that
indicate
that
atrazine
diminishes
norepinephrine
in
the
rat
hypothalamus
as
an
initial
or
early
site
of
action
which
in
turn
leads
to
diminished
GnRH
release.
Atrazine
also
increases
dopamine
levels
which
can
result
in
a
diminished
pituitary
secretion
of
prolactin.
Therefore,
atrazine
appears
to
operate
at
the
level
of
the
hypothalamus.
In
both
humans
and
rats,
hypothalamic
GnRH
controls
pituitary
hormone
secretion
(
e.
g.,
luteinizing
hormone
(
LH),
and
prolactin
(
PRL).
The
hypothalamicpituitary
axis
is
involved
in
the
development
of
the
reproductive
system,
and
its
maintenance
and
functioning
in
adulthood.
Additionally,
reproductive
hormones
modulate
the
function
of
numerous
other
metabolic
processes
(
i.
e.,
bone
formation,
and
immune,
central
nervous
system
(
CNS)
and
cardiovascular
functions).
Therefore,
altered
hypothalamic­
pituitary
function
can
potentially
broadly
affect
an
individual's
functional
status
and
lead
to
a
variety
of
health
consequences.

The
report
of
the
Scientific
Advisory
Panel
(
SAP)
convened
in
June
2000
to
consider
these
health
consequences
of
exposure
to
atrazine,
indicated
that
"..
it
is
not
unreasonable
to
expect
that
atrazine
might
cause
adverse
effects
on
hypothalamic­
pituitary
function
in
humans."
Therefore,
atrazine's
effect
on
ovarian
cycling
and
the
pre­
ovulatory
LH
surge
(
as
well
as
its
effects
on
pregnancy,
puberty,
suckling
induced
PRL
release
which
leads
to
67
prostatitis)
are
viewed
as
neuroendocrinopathies
or
biomarkers
indicative
of
atrazine's
ability
to
alter
hypothalamic­
pituitary
function
in
general.
It
should
be
noted
that
atrazine's
neuroendocrine
effects
have
been
demonstrated
in
several
strains
of
rats
(
SD,
Long
Evans,
and
Wistar)."

Therefore,
PETA
incorrectly
interpreted
the
SAP
report
on
atrazine
in
assuming
that
endocrine
testing
results
will
not
be
extrapolated
to
humans.
In
fact,
the
opposite
is
the
case;
the
SAP
viewed
the
endocrine
effects
in
the
rats
as
indicative
of
potential
endocrine
effects
in
humans.
Consequently,
the
entire
human
health
risk
assessment
for
atrazine
is
based
on
developmental
and
reproductive
endpoints
seen
in
test
animals
believed
to
be
associated
with
the
neuroendocrine
effects
of
atrazine.

As
to
the
use
of
human
dermal
absorption
data
in
the
risk
assessment,
the
revised
risk
assessment
used
a
6%
dermal
absorption
factor
based
on
human
data.
The
revised
preliminary
risk
assessment
used
the
animal
data
modified
by
the
human
data.

California
Department
of
Pesticide
Regulation
(
CDPR):

Comment
California
Department
of
Pesticide
Regulation
(
CDPR)
comments
that
up­
regulation
of
aromatase
may
be
the
mechanism
involved
in
sub
chronic/
chronic
effects
seen
in
rat
studies
and
used
in
the
risk
assessment.
They
cite
endocrine
effects
in
amphibian
species
in
support
of
this
hypothesis.
They
also
state
that
sex
organ
effects
are
extremely
sensitive
to
reduced
food
intake
and
as
such,
in
the
Wistar
and
SD
rat,
reduced
organ
weight,
delayed
preputial
separation
and
delayed
puberty
cannot
be
considered
direct
effects
of
atrazine
dosing.
Their
value
for
risk
assessment
must
therefore
be
considered
dubious.
They
cite
a
study
involving
exposure
of
male
SD
rats
during
postnatal
days
22­
47,
in
which
the
average
body
weight
of
the
rats
at
100
mg/
kg/
day
was
reduced
by
about
9%.
The
authors
also
pair­
fed
a
group
and
found
that
even
mild
food
restriction
resulted
in
reductions
in
serum
testosterone
concentration,
weights
of
androgendependent
organs,
and
serum
LH
concentration;
the
same
deficits
that
were
seen
in
atrazine
rats.
They
concluded
that
the
effects
of
atrazine
on
male
reproductive
tract
in
rats
receiving
greater
than
50
mg/
kg/
day
could
not
be
distinguished
from
the
effects
of
reduced
food
consumption.
The
dose
levels
in
this
study
were
1,
2.5,
5,
10,
25,
50,
100,
and
200
mg/
kg/
day.

HED
Response
Regarding
aromatase,
HED's
response
on
page
17
is
reiterated
below.

The
SAP
was
asked
to
comment
on
whether
alternative
modes
of
action
(
re:
mammary
tumors)
68
have
been
sufficiently
discussed
and
ruled
out
by
the
Agency.
The
SAP
stated
"
There
are
no
data
that
would
suggest
other
plausible
modes
of
action.
The
increased
level
of
hormones
and
the
increased
level
of
hormones
alone,
can
account
for
the
increased
incidence
of
mammary
tumors
in
Sprague
Dawley
female
rats.
The
proposed
mode
of
action
is
plausible
and
each
step
in
the
pathway
has
been
shown
to
be
affected
in
atrazine
treated
rats.
None
of
the
effects
are
based
on
speculation.

Previously,
OPP
concluded
that
it
is
plausible
that
enhanced
aromatase
activity
may
have
some
influence
on
the
development
of
mammary
tumors
in
SD
female
rats.
However,
whether
or
not
enhanced
aromatase
activity
is
a
significant
contribution
to
the
carcinogenicity,
or
other
effects,
of
atrazine
remains
to
be
determined.
EPA
acknowledged
the
fact
that
an
increase
in
aromatase
activity
would
be
consistent
with
dose­
response
increases
in
estradiol
and
estrone
and
decreases
in
testicular
testosterone
noted
in
a
study
that
examined
the
effects
of
atrazine
on
pubertal
development.
The
doses
that
resulted
in
effects
on
these
hormones
were
well
above
doses
that
led
to
reproductive/
developmental
effects.
Additionally,
it
was
acknowledged
that
it
is
plausible
that
enhanced
aromatase
activity
may
have
some
influence
on
the
development
of
mammary
tumors
in
SD
female
rats;
however,
there
are
no
data
to
date
on
whether
enhanced
aromatase
activity
significantly
contributes
to
the
carcinogenicity
observed.
The
effect
of
the
chlorotriazines
on
aromatase
remains
an
active
research
issue,
in
general.

The
EPA's
National
Health
and
Environmental
Research
Laboratory
(
Dr.
Ralph
Cooper's
laboratory)
have
recently
evaluated
the
effects
of
atrazine
and
DACT
on
aromatase
activity
in
the
rat.
Preliminary
results
show
that
DACT
does
not
effect
aromatase
activity
and
atrazine
actually
causes
a
decrease
in
aromatase,
but
only
at
high
doses.
Based
on
the
weight
of
evidence,
enhancing
aromatase
activity
does
not
appear
to
be
a
mode
of
carcinogenic
action,
particularly
given
the
recent
findings
of
Ralph
Cooper.
Further,
if
this
were
a
primary
mode
of
action,
a
more
consistent
finding
of
tumors
at
estrogen
sensitive
sites
would
be
anticipated
in
the
rodent
carcinogenicity
studies.
Lastly,
the
June
2000
FIFRA
Scientific
Advisory
Panel
was
specifically
asked
about
OPP's
assessment
of
other
possible
other
modes
of
carcinogenic
action,
and
the
SAP
agreed
that
there
is
an
insufficient
basis
to
link
effects
on
aromatase
to
the
mammary
gland
tumor
response
in
female
Sprague
Dawley
rats.

With
regard
to
research
data
relating
to
the
effects
of
atrazine
on
amphibians,
EPA
has
not
yet
reached
conclusions
on
these
data,
and
therefore
does
not
have
any
specific
comment
on
these
research
efforts.
EPA
is
planning
to
convene
an
independent
scientific
peer
review
[
the
FIFRA
Science
Advisory
Panel
(
SAP)]
of
information
related
to
potential
effects
of
atrazine
on
amphibians
sometime
in
mid­
2003.
69
Although
atrazine
and
food
restriction
produce
many
of
the
same
effects,
they
may
do
so
by
different
mechanisms.
The
study
cited
by
DPR
did
not
show
any
effects
at
dose
levels
that
did
not
affect
bodyweight;
however,
the
study
used
in
the
short­
term
risk
assessment
did
show
effects
at
dose
levels
not
affecting
body
weight.
In
the
cited
study
by
DPR,
restricted
food
consumption
was
observed
at
dose
levels
greater
than
50
mg/
kg/
day,
and
the
effects
on
testosterone
concentration,
weights
of
androgen­
dependent
organs,
and
serum
LH
concentration
were
observed
only
at
the
high­
dose
levels
>
50
[
at
100
and
200
mg/
kg/
day].
There
were
no
apparent
effects
on
these
parameters
at
dose
levels
where
body­
weight
effects
were
not
observed,
which
supports
DPR's
concern.

However,
in
the
Stoker
study
[
pubertal
study
in
males
used
for
short­
term
risk
assessment],
delayed
preputial
separation
was
observed
at
12.5
mg/
kg/
day
and
above,
ventral
prostate
weight
was
decreased
at
50
mg/
kg/
day
or
greater,
but
body
weights
were
decreased
mainly
at
the
200
mg/
kg/
day
dose
level
and
in
the
pair­
fed
control
group.
In
this
latter
study,
the
delay
in
preputial
separation
and
decreased
ventral
prostate
weight
were
observed
in
the
absence
of
any
effect
on
body
weight.
In
the
pubertal
assay
[
used
for
short­
term
risk
assessment],
the
NOAEL
is
6.25;
LOAEL
is
12.5
mg/
kg/
day.
Body
weights
on
post­
natal­
day
(
PND)
23
[
start
of
dosing]
at
12.5
mg/
kg/
day
were
96%
of
control
and
98%
of
control
on
the
day
of
preputial
separation
[
PPS];
92%
on
PND
43
and
95%
on
PND
53.
Dose
levels
tested
in
this
study
were
6.25,
12.5,
25,
50,
100,
150,
200,
and
a
pair­
fed
group.
At
50
mg/
kg/
day,
body
weight
was
greater
than
control
on
PND
23
and
at
PPS;
98%
of
control
at
all
other
times.
At
100
mg/
kg/
day,
99%
at
PPS
and
90%
on
PND
43,
etc.
There
were
changes
[
delays]
in
PPS
in
atrazine
groups
that
did
not
affect
body
weight
and
more
severe
delays
in
the
high­
dose
group
that
did
display
decreased
body
weight.
Ventral
prostate
weight
was
decreased
compared
to
the
vehicle
control
at
50
mg/
kg/
day
and
greater,
as
was
the
pair­
fed
group
;
also
an
effect
at
a
dose
level
not
affecting
body
weight.

One
member
on
the
June
2000
SAP
for
atrazine
felt
strongly
that
the
appetite
suppressant
properties
of
atrazine
are
what
induces
the
neuroendocrine
alterations
seen
following
atrazine
exposure.
The
easiest
way
to
examine
appetite
suppression
is
simply
to
look
at
food
consumption,
which
Cooper
et
al.
did
in
the
pubertal
assays.
If
atrazine
is
an
appetite
suppressant
then,
clearly,
atrazine
exposed
animals
will
show
decreased
food
consumption.

One
thing
that
becomes
evident
from
examining
food
consumption
in
the
studies
from
the
atrazine
database
is
that
if
atrazine
causes
appetite
suppression,
it
does
so
only
at
higher
doses
(
above
20
mg/
kg/
day)
and
even
then
the
appetite
suppression
is,
at
worst,
mild.
Dr.
Cooper
did
see
some
mild
suppression
at
high
doses
but
nothing
at
lower
doses
causing
effects.
Food
consumption
data
illustrating
this
point
from
6
studies
(
the
28
and
6
month
LH
surge
studies,
three
2­
year
bioassays
and
one
1­
year
bioassay)
and
their
references
are
shown
below:
70
The
greatest
decrease
in
food
consumption
seen
in
this
set
of
6
studies
was
at
the
29.44
mg/
kg/
day
group
of
the
28
day
study.
In
this
group
of
this
study
there
was
a
21%
decrease
in
food
consumption
during
week
one.
Other
than
this
dose,
at
this
time
point
in
this
study,
no
decrease
in
food
consumption
was
greater
than
8%
compared
to
controls.

28
day
LH
surge
study;
MRID
43934406;
TXR
013996
Food
consumption.
Values
shown
are
in
grams.

Control
2.5
5.0
40
200
Week
1
0=
129
SD=
15.8
0=
128
SD=
15.1
0=
129
SD=
12.7
0=
124*
SD=
13.2
0=
102*
SD=
12.4
Week
5
0=
143
SD=
15.7
0=
140
SD=
19.2
0=
141
SD=
18
0=
141
SD=
15.3
0=
133*
SD=
15.7
Weeks
1­
5
0=
671
SD=
62.7
0=
667
SD=
66.6
0=
675
SD=
58.8
0=
667
SD=
59
0=
620*
SD=
60.2
*
p#
0.05
compared
to
control.

In
this
study
there
is
little
effect
of
atrazine
on
food
consumption
at
40
mg/
kg/
day
where
LH
surge
suppression
was
noted.
Food
consumption
between
control
and
40
mg/
kg/
day
at
5
weeks
and
for
the
entire
study
differ
by
less
than
1.5%.
At
week
one
there
is
a
statistically
significant
difference
between
the
two
groups,
however
the
percent
difference
is
still
only
3.9%.

6­
month
LH
surge
study;
MRID
44152102;

Food
consumption.
Values
shown
are
in
grams.

Week
1
Week
13
Week
25
Weeks
1­
25
Control
0=
124
SD=
17.4
0=
138
SD=
14.4
0=
137
SD=
16
0=
3438
SD=
255.1
1.8
mg/
kg
0=
131*
SD=
16.6
0=
141
SD=
14.8
0=
143
SD=
16.1
0=
3462
SD=
259.6
3.65
mg/
kg
0=
127
SD=
16.7
0=
131*
SD=
15.6
0=
135
SD=
19
0=
3455
SD=
302.9
29.44
0=
114*
0=
127*
0=
135
0=
3309*
71
mg/
kg
SD=
11.1
SD=
12
SD=
14.9
SD=
293.7
*
p#
0.05
compared
to
control
At
week
13
food
consumption
is
statistically
significantly
decreased
compared
to
controls,
but
this
decrease
is
only
5%.
For
the
entire
study
food
consumption
is
similar
between
control
and
3.65
mg/
kg/
day
and
is,
in
fact,
a
tiny
bit
greater
at
3.65
compared
to
control.

In
both
28
day
and
6­
month
LH
surge
LH
surge
and
estrous
cycles
are
altered
at
atrazine
doses
which
affect
food
consumption
little
or
not
at
all.

Thakur
terminal
sacrifice
study
with
SD;
MRID
42204401
Food
consumption.
Values
shown
are
in
grams.

Control
3.79
23.01
Weeks
1­
24
0=
2610.9
SD=
196
0=
2637.5
SD=
240.8
0=
2544
(­
2.5%)
SD=
181.9
Weeks
1­
52
0=
3659.7
SD=
287.3
0=
3661.7
SD=
275.9
0=
3573.1
(­
2.4%)
SD=
242.5
Weeks
1­
104
0=
5725
SD=
398.6
0=
5632.6
SD=
355.5
0=
5662.1
(­
1.1%)
SD=
335.5
*
p#
0.05
compared
to
control.

Morseth
2
year
study
intact
vs
OVX;
MRID
44544701
Food
consumption.
Values
shown
are
in
grams.
Food
consumption
measured
weekly
from
weeks
1­
13
and
every
4th
week
thereafter
Control
1.5
3.1
4.2
24.4
Weeks
1­
21
0=
2049
0=
1988
0=
2095
0=
2071
0=
1939
(­
5.4%)

Weeks
1­
52
0=
3145
0=
3153
0=
3266
0=
3252
0=
3078
(­
2.1%)

Weeks
1­
104
0=
4874
SD=
266.3
0=
5075
SD=
359.5
0=
5118
SD=
499.2
0=
5213
SD=
383.6
0=
4830
SD=
343.5
72
(­
1.0%)

The
food
consumption
data
from
the
pair
of
2­
year
bioassays
shown
above
shows
little
indication
of
an
appetite
suppressant
effect.
The
food
consumption
is
decreased
most
at
doses
above
20
mg/
kg/
day
at
the
early
timepoints.
Even
then
the
decrease
is
only
5%
at
most
(
compared
to
controls).
Early
onset
of
mammary
tumors,
particularly
carcinomas
was
evident
in
both
these
studies
at
3.79
and
4.2
mg/
kg/
day
­
doses
at
which
food
consumption
was
similar
to
control
values
(
and
in
fact
was
slightly
increased
compared
to
controls).

Female
daily
mean
food
consumption
from
Mayhew
(
MRID
00141874).
Values
shown
are
in
grams.

Control
0.5
mg/
kg/
day
3.5
mg/
kg/
day
25
mg/
kg/
day
50
mg/
kg/
day
Week
1
17.5
17.8
17.9
16.1**
14.4**

Week
26
19.7
19.3
19.6
19.1
18.4*

Week
52
20.7
20.5
20
20
19.8
Week
104
18.1
17.4
17.3
18.1
16.5
*
p
<
0.05
**
p
<
0.01
One
year
study;
MRID
43934402
Mean
weekly
food
consumption.
Values
shown
are
in
grams.

Week
1
Week
26
Week
50
Control
0=
16.34
0=
17.23
0=
19.42
0.8
0=
16.66
0=
17.3
0=
18.68
1.7
0=
16.25
0=
17.0
0=
19.18
2.8
0=
16.27
0=
16.89
0=
18.12
4.1
0=
16.71
0=
16.83
0=
19.52
23.9
0=
15.8
0=
17.04
0=
18.55
73
The
data
from
these
two
studies
again
shows
that
decreased
food
consumption
occurred
at
above
20
mg/
kg/
day
and
the
decreases
were
most
severe
at
the
early
timepoints.

In
conclusion,
one
member
of
the
SAP
(
Dr.
Phil
Landfield)
has
advanced
an
hypothesis
that
atrazine's
appetite
suppressant
properties
are
what
induces
the
neuroendocrine
alterations
leading
to
mammary
tumors.
This
hypothesis
first
assumes
that
atrazine
actually
has
appetite
suppressant
properties,
and
second,
assumes
that
these
properties
induce
the
neuroendocrine
alterations.

However,
there
is
not
strong
evidence
that
atrazine
has
any
appetite
suppressant
properties
at
all.
Food
consumption
is
decreased
if
the
doses
are
high
enough
(
above
20
mg/
kg/
day),
but
it
is
rarely
decreased
by
more
than
10%.
Even
then,
the
effect
is
seen
only
in
the
first
few
weeks
of
dosing.
The
atrazine
database
provides
ample
evidence
of
neuroendocrine
alterations
(
and
tumor
development)
occurring
at
doses
below
20
mg/
kg/
day.