OFFICE
OF
PREVENTION,
PESTICIDES,
AND
TOXIC
SUBSTANCES
UNITED
STATES
ENVIRONMENTAL
PROTECTION
AGENCY
WASHINGTON,
D.
C.
20460
TXR
No.:
0053852
MEMORANDUM
DATE:
November
10,
2005
SUBJECT:
IODOMETHANE:
Report
of
the
Cancer
Assessment
Review
Committee
PC
Code:
000011
FROM:
Jessica
Kidwell,
Executive
Secretary
Cancer
Assessment
Review
Committee
Health
Effects
Division
(
7509C)

TO:
Elizabeth
Méndez,
Toxicologist/
Risk
Assessor
(
RRB1)
Jeff
Dawson,
Risk
Assessor
(
RRB1)
Health
Effects
Division
(
7509C)

Mary
Waller
Fungicide
Branch,
Registration
Division
(
7505C)

The
Cancer
Assessment
Review
Committee
met
on
October
19,
2005
to
evaluate
the
carcinogenic
potential
of
Iodomethane.
Attached
please
find
the
Final
Cancer
Assessment
Document.

cc:
J.
Pletcher
Y.
Woo
CANCER
ASSESSMENT
DOCUMENT
EVALUATION
OF
THE
CARCINOGENIC
POTENTIAL
OF
IODOMETHANE
(
PC
Code
000011)

November
10,
2005
CANCER
ASSESSMENT
REVIEW
COMMITTEE
HEALTH
EFFECTS
DIVISION
OFFICE
OF
PESTICIDE
PROGRAMS
IODOMETHANE
CANCER
ASSESSMENT
DOCUMENT
FINAL
iii
DATA
PRESENTATION/
DOCUMENT
PREPARATION:

Elizabeth
Méndez,
PhD,
Toxicologist
DOCUMENT
PREPARATION:
Jessica
Kidwell,
Executive
Secretary
COMMITTEE
MEMBERS
IN
ATTENDANCE:
(
Signature
indicates
concurrence
with
the
assessment
unless
otherwise
stated).

Karl
Baetcke
Lori
Brunsman,
Statistician
William
Burnam,
Chair
Marion
Copley
Vicki
Dellarco
Kit
Farwell
Abdallah
Khasawinah
Nancy
McCarroll
Tim
McMahon
Jess
Rowland
Linda
Taylor
Yin­
Tak
Woo
NON­
COMMITTEE
MEMBERS
IN
ATTENDANCE
(
Signature
indicates
concurrence
with
the
pathology
report)

John
Pletcher,
Consulting
Pathologist
OTHER
ATTENDEES:
Whang
Phang
(
HED/
RRB1),
Santhini
Ramasamy
(
HED/
RRB4),
Mike
Metzger
(
HED/
RRB1),
Felicia
Fort
(
HED/
RRB1),
Jeff
Dawson
(
HED/
RRB1),
Alberto
Protzel
(
HED/
TB);
via
conference
call:
Doug
Wolf
(
EPA/
ORD/
NHEERL/
RTP),
Lori
Lim
(
CalEPA),
Chuck
Aldus
(
CalEPA),
Ruby
Reed
(
CalEPA)
IODOMETHANE
CANCER
ASSESSMENT
DOCUMENT
FINAL
iv
TABLE
OF
CONTENTS
I.
INTRODUCTION
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5
II.
BACKGROUND
INFORMATION
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III.
EVALUATION
OF
CARCINOGENICITY
STUDIES
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6
Combined
Chronic
Toxicity/
Carcinogenicity
Study
with
Iodomethane
in
Rats
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Carcinogenicity
Study
in
Mice
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12
IV.
TOXICOLOGY
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16
Metabolism
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16
Mutagenicity
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18
Structure­
Activity
Relationship
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20
Subchronic
and
Chronic
Toxicity
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21
Mode
of
Action
Studies
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22
V.
COMMITTEE'S
ASSESSMENT
OF
THE
WEIGHT­
OF­
THE
EVIDENCE
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31
1.
Carcinogenicity
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2.
Mutagenicity
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33
3.
Structure
Activity
Relationship
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4.
Mode
of
Action
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33
VI.
CLASSIFICATION
OF
CARCINOGENIC
POTENTIAL
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35
VII.
QUANTIFICATION
OF
CARCINOGENIC
POTENTIAL
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VIII.
BIBLIOGRAPHY
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36
IODOMETHANE
CANCER
ASSESSMENT
DOCUMENT
FINAL
1
EXECUTIVE
SUMMARY
On
October
19,
2005
the
Cancer
Assessment
Review
Committee
of
the
Health
Effects
Division
of
the
Office
of
Pesticide
Programs
met
to
evaluate
the
carcinogenic
potential
of
Iodomethane.

Dr.
Elizabeth
Méndez
of
Reregistration
Action
Branch
I
presented
chronic
toxicity/
carcinogenicity
studies
in
Crl:
CD
®
(
SD)
IGS
BR
rats
and
CD­
1
mice
by:
describing
the
experimental
design;
reporting
on
survival
and
body
weight
effects,
treatment­
related
nonneoplastic
and
neoplastic
lesions,
statistical
analysis
of
the
tumor
data,
the
adequacy
of
the
dose
levels
tested
and
presenting
the
weight
of
the
evidence
for
the
carcinogenicity
of
Iodomethane.
Dr.
Méndez
also
discussed
the
toxicology,
metabolism
and
structure
activity
relationships
while
Dr.
Nancy
McCarroll
presented
the
mutagenicity
data.

In
the
rat
combined
chronic
toxicity/
carcinogenicity
study
Iodomethane
(
97.9­
99.8%
a.
i.)
was
administered
to
Crl:
CD
®
(
SD)
IGS
BR
rats
via
whole
body
inhalation
at
concentrations
of
0,
5,
20,
or
60
ppm
for
6
hours/
day
5
days/
week
for
104
weeks.
Sixty
animals/
sex/
concentration
were
exposed
to
0,
5,
or
20
ppm
iodomethane
while
70/
sex
were
exposed
at
the
60
ppm
level.
In
the
carcinogenicity
study
in
mice,
microencapsulated
iodomethane
was
administered
in
the
diet
to
groups
of
50
male
and
50
female
Crl:
CD
®
1(
ICR)
mice
at
concentrations
of
0,
60,
200,
or
600
ppm
(
0,
8,
28,
or
84
mg/
kg
bw/
day,
respectively,
for
males
and
0,
10,
35,
or
100
mg/
kg
bw/
day,
respectively,
for
females)
for
18
months.

Also
available
for
consideration
were
several
mechanistic
studies
used
in
support
of
the
proposed
antithyroidal
mode
of
action
(
MOA)
for
the
thyroid
carcinogenic
response
observed
after
iodomethane
exposure.

After
careful
consideration
of
all
the
available
data,
the
CARC
reached
the
following
conclusions:

Carcinogenicity
Rat
<
An
increased
incidence
of
thyroid
follicular
cell
tumors
was
observed
in
male
rats
exposed
to
60
ppm
iodomethane
via
the
inhalation
route.
The
CARC
considered
the
thyroid
follicular
tumors
(
adenoma
driven)
at
the
high
dose
to
be
treatment­
related
since
there
were
significant
positive
trends
for
all
three
types
(
adenomas,
p<
0.01;
carcinomas,
p<
0.05;
combined
adenomas/
carcinomas,
p<
0.01),
as
well
as
significant
differences
in
the
pair­
wise
comparisons
of
the
60
ppm
dose
group
with
the
controls
for
adenomas
(
10/
42,
24%
,
p<
0.01,
vs
2/
45,
4%
controls)
and
combined
adenomas
and/
or
carcinomas,
(
12/
42,
29%,
p<
0.05
vs.
4/
45,
9%
controls).
In
addition,
the
incidences
at
the
high
dose
exceeded
the
historical
control
ranges
for
adenomas
(
1.67­
12%)
and
for
carcinomas
(
0.87­
3.85%).
Females
were
not
affected.
Iodomethane
only
caused
a
significant
increase
in
thyroid
IODOMETHANE
CANCER
ASSESSMENT
DOCUMENT
FINAL
2
tumors
in
male
rats
as
commonly
observed
in
classical
antithyroidal
agents
where
male
rats
are
frequently
found
to
be
more
sensitive
to
the
induction
of
thyroid
follicular
cell
tumors.
In
keeping
with
this,
TSH
levels
are
typically
higher
in
male
rats
than
in
females.

<
Dosing
at
the
high
dose
in
male
and
female
rats
was
considered
to
be
adequate
based
on
increased
incidences
in
both
sexes
of
non­
neoplastic
lesions
in
the
thyroid,
nasal
cavity,
and
salivary
glands,
decreased
body
weight
(
918­
20%,
p<
0.01)
and
body
weight
gains
(
927­
28%,
p<
0.01)
as
well
as
perturbations
of
thyroid
hormone
homeostasis
(
T
3
,
T
4
,
and
TSH).

Mice:

<
At
the
highest
dose
tested
(
600
ppm),
male
mice
exhibited
a
slight
increase
(
6%
vs
0
in
control)
with
a
positive
trend
in
the
combined
incidence
of
thyroid
follicular
cell
tumors
(
adenomas
&
carcinomas),
exceeding
the
maximum
incidence
(
2%)
observed
in
historical
control
data
from
Charles
River
Lab
(
2005)
for
either
tumor
type.
 
Primarily,
the
positive
trend
was
driven
by
the
incidence
of
adenomas
(
4%)
rather
than
carcinomas
(
2%).
 
This
incidence
of
thyroid
tumors
is
consistent
with
perturbations
of
thyroid
hormone
economy.

<
A
slight
increase
in
the
incidence
of
uterine
and
cervical
fibromas
was
observed
in
female
CD­
1
mice
at
600
ppm.
Although
significant
positive
trends
for
cervical
fibromas
(
p<
0.05)
and
combined
cervical/
uterine
fibromas
(
p<
0.01)
were
reported,
the
lesions
were
not
considered
to
be
treatment­
related
for
the
following
reasons:
 
Microscopic
in
size
 
Occurred
only
at
the
terminal
sacrifice
 
Had
no
precursor
lesions
(
hyperplasia)
 
Not
found
in
the
rat
bioassay
and;
 
Fibromas,
consisting
primarily
of
collagen
fibers,
have
not
been
associated
with
chemical
carcinogenicity.
 
Moreover,
the
reproductive
tract
of
female
mice
of
this
age
occasionally
exhibit
these
types
of
lesions.

<
Dosing
at
the
high
dose
in
male
and
female
mice
was
considered
to
be
adequate
for
this
study
based
on
the
increased
incidence
of
non­
neoplastic
lesions
in
the
thyroid,
esophagus,
pharynx,
stomach,
and
pituitary,
decreased
body
weights
(
96­
11%,
p<
0.01)
and
body
weight
gains
(
921­
92%,
p<
0.01),
as
well
as
changes
in
serum
thyroid/
pituitary
hormone
levels.
Thyroid
hormone
homeostasis
was
impaired
in
male
mice
but
not
females
at
the
highest
dose
tested
(
600
ppm).
T
4
was
decreased
by
.30%
while
TSH
was
increased
by
.91%.
Mutagenicity
IODOMETHANE
CANCER
ASSESSMENT
DOCUMENT
FINAL
3
Although
the
guideline
mutagenicity
studies
submitted
by
the
registrant
are
negative
for
genotoxicity,
there
is
concern
that
appropriate
measures
to
prevent
compound
volatilization
may
not
have
been
taken.
In
particular,
re­
evaluation
of
the
Bacterial
Reverse
Gene
Mutation
test
(
MRID
45593813)
indicates
that
this
is
not
a
valid
test
because
the
study
report
did
not
describe
what
measures
were
taken,
if
any,
to
keep
the
test
substance
"
in
contact"
with
the
cells.

Numerous
studies
in
the
open
literature
indicate
that
iodomethane
is
a
methylating
agent
and
consequently
a
potential
mutagen.
Evidence
of
this
mutagenic
potential
is
available
from
numerous
in
vitro
assays
and
one
in
vivo
assay
(
e.
g.,
S.
typhimurium,
E.
coli,
CHO
cells,
mouse
lymphoma
assay,
and
an
in
vivo
DNA
adduct
formation
test).

Although
iodomethane
has
been
shown
to
demonstrate
mutagenic
potential,
it
is
not
considered
to
operate
through
a
mutagenic
mode
of
action.
The
majority
of
the
neoplastic
lesions
observed
after
iodomethane
exposure
were
benign
and
were
observed
at
the
terminal
sacrifice
unlike
tumors
induced
through
a
mutagenic
MOA.
Another
aspect
that
contradicts
a
mutagenic
MOA
is
that
although
DNA
adducts
are
found
in
multiple
organs
(
e.
g.,
liver,
lungs,
forestomach)
tumors
are
only
seen
in
the
thyroid
in
the
rodent
bioassays.
This
is
consistent
with
the
observation
that
in
standard
rodent
bioassays,
no
thyroid
carcinogen
acting
by
a
mutagenic
MOA
has
been
identified
that
does
not
induce
tumors
at
multiple
sites.
Finally,
the
lack
of
a
tumorigenic
response
at
the
port­
of­
entry
(
respiratory
tract)
in
the
Inhalation
Combined
Chronic/
Carcinogenicity
study
in
rats
also
demonstrates
that
mutagenicity
is
not
contributing
to
the
carcinogenic
profile
of
iodomethane
since
tumors
in
the
respiratory
tract
(
particularly
the
nasal
cavity)
would
be
expected
if
iodomethane
were
acting
through
a
mutagenic
MOA.

Structure­
Activity
Relationship
Methyl
bromide
(
MeBr),
a
monohalogenated
methane
like
iodomethane,
was
considered
with
regards
to
its
SAR
to
iodomethane.
MeBr
was
classified
as
"
not
likely
to
be
carcinogenic
to
humans"
based
on
the
lack
of
tumorigenic
response
in
two
rodent
bioassays
in
spite
of
several
positive
mutagenicity
assays.
Iodinated
glycerol
(
which
contains
3­
iodo­
1,2­
propanediol
as
its
major
component),
a
close
structural
analog
of
iodomethane,
is
an
alkyl
iodide
with
alkylating
and
mutagenic
activities
and
has
been
shown
to
induce
the
same
type
of
thyroid
tumors
as
iodomethane.
However,
iodinated
glycerol
is
a
multi­
target
carcinogen
(
including
port
of
entry)
whereas
iodomethane's
carcinogenic
effect
seems
to
be
confined
to
the
thyroid
gland
in
rodents.
In
contrast,
a
number
of
nongenotoxic
iodinated
compounds
with
little
or
no
structural
similarity
to
iodomethane
(
e.
g.,
amiodarone,
potassium
iodide)
have
been
shown
to
elicit
similar
thyroid
carcinogenic
effects
as
iodomethane
suggesting
that
iodide
may
be
the
key
common
link
for
the
thyroid
activity.

Mode
of
Action
(
MOA)
IODOMETHANE
CANCER
ASSESSMENT
DOCUMENT
FINAL
4
There
is
compelling
evidence
indicating
that
iodomethane
induces
thyroid
follicular
cell
tumors
through
an
antithyroidal
MOA.
Although
iodomethane
has
been
shown
to
be
mutagenic
primarily
in
in
vitro
studies
and
produced
DNA
adducts
in
one
study
in
rats,
it
is
not
considered
to
operate
through
a
mutagenic
MOA.
The
weight­
of­
evidence
(
WOE)
indicates
that
perturbation
of
thyroid
homeostasis
is
the
key
event
in
the
thyroid
tumorigenic
response
observed
after
iodomethane
exposure.

Among
the
evidence
supporting
an
antithyroidal
MOA
is
the
observation
that
only
male
rodents
exhibit
increases
in
thyroid
tumors.
This
is
a
common
response
pattern
for
classical
antithyroidal
agents.
In
addition,
the
increases
of
cell
growth
in
vivo
(
e.
g.,
increases
in
thyroid
weights
and
hyperplasia)
progressing
to
follicular
cell
tumors
were
only
seen
in
the
presence
of
thyroid/
pituitary
hormone
changes
(
decreased
T
3
and
T
4
in
conjunction
with
profound
TSH
increases)
thus
exhibiting
a
pattern
of
both
dose
and
temporal
concordance.
The
fact
that
iodomethane
exposure
leads
to
a
dramatic
increase
in
serum
iodide
levels
coupled
with
the
changes
in
thyroid/
pituitary
hormone
levels,
thyroid
weights,
and
diffuse
follicular
cell
hyperplasia
points
to
an
intrathyroidal
site
of
action
further
supported
by
the
fact
that
excess
iodide
is
widely
recognized
as
a
goitrogenic
agent.

In
accordance
with
the
EPA's
Final
Guidelines
for
Carcinogen
Risk
Assessment
(
March,
2005),
the
CARC
classified
Iodomethane
as
"
Not
likely
to
be
Carcinogenic
to
humans
at
doses
that
do
not
alter
rat
thyroid
hormone
homeostasis."
The
point
of
departure
for
the
iodomethane
longterm
inhalation
risk
assessment
will
be
based
on
salivary
gland
metaplasia,
respectively
since
this
endpoint
is
approximately
7­
fold
more
sensitive
than
the
thyroid
hormone
effects
and
thus
health
protective
of
any
non­
cancer
adverse
outcomes
that
may
be
related
to
perturbations
in
thyroid
hormone
homeostasis.
IODOMETHANE
CANCER
ASSESSMENT
DOCUMENT
FINAL
5
I.
INTRODUCTION
On
October
19th,
2005
the
Cancer
Assessment
Review
Committee
of
the
Health
Effects
Division
of
the
Office
of
Pesticide
Programs
met
to
evaluate
the
carcinogenic
potential
of
Iodomethane.

II.
BACKGROUND
INFORMATION
The
Health
Effects
Division
(
HED)
of
EPA's
Office
of
Pesticide
Programs
has
conducted
a
preliminary
human
health
risk
assessment
for
the
new
active
ingredient
iodomethane,
also
referred
to
as
methyl
iodide
or
CH3I.

Empirical
Formula:
CH
3
I
Molecular
Weight:
141.95
CAS
Registry
No.:
74­
88­
4
PC
Code:
000011
Chemical
Class:
Alkyl
Iodide
The
proposed
use
of
iodomethane
is
as
a
pre­
plant
soil
fumigant
in
strawberry,
tomato,
peppers,
and
ornamental
fields
(
flowers,
plants,
and
bushes).
Iodomethane
has
been
identified
as
a
possible
replacement
for
methyl
bromide
(
MeBr),
a
fumigant
with
numerous
registered
uses.
Although
iodomethane
will
be
used
as
an
agricultural
pesticide,
it
is
considered
a
non­
food
use
chemical
since
it
is
quickly
degraded
or
metabolized
into
non­
toxic
degradates
and
subsequently
incorporated
into
natural
plant
constituents.
Furthermore,
iodomethane
residues
must
dissipate
in
the
soil
prior
to
planting
to
prevent
phytotoxicity.
Accordingly,
HED
concludes
that
tolerances
are
not
required
for
iodomethane
at
this
time.

The
primary
exposure
pathway
for
iodomethane
is
via
inhalation.
The
general
public
may
be
exposed
to
iodomethane
in
air
because
of
its
volatility
following
application.
Specifically,
fumigants
such
as
iodomethane
can
off­
gas
into
air
and
be
transported
by
diffusion
and
wind
offsite
Based
on
the
proposed
use
patterns,
the
Agency
anticipates
exposures
would
be
for
shortand
intermediate­
terms
(
i.
e.,
#
6
months).
In
addition,
the
U.
S.
population
may
be
exposed
to
iodomethane
through
the
drinking
water.

The
pattern
of
toxicity
attributed
to
iodomethane
exposure
via
the
inhalation
route
includes
developmental
toxicity
(
manifested
as
fetal
losses
and
decreased
live
births),
histopathology
findings
(
respiratory
tract
lesions
and
salivary
gland
squamous
cell
metaplasia
),
thyroid
toxicity,
neurotoxicity
and
generalized
systemic
toxic
effects
(
body
weight
and
body
weight
gain
decreases).

Since
iodomethane
is
a
new
active
ingredient,
it
has
not
been
previously
reviewed
by
the
CARC.
However,
the
International
Agency
for
Research
on
Cancer
(
IARC,
1999)
has
concluded
that
iodomethane
is
"
not
classifiable
as
to
its
carcinogenicity
to
humans."
IODOMETHANE
CANCER
ASSESSMENT
DOCUMENT
FINAL
6
III.
EVALUATION
OF
CARCINOGENICITY
STUDIES
1.
Combined
Chronic
Toxicity/
Carcinogenicity
Study
with
Iodomethane
in
Rats
Reference:
A
24­
Month
Inhalation
Combined
Chronic
Toxicity/
Carcinogenicity
Study
of
Iodomethane
in
Rats.
WIL
Research
Laboratories,
LLC,
1407
George
Rd.,
Ashland,
OH.
Study
No.
WIL­
418019,
March
29,
2005.
MRID
46512401.
Unpublished.

A.
Experimental
Design
Iodomethane
(
97.9­
99.8%
a.
i.)
was
administered
to
Crl:
CD
®
(
SD)
IGS
BR
rats
via
whole
body
inhalation
at
concentrations
of
0,
5,
20,
or
60
ppm
for
6
hours/
day
5
days/
week
for
104
weeks.
Sixty
animals/
sex/
concentration
were
exposed
to
0,
5,
or
20
ppm
iodomethane
while
70/
sex
were
exposed
at
the
60
ppm
level.

B.
Discussion
of
Tumor
Data
Male
rats
had
significant
trends
for
thyroid
follicular
cell
adenomas
and
adenomas
and/
or
carcinomas
combined,
both
at
p
<
0.01.
There
was
also
a
significant
trend
for
thyroid
follicular
cell
carcinomas
at
p
<
0.05.
There
were
significant
differences
in
the
pair­
wise
comparisons
of
the
60
ppm
dose
group
with
the
controls
for
thyroid
follicular
cell
adenomas
at
p
<
0.01
and
for
thyroid
follicular
cell
adenomas
and/
or
carcinomas
combined
at
p
<
0.05
(
Table
1).
The
increased
incidence
of
follicular
cell
adenoma
(
24%)
at
60
ppm
was
greater
than
the
historical
control
incidence
(
2.21%)
at
the
test
facility
(
WIL)
and
the
spontaneous
incidence
range
(
1.67­
12.0%)
reported
by
Charles
River
Laboratories
(
CRL)
for
this
strain.
The
increased
incidence
of
follicular
cell
carcinoma
(
10%)
in
60
ppm
males
was
not
statistically
significant
compared
with
concurrent
controls,
however,
it
was
greater
than
the
historical
control
incidence
(
0.88%)
at
the
test
facility
and
exceeded
the
range
of
spontaneous
incidence
(
0.87­
3.85%)
reported
for
this
strain
by
CRL.
No
treatment­
related
increase
in
incidence
of
neoplasms
was
observed
in
female
rats
at
any
dose.
IODOMETHANE
CANCER
ASSESSMENT
DOCUMENT
FINAL
7
Table
1.
Male
Rats:
Thyroid
Follicular
Cell
Tumor
Rates+
and
Exact
Trend
Test
and
Fisher's
Exact
Test
Results.

Tumor
Type
Exposure
Concentration
(
ppm)

0
5
20
60
Adenoma
%
p
=
2/
45
(
4)
0.00065**
2/
45
(
4)
0.69179
4/
49
(
8)
0.38018
10a/
42
(
24)
0.00936**

Carcinoma
%
p
=
2/
45
(
4)
0.03136*
0/
45
(
0)
1.0000
0/
49
(
0)
1.0000
4b/
42
(
10)
0.30563
Combined
%
p
=
4/
45
(
9)
0.00045**
2/
45
(
4)
0.89861
4/
49
(
8)
0.68982
12c/
42
(
29)
0.01745*

+
Number
of
tumor
bearing
animals/
Number
of
animals
examined,
excluding
those
that
died
or
were
sacrificed
before
week
53.

aFirst
adenoma
observed
at
week
59,
dose
60
ppm.
bFirst
carcinoma
observed
at
week
90,
dose
60
ppm.
cTwo
animals
in
the
60
ppm
dose
group
had
both
an
adenoma
and
a
carcinoma.

Note:
Interim
sacrifice
animals
have
been
excluded
from
this
analysis.
Three
interim
sacrifice
animals
in
the
60
ppm
dose
group
had
an
adenoma.
Significance
of
trend
denoted
at
control.
Significance
of
pair­
wise
comparison
with
control
denoted
at
dose
level.
If
*,
then
p
<
0.05.
If
**,
then
p
<
0.01.

C.
Non­
Neoplastic
Lesions
Histopathologic
lesions
are
presented
in
Tables
2
(
interim
sacrifice),
3
(
thyroid
gland,
main
study),
4
(
nasal
cavity,
main
study),
and
5
(
salivary
gland,
main
study).
The
incidences
of
several
thyroid
gland
lesions
were
increased
primarily
in
60
ppm
males
at
52
weeks,
and
the
incidences
of
nasal
cavity
and
salivary
gland
lesions
were
increased
in
60
ppm
male
and
female
rats
at
52
weeks.
In
the
main
study,
there
were
treatment­
related
increases
in
the
incidence
and
severity
of
thyroid
lesions,
seen
primarily
in
60
ppm
males,
which
is
consistent
with
gross
pathology
(
enlarged
thyroid),
organ
weight
(
increased
weight),
and
other
histopathologic
data
(
increased
incidence
of
neoplastic
lesions).
There
was
increased
severity
and/
or
incidence
of
follicular
cell
hyperplasia,
follicular
cyst,
cytoplasmic
vacuolation,
follicular­
cystic
hyperplasia
and
ultimobranchial
cyst.
The
incidence
of
follicular
cell
hyperplasia
was
also
increased
in
60
ppm
females;
increased
incidence
of
ultimobranchial
cyst
was
observed
at
20
and
60
ppm
in
females.
Follicular
cell
hyperplasia
is
consistent
with
the
elevated
levels
of
TSH
in
these
animals.
IODOMETHANE
CANCER
ASSESSMENT
DOCUMENT
FINAL
8
Treatment­
related
changes
in
the
olfactory
epithelium
along
the
dorsal
aspects
of
the
turbinates
and
septum,
which
was
evident
from
epithelium
degeneration
and
the
formation
of
epithelial
cysts,
were
seen
in
60
ppm
males
and
females
(
Table
4).
These
lesions
were
found
in
levels
III­
VI
of
the
olfactory
epithelium.
The
investigator
reported
that
the
overall
incidence
of
olfactory
epithelium
degeneration
was
90%
for
males
and
75%
for
females
after
1
year
and
100%
for
both
sexes
after
2
years.

Treatment­
related
effects
were
also
seen
in
salivary
glands
in
all
treatment
groups
in
both
sexes
(
Table
5).
An
increased
incidence
of
squamous
cell
metaplasia,
primarily
at
20
and
60
ppm
and
atrophy,
most
extensive
at
60
ppm,
was
observed.

TABLE
2.
Non­
neoplastic
lesions
in
thyroid
from
rats
exposed
to
Iodomethane
by
inhalation
 
interim
studya
Organ/
lesion
Exposure
concentration
(
ppm)

0
5
20
60
0
5
20
60
Males
Females
No.
examined
10
10
10
20
10
10b
10
20
Thyroid
gland
Follicular
cell
hyperplasia
Follicular
cyst
Cytoplasmic.
vacuolation
Follicular
cyst
hyperplasia
Ultimobranchial
cyst
0
0
0
0
3
1
0
1
0
2
1
0
0
0
4
8
3
8
2
13
0
0
0
0
6
0
0
0
0
4
0
0
0
0
3
2
0
0
0
10
Nasal
Cavity
Level
III
Olfactory
epithelial
degen.
Olfactory
epithelial
cyst
0
0
0
0
0
0
13
11
0
0
0
0
0
0
1
3
Level
IV
Olfactory
epithelial
degen.
Olfactory
epithelial
cyst
0
0
0
0
0
0
15
11
0
0
1
0
1
1
6
10
Level
V
Olfactory
epithelial
degen.
Olfactory
epithelial
cyst
0
0
0
0
1
0
18
14
0
0
0
0
0
0
15
15
Level
VI
Olfactory
epithelial.
degen.
Olfactory
epithelial
cyst
0
0
0
0
0
0
16
5
0
0
0
0
0
0
8
8
Salivary
gland
Squamous
metaplasia.
Atrophy
0
0
0
0
3
0
16
8
0
0
0
0
3
0
18
1
Data
obtained
from
pages
553­
596
of
MRID
46512401
a
Values
are
number
of
animals
bSalivary
gland
examined
in
only
9
females
at
5
ppm.
Statistical
analyses
not
reported
IODOMETHANE
CANCER
ASSESSMENT
DOCUMENT
FINAL
9
TABLE
3.
Non­
neoplastic
lesions
in
thyroid
from
rats
exposed
to
Iodomethane
by
inhalation
 
main
studya
Severity
Exposure
concentration
(
ppm)

0
5
20
60
0
5
20
60
Males
Females
No.
examined
50
50
50
50
50
49
50
50
Follicular
cell
hyperplasia
Minimal
Mild
Moderate
Total
0
0
0
0
0
1
0
1
(
2.00)
b
0
0
0
0
9
3
1
13
(
1.38)
0
0
0
0
1
1
0
2
(
1.50)
1
0
0
1
(
1.00)
6
3
1
10
(
1.50)

Follicular
cyst
Minimal
Mild
Moderate
Total
0
0
1
1
(
3.00)
1
3
0
4
(
1.75)
0
3
1
4
(
2.25)
0
5
0
5
(
2.00)
0
1
0
1
(
2.00)
0
2
0
2
(
2.00)
0
1
0
1
(
2.00)
0
1
0
1
(
2.00)

Cytoplasmic
vacuolation
Minimal
Mild
Total
0
0
0
0
0
0
0
0
0
5
3
8
(
1.38)
0
0
0
1
0
1
(
1.00)
0
0
0
1
0
1
(
1.00)

Follicular,
cystic
hyperplasia
Minimal
Mild
Moderate
Severe
Total
0
1
0
0
1
(
2.00)
1
3
1
0
5
(
2.00)
0
0
3
1
4
(
3.25)
1
4
1
0
6
(
2.00)
0
0
0
0
0
2
0
1
0
3
(
1.67)
2
0
0
0
2
(
1.00)
0
2
0
0
2
(
2.00)

Ultimobranchial
cyst
Minimal
Mild
Moderate
Total
4
2
0
6
(
1.33)
6
2
0
8
(
1.25)
6
0
1
7
(
1.29)
11
2
2
15
(
1.40)
7
1
0
8
(
1.13)
6
6
0
12
(
1.50)
13
7
0
20
(
1.35)
11
5
0
16
(
1.31)

Data
obtained
from
page
499­
544
and
597­
632
of
MRID
46512401
a
Values
are
number
of
animals
b
Average
severity
score
for
animals
with
lesions:
1
=
minimal,
2
=
mild,
3
=
moderate,
4
=
severe
Statistical
analyses
not
reported
IODOMETHANE
CANCER
ASSESSMENT
DOCUMENT
FINAL
10
TABLE
4.
Non­
neoplastic
lesions
in
nasal
level
III­
VI
in
rats
exposed
to
Iodomethane
by
inhalationa
Severity
Exposure
concentration
(
ppm)

0
5
20
60
0
5
20
60
Males
Females
No.
examined
50
50
50
50
49
50
50
50
Olfactory
epithelium
degeneration
(
level
III)

Minimal
Mild
Moderate
Total
0
0
0
0
0
0
0
0
1
0
0
1
(
1.00)
18
5
5
28
(
1.54)
0
0
0
0
0
0
0
0
4
0
0
4
(
1.00)
16
2
1
19
(
1.21)

Olfactory
epithelium
cyst
(
level
III)

Minimal
Mild
Total
0
0
0
0
1
1
(
2.00)
0
0
0
5
0
5
(
1.00)
0
0
0
0
0
0
0
0
0
5
1
6
(
1.17)

Olfactory
epithelium
degeneration
(
level
IV)

Minimal
Mild
Moderate
Severe
Total
0
0
0
0
0
2
0
0
0
2
(
1.00)
4
0
0
0
4
(
1.00)
22
14
7
1
44
(
1.70)
0
0
0
0
0
0
0
0
0
0
2
1
0
0
3
(
1.33)
20
9
7
1
37
(
1.70)

Olfactory
epithelium
cyst
(
level
IV)

Minimal
Mild
Total
0
0
0
0
0
0
0
0
0
10
0
10
(
1.00)
1
0
1
(
1.00)
0
0
0
0
0
0
8
0
8
(
1.00)

Olfactory
epithelium
degeneration
(
level
V)

Minimal
Mild
Moderate
Severe
Total
0
0
0
0
0
1
0
0
0
1
(
1.00)
3
0
0
0
3
(
1.00)
17
18
7
3
45
(
1.91)
0
0
0
0
0
0
0
0
0
0
3
1
0
0
4
(
1.25)
17
18
6
4
45
(
1.93)

Olfactory
epithelium
cyst
(
level
V)

Minimal
Mild
Total
0
0
0
0
0
0
0
0
0
17
4
21
(
1.19)
0
0
0
0
0
0
1
0
1
(
1.00)
20
0
20
(
1.00)

Olfactory
epithelium
degeneration
(
level
VI)

Minimal
Mild
Moderate
Severe
Total
1
0
0
0
1
(
1.00)
0
0
0
0
0
2
1
0
0
3
(
1.33)
7
21
8
2
38
(
2.13)
0
0
0
0
0
0
0
0
0
0
1
1
0
0
2
(
1.50)
17
17
7
2
43
(
1.86)

Olfactory
epithelium
cyst
(
level
VI)

Minimal
Mild
Total
0
0
0
0
0
0
0
0
0
13
1
14
(
1.07)
0
0
0
0
0
0
0
0
0
20
0
20
(
1.00)

Data
obtained
from
pages
499­
544
and
597­
632
of
MRID
46512401
a
Values
are
number
of
animals
Statistical
analyses
not
reported
IODOMETHANE
CANCER
ASSESSMENT
DOCUMENT
FINAL
11
TABLE
5.
Non­
neoplastic
lesions
in
salivary
glands
from
rats
exposed
to
Iodomethane
by
inhalationa
Severity
Exposure
concentration
(
ppm)

0
5
20
60
0
5
20
60
Males
Females
No.
examined
50
49
49
50
50
50
50
50
Squamous
metaplasia
Minimal
Mild
Moderate
Total
1
0
0
1
(
1.00)
3
1
0
4
(
1.25)
20
2
0
22
(
1.09)
22
25
0
47
(
1.53)
0
0
0
0
1
2
0
3
(
1.67)
16
6
0
22
(
1.27)
29
9
2
40
(
1.33)

Atrophy
Minimal
Mild
Moderate
Total
0
0
0
0
2
3
0
5
(
1.60)
2
2
0
4
(
1.50)
11
3
0
14
(
1.40)
0
0
0
0
2
0
0
2
(
1.00)
2
3
0
5
(
1.60)
8
1
0
9
(
1.11)

Data
obtained
from
pages
499­
544
and
597­
632
of
MRID
46512401
a
Values
are
number
of
animals
Statistical
analyses
not
reported
D.
Adequacy
of
the
Dosing
for
Assessment
of
Carcinogenicity
Though
survival
was
low
(
34­
38%
for
control
and
60
ppm
males
and
females,
46­
48%
for
the
other
groups),
it
did
not
appear
to
be
affected
by
exposure
to
the
test
article
since
the
high­
dose
and
control
groups
had
comparable
mortality
rates.
In
addition
to
the
histopathology
findings
described
above,
iodomethane
exposure
led
to
decreases
in
body
weight(
918­
20%)
and
body
weight
gains
(
927­
28%)
in
both
sexes.
Iodomethane
exposure
at
a
concentration
of
60
ppm
also
elicited
significant
perturbations
of
thyroid
hormone
homeostasis
as
evidenced
by
the
decreases
in
T
3
serum
levels
(
911­
34%)
and
the
sustained
increases
in
TSH
and
rT
3
(
8305­
1141%
and
111­
133%,
respectively).
Interestingly,
changes
in
T
4
serum
levels
were
inconsistent
decreasing
by
56%
on
week
26,
increasing
by
34%
on
week
52,
and
being
comparable
to
control
during
the
week
104
evaluation.
A
similar
pattern
of
effects
was
noted
in
females
at
the
highest
concentration
tested.
However,
in
general,
the
magnitude
of
the
changes
in
serum
hormone
levels
was
not
as
robust
as
in
the
case
of
males
(
T
3
:
911­
27%,
TSH:
858­
634%,
rT
3
:
890­
380%)
particularly
for
TSH.
The
CARC
considered
dosing
at
the
high
dose
in
both
sexes
to
be
adequate
for
the
assessment
of
carcinogenicity
of
iodomethane.
IODOMETHANE
CANCER
ASSESSMENT
DOCUMENT
FINAL
12
2.
Carcinogenicity
Study
in
Mice
Reference:
An
18
month
dietary
carcinogenicity
study
of
miroencapsulated
iodomethane
in
mice.
WIL
Research
Laboratories,
LLC,
1407
George
Road,
Ashland,
OH
44805,
Project
ID.
WIL­
418025.
June
24,
2005.
MRID
46582801.
Unpublished.

A
Pathology
Working
Group
(
PWG)
Peer
Review
of
proliferative
lesions
reported
in
the
uterus
and
cervix.
Supplemental
to
Vol.
118:
An
18­
month
carcinogenicity
study
of
microencapsulated
iodomethane
in
female
CD­
1
mice.
Experimental
Pathology
Laboratories,
Inc.,
P.
O.
Box
12766,
Research
Triangle
Park,
NC
27709,
Project
ID
No.
758­
011.
June
23,
2005.
MRID
46582802.
Unpublished
A.
Experimental
Design
Microencapsulated
iodomethane
(
batch/
lot
#:
20­
379,
20­
380,
20­
386,
20­
728,
20­
430,
20­
442,
20­
443,
20­
454,
20­
456,
20­
481,
20­
483,
20­
490,
20­
496,
20­
500,
20­
517,
20­
525,
20­
528)
was
administered
in
the
diet
to
groups
of
50
male
and
50
female
Crl:
CD
®
1(
ICR)
mice
at
concentrations
of
0,
60,
200,
or
600
ppm
(
0,
8,
28,
or
84
mg/
kg
bw/
day,
respectively,
for
males
and
0,
10,
35,
or
100
mg/
kg
bw/
day,
respectively,
for
females)
for
18
months.

B.
Discussion
of
Tumor
Data
As
shown
in
Table
6,
an
increase
in
the
incidence
of
thyroid
follicular
cell
adenoma/
carcinoma
combined
in
high­
dose
male
mice
was
noted;
the
incidence
was
0%,
0%,
2%,
and
6%
in
the
control,
low­,
mid­,
and
high­
dose
groups,
respectively.
Follicular
cell
adenoma
in
mice
are
rare
and
occurred
in
none
of
the
historical
controls
from
the
performing
laboratory.

In
the
case
of
the
increased
incidence
of
fibromas
seen
in
the
uterus
and
cervix,
two
PWGs
were
convened
to
further
evaluate
the
female
reproductive
tract
findings
(
Drs.
Marion
Copley
and
John
Pletcher
attended
these
meetings).
The
reviews
consisted
of
re­
examination
of
all
sections
of
the
ovary,
uterus,
and
cervix
containing
lesions
initially
diagnosed
as
histiocytic
sarcoma
as
well
as
other
proliferative
mesenchymal
lesions
in
the
uterus
and/
or
cervix,
and
re­
examination
of
lesions
in
which
a
different
diagnosis
was
presented
by
the
study
pathologist
and
reviewing
pathologists.
Additional
sections
from
wet
tissues
and
paraffin
blocks
were
examined
after
staining
with
hematoxylin,
eosin,
and
PAS
to
investigate
proliferative
granular
cell
lesions.
Sections
were
stained
immunohistochemically
for
S100
protein,
Actin,
and
Desmin
and
histochemically
with
a
Trichrome
stain
to
identify
collagen
and
muscle
fibers
in
tissues.
The
PWG
also
re­
examined
lesions
diagnosed
as
granular
cell
tumors,
leiomyoma,
leiomyosarcoma,
and
endometrial
stromal
sarcoma.
The
lesions
were
classified
according
to
the
criteria
and
nomenclature
approved
by
the
Society
of
Toxicologic
Pathology
(
STP)
and
the
International
Agency
on
Research
in
Cancer
(
IARC).
The
PWGs
concluded
that
the
lesions
evaluated
were
not
treatment
related
since
they
occurred
only
in
animals
sacrificed
at
study
termination,
were
microscopic
in
size,
had
no
IODOMETHANE
CANCER
ASSESSMENT
DOCUMENT
FINAL
13
precursor
lesion
(
hyperplasia),
and
were
not
found
in
rats
treated
with
iodomethane
for
2
years.
The
slight
increase
in
benign
fibrous
tumors
(
fibromas)
in
the
uterus/
cervix
of
the
600
ppm
females
was
considered
incidental.
Such
tumors,
consisting
primarily
of
collagen
fibers,
have
not
been
associated
with
chemical
carcinogenicity.
In
Table
7,
there
were
statistically
significant
trends
for
cervix
adenomas
(
p<
0.05)
and
combined
cervix
adenomas
and
uterine
fibromas
(
p<
0.01).
No
statistically
significant
pair­
wise
comparisons
with
controls
were
noted.

Table
6.
Male
Thyroid
Follicular
Cell
Tumor
Rates+
and
ad
hoc
Fisher's
Exact
Test
and
Exact
Test
for
Trend
Test
Results
Tumor
Type
Dose
(
mg/
kg/
day)

0
8
28
84
Adenomas
%
p
=
0/
50
(
0)
0.05969
0/
50
(
0)
1.00000
1/
50
(
2)
0.50000
2/
49
(
4)
0.24242
Carcinomas
%
p
=
0/
50
(
0)
0.1841
0/
50
(
0)
1.00000
1/
50
(
2)
0.50000
1/
49
(
2)
0.49495
Combined
%
p
=
0/
50
(
0)
0.01787*
0/
50
(
0)
1.00000
1/
50
(
2)
0.50000
3/
49
(
6)
0.11746
+
Number
of
tumor
bearing
animals/
Number
of
animals
examined.
Note:
Significance
of
trend
denoted
at
control.
Significance
of
pair­
wise
comparison
with
control
denoted
at
dose
level.
If
*,
then
p
<
0.05.
If
**,
then
p
<
0.01.
IODOMETHANE
CANCER
ASSESSMENT
DOCUMENT
FINAL
14
Table
7.
Female
Cervix
and
Uterine
Tumor
Rates+
and
ad
hoc
Fisher's
Exact
Test
and
Exact
Test
for
Trend
Test
Results
Tumor
Type
Dose
(
mg/
kg/
day)

0
10
35
100
Cervix
Fibromas
%
p
=
0/
49
(
0)
0.03575*
1/
50
(
2)
0.50505
0/
47
(
0)
1.00000
3/
50
(
6)
0.12496
Uterine
Fibromas
%
p
=
0/
50
(
0)
0.3128
1/
50
(
2)
0.50000
0/
50
(
0)
1.00000
1/
50
(
2)
0.50000
Combined
%
p
=
0/
50
(
0)
0.00992**
1/
50
(
2)
0.50000
0/
50
(
0)
1.00000
4/
50
(
8)
0.05873
+
Number
of
tumor
bearing
animals/
Number
of
animals
examined.

Note:
Significance
of
trend
denoted
at
control.
Significance
of
pair­
wise
comparison
with
control
denoted
at
dose
level.
If
*,
then
p
<
0.05.
If
**,
then
p
<
0.01.

C.
Non­
Neoplastic
Lesions
Notable
non­
neoplastic
lesions
are
presented
in
Table
8.
Administration
of
iodomethane
primarily
affected
the
thyroid
gland,
pharynx,
esophagus,
and
nonglandular
stomach,
in
both
sexes.
The
incidence
of
hyperkeratosis
in
the
esophagus,
pharynx,
and
stomach
was
significantly
increased
in
both
sexes
at
doses
$
200
ppm,
females
in
the
60
ppm
group
also
exhibited
a
statistically
significant
increase
in
the
incidence
of
hyperkeratosis
in
the
esophagus.
Hyperkeratosis
in
the
esophagus,
pharynx,
and
nonglandular
stomach
was
seen
in
23­
64%
of
mid­
dose
males,
33­
68%
of
mid­
dose
females,
53­
78%
of
high­
dose
males,
and
62­
90%
of
high­
dose
females.
Incidences
were
1­
10%,
control
males
and
0­
38%
in
control
females.
The
incidence
of
hyperkeratosis
in
the
esophagus
of
low­
dose
females
was
10%.
The
incidences
of
epithelial
hyperplasia
in
the
esophagus
in
high­
dose
male
mice
and
hyperkeratosis
in
the
pharynx
in
low­
dose
female
mice
were
increased
but
not
significantly
compared
with
control
incidences.
The
severity
of
the
lesions
in
the
esophagus,
pharynx,
and
stomach
did
not
show
a
clear
dose­
related
trend
in
either
sex.
The
incidence
of
basophil
hypertrophy
in
the
pituitary
was
significantly
increased
at
all
doses
in
females
(
61­
70%).
The
severity
of
the
lesion
was
minimal
in
almost
all
animals.
The
incidence
of
basophil
hypertrophy
showed
no
clear
dose­
related
trend.

The
thyroid
gland
was
the
primary
target
of
iodomethane
in
male
and
female
mice.
Both
sexes
had
significantly
increased
incidences
of
cytoplasmic
vacuolation
of
follicular
epithelial
cells
(
24­
44%
in
males
and
24­
30%
in
females
vs
0
control)
and
increased
colloid
in
the
follicular
epithelial
cells
(
56­
88%
in
males
and
62­
72%
in
females)
at
all
dose
levels
compared
with
control
incidences
of
IODOMETHANE
CANCER
ASSESSMENT
DOCUMENT
FINAL
15
0%
for
cytoplasmic
vacuolation
and
6%
and
16%
for
increased
colloid
in
control
males
and
females,
respectively.
Female
mice
at
all
dose
levels
and
high­
dose
male
mice
had
a
significantly
increased
incidence
of
follicular
cell
hyperplasia
(
44­
52%
in
females
and
12%
in
males
compared
with
0­
2%
in
controls).
The
incidence
of
hyperplasia
of
follicular
epithelial
cells
(
referred
to
as
hyperplasia)
was
significantly
increased
in
high­
dose
male
mice
as
well
as
in
mid­
and
high­
dose
females,
(
not
statistically
significant).
Increased
colloid
and
follicular
cell
hyperplasia
in
male
mice
were
the
only
thyroid
gland
lesions
that
showed
clear
dose­
related
trends;
nevertheless,
all
the
thyroid
gland
lesions
are
considered
treatment
related.
The
severity
of
the
lesions
was
generally
increased
in
treated
mice
compared
with
controls,
but
no
clear
dose­
related
trend
was
observed.

TABLE
8.
Microscopic
lesions
in
male
and
female
mice
receiving
microencapsulated
iodomethane
for
78
weeks
Organ/
lesion
Dietary
concentration
(
ppm)

0
60
200
600
Males
Esophagus
[
No.
examined]
Hyperkeratosis
Epithelial
hyperplasia
[
50]
3
(
1.00)
a
0
[
50]
4
(
1.25)
0
[
50]
28**
(
1.11)
0
[
49]
38**
(
1.18)
4
(
1.00)

Pharynx
[
No.
examined]
Hyperkeratosis
[
50]
1
(
2.00)
[
50]
3
(
1.00)
[
48]
11**
(
1.00)
[
49]
26**
(
1.08)

Stomach,
nonglandular
[
No.
examined]
Hyperkeratosis
[
49]
5
(
1.00)
[
50]
11
(
1.09)
[
50]
32**
(
1.06)
[
49]
38**
(
1.16)

Thyroid
gland
[
No.
examined]
Cytoplasmic
vacuolation
Increased
colloid
Hyperplasia
of
follicular
epithelial
cells
Follicular
cell
hyperplasia
[
50]
0
3
(
1.00)
0
0
[
50]
12**
(
1.25)
28**
(
1.43)
4
(
1.50)
1
(
1.00)
[
50]
22**
(
1.09)
37**
(
1.38)
2
(
1.50)
3
(
1.00)
[
49]
15**
(
1.13)
44**
(
1.48)
8**
(
1.13)
6*
(
1.00)

Females
Esophagus
[
No.
examined]
Hyperkeratosis
[
50]
0
[
50]
5*
(
1.00)
[
50]
27**
(
1.00)
[
50]
45**
(
1.13)

Pharynx
[
No.
examined]
Hyperkeratosis
[
49]
1
(
1.00)
[
50]
5
(
1.00)
[
49]
16**
(
1.06)
[
50]
31**
(
1.16)

Pituitary
[
No.
examined]
Basophil
hypertrophy
[
48]
13
(
1.15)
[
49]
30**
(
1.00)
[
49]
28**
(
1.00)
[
50]
35**
(
1.03)

Stomach,
nonglandular
[
No.
examined]
Hyperkeratosis
[
50]
19
(
1.11)
[
50]
20
(
1.15)
[
50]
34**
(
1.06)
[
50]
36**
(
1.14)
IODOMETHANE
CANCER
ASSESSMENT
DOCUMENT
FINAL
TABLE
8.
Microscopic
lesions
in
male
and
female
mice
receiving
microencapsulated
iodomethane
for
78
weeks
Organ/
lesion
Dietary
concentration
(
ppm)

0
60
200
600
16
Thyroid
gland
[
No.
examined]
Cytoplasmic
vacuolation
Increased
colloid
Hyperplasia
of
follicular
epithelial
cells
Follicular
cell
hyperplasia
[
50]
0
8
(
1.13)
1
(
1.00)
1
(
1.00)
[
50]
15**
(
1.00)
35**
(
1.17)
2
(
1.50)
25**
(
1.28)
[
50]
14**
(
1.21)
31**
(
1.29)
5
(
1.00)
22**
(
1.27)
[
50]
12**
(
1.08)
36**
(
1.33)
5
(
1.00)
26**
(
1.19)

Data
taken
from
Tables
55
(
pp.
445­
484)
and
57
(
pp.
489­
531),
MRID
46582801.
aaverage
severity
of
the
animals
with
lesions,
calculated
by
the
reviewer:
1
=
minimal,
2
=
mild,
3
=
moderate.
*
p#
0.05,
**
p#
0.01,
statistically
significant
D.
Adequacy
of
Dosing
for
Assessment
of
Carcinogenicity
Dosing
was
considered
adequate
for
this
study
based
on
decreased
body
weight
(
96­
11%,
p<
0.01)
and
weight
gain
(
921­
92%,
p<
0.01),
induction
of
non­
neoplastic
lesions
in
the
thyroid,
pharynx,
esophagus,
stomach,
and
pituitary
gland,
as
well
as
the
changes
in
serum
hormone
levels
(
TSH
and
T4).

IV.
TOXICOLOGY
1.
Metabolism
A
rat
metabolism
study
comparing
absorption
after
oral
and
inhalation
administration
is
available.
Sprague­
Dawley
rats
were
orally
dosed
or
exposed
via
inhalation
with
[
14C]
CH
3
I.
Maximum
blood
concentrations
were
achieved
within
4
hours
(
oral)
and
0­
2
hours
(
inhalation),
and
were
proportional
to
dose/
concentration.
Initial
t
½
was
5.1­
7.2
hours,
and
terminal
t
½
was
116­
136
hours.
Radioactivity
recovery
was
low
in
the
main
test
due
to
inefficient
CO
2
trapping.
Overall
recovery
in
the
supplementary
test
was
increased
due
to
increased
recovery
of
carbon
dioxide.
Recovered
radioactivity
was
primarily
as
CO
2
(
39.40­
60.81%
dose)
and
in
the
urine
(
26.50­
33.40%
dose)
in
all
treated
groups,
while
feces
accounted
for
<
2%
dose.
Radioactivity
remained
in
the
carcasses
(
11.92­
14.39%
dose)
of
all
treated
animals
168
hours
following
treatment
in
the
main
test.
Elimination
t
½
were
17.8­
22.3
hours
for
urine
and
29.7­
38.0
hours
for
feces
in
all
treatment
groups
of
the
main
test.
The
elimination
t
½
was
5.8­
6.8
hours
for
CO
2
in
all
treatment
groups
of
the
supplementary
test.
These
half­
lives,
however,
are
measured
on
the
basis
of
the
14C
radiolabel
and
may
not
accurately
reflect
the
amount
of
iodomethane
or
iodide
remaining
in
the
body
since
the
methyl
and
iodide
moieties
of
iodomethane
are
expected
to
quickly
dissociate
after
administration.
IODOMETHANE
CANCER
ASSESSMENT
DOCUMENT
FINAL
17
At
0­
1
hour
post­
treatment
in
orally
treated
rats
and
233
ppm
inhalation
exposed
rats,
relatively
high
levels
of
radioactivity
were
observed
in
the
liver
and
GI
tract.
Radioactivity
was
relatively
high
in
the
kidney,
lung,
and
nasal
turbinates
of
the
25
ppm
inhalation
exposed
rats
and
in
the
kidney,
thyroid,
and
lung
of
the
233
ppm
inhalation
exposed
rats.
At
6
hours
post­
oral
dosing,
tissue
concentrations
increased
in
the
spleen
(
at
1.5
mg/
kg
only),
kidney,
brain,
thyroid,
lung,
nasal
turbinates,
and
fat
(
at
1.5
mg/
kg
only).
Tissue
concentrations
decreased
in
all
tissues
of
the
inhalation
exposed
rats
at
6
hours
after
exposure.
At
168
hours
post­
dose,
radioactivity
had
declined
in
all
tissues
and
was
highest
in
the
kidney,
liver,
and
thyroid.
The
data
in
this
study
indicate
that
iodomethane
is
quickly
absorbed
through
both
routes
of
exposure
(
maximum
blood
concentration
at
2­
4
hours).
In
contrast,
the
elimination
profile
indicates
that
excretion
of
14Clabeled
iodomethane
is
biphasic
with
the
initial
half­
life
of
5­
7
hours
and
a
terminal
half­
life
of
approximately
116­
136
hours.
Radioactivity
accumulates
in
a
variety
of
tissues
including
the
thyroid
(
radioactivity
concentration
of
106­
198
:
g/
g
tissue).

Since
inorganic
iodide
levels
in
the
serum
have
been
implicated
in
the
MOA
proposed
by
the
registrant
for
both
the
rabbit
fetal
losses
and
the
rat
thyroid
tumorigenesis,
serum
inorganic
iodide
concentrations
were
measured
in
several
studies
including
a
2
Day
Inhalation
Toxicity
Study
in
rats
exposed
to
0,
25,
or
100
ppm
iodomethane
for
6
hours/
day.
Serum
sample
in
this
study
were
collected
at
0,
1,
3,
6,
9,
24,
25,
27,
30,
33
,
and
48
hours.
Inorganic
iodide
increased
dramatically
during
the
exposure
period
at
the
25
and
100
ppm
concentrations
(
8.300­
1400X
and
1300­
3500X,
respectively).
Forty
eight
hours
after
iodomethane
exposure
inorganic
iodide
serum
concentrations
were
still
53X
and
321X
higher
than
controls.
In
general,
serum
iodide
concentrations
exhibited
a
biphasic
pattern
with
peaks
occurring
at
approximately
3­
9
hours
and
at
30­
33
hours
of
exposure.
A
similar
pattern
of
iodide
disposition
was
observed
in
a
MOA
study
in
rabbits
designed
to
further
characterize
the
fetal
losses
seen
in
various
Developmental
Toxicity
Studies
in
rabbits.
Additional
information
on
these
experiments
is
provided
on
the
Mode
of
Action
section
of
this
document.

Also
available
is
a
series
of
in
vitro
studies
designed
to
determine
partition
coefficients
for
rat
and
rabbit
tissues,
rabbit
fetal
and
maternal
blood,
and
human
blood.
Overall,
the
partition
coefficients
for
rat
and
rabbit
tissues
(
brain,
fat,
kidney,
muscle,
and
nasal
tissue)
were
similar.
Some
speciesdependent
variability
in
partition
coefficients
was
detected.
Specifically,
the
partition
coefficient
for
rabbit
thyroid
gland
tissue
was
3­
fold
greater
than
that
for
rats
(
39:
11)
and
the
partition
coefficient
for
rat
liver
tissue
was
2­
fold
greater
(
24:
13)
than
that
for
rabbit.
The
partition
coefficients
for
rat,
rabbit
and
human
blood
were
39,
16,
and
18,
respectively.
Partition
coefficients
for
male
and
female
human
blood
were
similar
and
partition
coefficients
for
rabbit
maternal
and
fetal
blood
were
similar
(
12:
16).
These
data
were
collected
to
provide
critical
information
for
the
development
of
a
computational
fluid
dynamics
PB­
PK
model
for
use
in
risk
assessment
for
iodomethane.

2.
Mutagenicity
IODOMETHANE
CANCER
ASSESSMENT
DOCUMENT
FINAL
18
With
the
exception
of
a
positive
finding
in
the
In
Vitro
Chromosomal
Aberration
in
Chinese
Hamster
Ovary
Assay,
all
guideline
mutagenicity
studies
submitted
by
the
registrant
were
negative
for
mutagenicity.
However,
there
are
numerous
reports
in
the
peer­
reviewed
literature
that
indicate
methyl
iodide
is
mutagenic
in
a
variety
of
in
vitro
and
in
vivo
assays.
Given
that
iodomethane
is
highly
volatile,
it
is
possible
that
the
guideline
studies
were
negative
because
the
compound
was
not
"
in
contact"
with
the
cells
for
a
sufficient
period
of
time
to
cause
its
mutagenic
effect.

(
i)
In
an
Ames
assay,
when
tested
in
Salmonella
typhimurium
strains
TA98,
TA100,
TA1535,
and
TA1537;
and
in
Escherichi
coli
at
concentrations
ranging
from
0.015­
5000
µ
g/
plate
iodomethane
was
non
mutagenic
with
or
without
metabolic
activation
(
MRID
No.
45593813).

(
ii)
In
an
In
vitro
Chromosomal
Aberrations
in
Chinese
Hamster
Ovary
Cells
Assay,
iodomethane
was
positive
for
structural
chromosome
aberrations
(
clastogenesis)
but
negative
for
induction
of
numerical
aberrations
at
exposures
concentrations
ranging
from
25­
350
µ
g/
mL
(
MRID
No.
45593815).

(
iii)
In
an
In
Vitro
Mammalian
Cell
Mutation
Test
in
Chinese
Hamster
Ovary
Cells,
iodomethane
was
negative
for
increases
in
mutant
colonies
(
with
or
without
metabolic
activation)
at
exposure
concentrations
ranging
from
100­
600
µ
g/
mL
(
MRID
45593815).

(
iv)
In
a
micronucleus
test,
no
increases
in
micronuclei
was
seen
following
a
single
intraperitoneal
injection
at
doses
of
25,
50,
or
100
mg/
kg
(
MRID
No.
45593816).

(
v)
Several
005366
studies
are
available
in
the
peer
reviewed
literature
(
see
Review
of
Iodomethane
Mutagenicity
Studies,
TXR
0053665).
In
general,
these
studies
provide
compelling
evidence
of
the
mutagenic
potential
of
iodomethane.

 
Based
on
a
revisit
of
the
mutagenicity
studies
submitted
by
the
Registrant
and
an
independent
assessment
of
the
data
from
the
open
literature,
HED
concludes
that:

C
Due
to
the
volatility
of
CH
3
I
at
42
°
C,
the
bacterial
reverse
gene
mutation
test
(
OPPTS
870.5100
(
§
84­
2)])
submitted
by
the
Registrant
(
MRID
45593813)
is
not
a
valid
study
and
is
unacceptable
because
the
provisions
claimed
by
TSG
were
not
included
in
the
Final
Report
and,
therefore,
could
not
be
verified.

C
There
is
convincing
evidence
that
CH
3
I
is
mutagenic
in
somatic
cells
(
producing
multiple
effects,
such
as
gene
mutations
and
chromosomal
aberrations)
from
a
diverse
range
of
phylogenetically
distinct
species
such
as
bacteria,
yeast,
and
mammalian
cells
but
only
if
steps
are
taken
to
contain
the
test
substance
(
e.
g.,
performing
the
assay
in
a
desiccator,
performing
the
assay
on
cultures
in
suspension,
or
using
sealed
petri
dishes;
if
a
filter
disc
IODOMETHANE
CANCER
ASSESSMENT
DOCUMENT
FINAL
19
is
used,
it
must
be
impregnated
and
placed
on
top
of
the
agar).

C
There
is
convincing
evidence
that
CH
3
I
is
DNA
reactive,
binds
to,
or
damages
DNA
from
multiple
test
systems
including
DNA
damage
in
bacteria,
in
vitro
and
in
vivo
DNA
adduct
formation.

C
There
are
positive
results
from
at
least
one
whole
animal
genetic
toxicology
assay
(
i.
e,
DNA
adduct
formation
in
the
liver,
lung,
stomach
and
forestomach
of
male
and
female
F344
rats
exposed
either
via
the
oral
or
inhalation
routes)
which
suggests
that
CH
3
I
has
a
systemic
genotoxic
effect.
IODOMETHANE
CANCER
ASSESSMENT
DOCUMENT
FINAL
20
H
H
H
Br
Iodinated
glycerol
3.
Structure­
Activity
Relationship
Methyl
bromide
has
been
classified
as
"
not
likely
to
be
carcinogenic
to
humans"
based
on
the
lack
of
carcinogenic
response
in
the
Combined
Chronic/
Carcinogenicity
Study
in
rats
and
the
Carcinogenicity
Study
in
Mice
although
there
was
evidence
of
mutagenicity
in
several
guideline
mutagenicity
studies.

CAS
No.
74­
83­
9
Methyl
chloride
has
been
classified
by
the
Agency
as
well
as
the
International
Agency
for
Research
on
Cancer
(
IARC)
"
not
classifiable
as
to
its
human
carcinogenicity."
However,
weak
to
moderate
mutagenicity
has
been
demonstrated
in
S.
typhimurium
(
albeit
at
high
concentrations),
and
an
increased
incidence
of
tumor
formation
(
benign
and
malignant)
in
B3C6F1
male
mouse
kidneys
at
doses
of
225
and
1000
ppm
does
provide
some
suggestive
information
of
carcinogenic
risk,
although
no
renal
tumors
were
found
in
female
mice
or
in
either
sex
of
rats
tested
in
the
same
study.

Iodinated
glycerol
(
which
contains
3­
iodo­
1,2­
propanediol
as
its
major
component),
a
close
structural
analog
of
iodomethane,
is
also
an
alkyl
iodide
with
alkylating
and
mutagenic
activities
and
has
been
shown
to
induce
the
same
type
of
thyroid
tumors
as
iodomethane.
However,
iodinated
glycerol
is
a
multi­
target
carcinogen
(
including
port
of
entry)
whereas
iodomethane's
carcinogenic
effect
seems
to
be
confined
to
the
thyroid
gland
in
rodents.
In
contrast,
a
number
of
nongenotoxic
iodinated
compounds
with
little
or
no
structural
similarity
to
iodomethane
(
e.
g.,
amiodarone,
potassium
iodide)
have
been
shown
to
elicit
similar
thyroid
carcinogenic
effects
as
iodomethane
suggesting
that
iodide
may
be
the
key
common
link
for
the
thyroid
activity.

Amiodarone
4.
Subchronic
and
Chronic
Toxicity
IODOMETHANE
CANCER
ASSESSMENT
DOCUMENT
FINAL
21
a)
Subchronic
Toxicity
In
a
subchronic
inhalation
toxicity
study
(
MRID
45593810),
rats
were
dynamically
exposed
to
iodomethane
vapor
for
6
hours/
day,
5
days/
week
for
13
weeks
at
analytical
concentrations
of
0,
5,
21,
or
70
ppm
(
0,
0.029,
0.12,
or
0.41
mg/
L/
day).
There
were
no
effects
on
mortality,
ophthalmology,
urinalysis,
hematology,
organ
weights,
or
gross
pathology.
The
NOAEL
is
21
ppm
(
0.12
mg/
L/
day),
and
the
LOAEL
is
70
ppm
(
0.41
mg/
L/
day)
based
on
initial
decreases
in
body
weights,
body
weight
gains,
and
food
consumption
(
males);
and
nasal
degeneration.
Respiratory
irritation
was
observed
at
the
interim
(
4
weeks)
and
terminal
sacrifices.
Microscopic
findings
indicated
minimal
to
mild
degeneration/
regeneration
of
the
nasal
tissues
characterized
by
subacute
inflammation,
respiratory
epithelial
metaplasia,
degeneration,
goblet
cell
hypertrophy,
squamous
cell
hyperplasia,
and
minimal
alveolar
macrophages
(
females
only).
Notably,
no
effects
on
thyroid
histopathology
were
observed
during
this
study
(
thyroid
hormone
levels
were
not
measured).

b)
Chronic
Toxicity
A
Chronic
Toxicity
Study
in
dogs
is
not
available
for
iodomethane.
Thus
the
only
studies
that
evaluate
the
potential
impact
of
chronic
exposure
to
iodomethane
are
the
Inhalation
Combined
Chronic
Toxicity/
Carcinogenicity
in
Rats
and
the
Dietary
Carcinogenicity
Study
in
Mice.
The
executive
summaries
on
non­
neoplastic
findings
for
these
two
studies
follow:

(
i)
EXECUTIVE
SUMMARY
for
Chronic
Toxicity
in
Rats:
Details
are
discussed
in
Section
III.

The
systemic
LOAEL
for
iodomethane
in
rats
is
20
ppm
based
on
increased
incidence
of
salivary
gland
squamous
cell
metaplasia.
The
NOAEL
is
5
ppm.
The
port­
of­
entry
LOAEL
is
60
ppm
based
on
increased
incidence
of
olfactory
epithelium
degeneration
and
cysts.
The
NOAEL
is
20
ppm.

(
ii)
EXECUTIVE
SUMMARY
for
Carcinogenicity
Study
in
Mice:
Details
are
discussed
in
section
III.

The
LOAEL
for
microencapsulated
iodomethane
in
mice
is
60
ppm
(
8
and
10
mg/
kg
bw/
day
for
males
and
females,
respectively)
based
on
histopathologic
findings
in
the
thyroid
gland
(
cytoplasmic
vacuolation
and
increased
colloid)
in
both
sexes,
and
hyperkeratosis
in
the
esophagus
of
females.
The
NOAEL
was
not
established.

c)
Open
Literature
IODOMETHANE
CANCER
ASSESSMENT
DOCUMENT
FINAL
1
Poirier,
LA
et
al.,
(
1975)
"
Bioassay
of
Alkyl
Halides
and
Nucleotide
Base
Analogs
by
Pulmonary
Tumor
Response
in
Strain
A
Mice"
Cancer
Res.
35:
1411­
1415
2
Pisarev
MA,
Gartner
R
(
2000).
Autoregulatory
actions
of
iodine.
In:
Braverman
LE,
Utiger
RD
eds.
Werner
and
Ingbar's
the
thyroid:
A
fundamental
and
clinical
text.
Pp
85­
90
22
In
addition
to
the
guideline
studies,
the
committee
discussed
two
rodent
bioassays
from
the
open
literature.
In
the
first
study,
strain
A
mice
were
exposed
once
weekly
to
0,
0.06,
0.15,
or
0.31
nmoles/
kg
mouse
of
iodomethane
via
intraperitoneal
injection
(
an
exposure
pathway
not
relevant
for
the
iodomethane
risk
assessment)
for
24
weeks.
A
slight
increase
in
the
average
number
of
lung
tumors/
mice
was
reported
at
the
highest
dose
tested
(
0.55
vs
0.28).
It
is
important
to
note,
however,
that
this
is
a
multiplicity
model
rather
than
an
incidence
model
since
the
strain
is
prone
to
developing
lung
tumors
in
the
absence
of
any
carcinogen.
Shimkin
and
Stoner
­
developers
of
this
assay
­
have
set
forth
criteria
for
interpretation
of
lung
tumor
data
in
the
strain
A
mouse.
The
first
criterion
is
that
lung
tumor
multiplicity
must
be
statistically
significant
higher
than
in
control
and
preferably
higher
than
1.1
In
the
case
of
iodomethane,
the
increased
incidence
was
statistically
significant
at
the
0.05
level
but
was
not
higher
than
1.
Thus
under
the
conditions
of
this
assay,
iodomethane
may
be
classified
as
a
weak
carcinogen.
In
the
second
study
obtained
from
the
literature,
535­
DB
strain
rats
received
a
weekly
dose
of
10
or
20
mg/
kg
iodomethane
via
subcutaneous
injection
(
an
exposure
pathway
not
relevant
for
the
iodomethane
risk
assessment).
These
rats
developed
local
sarcomas
which
occasionally
metastasized
into
the
lungs
and
lymph
nodes.
However,
the
study
had
to
be
terminated
earlier
than
expected
since
necrosis
frequently
occurred
at
the
injection
site.
It
is
important
to
note
that
when
the
compound
was
administered
via
the
oral
route
or
intravenous
injections
no
tumors
developed.
Thus
it
appears
that
the
carcinogenic
response
is
weak
given
the
induction
time
needed
to
elicit
the
tumorigenic
response
and
limited
to
the
port­
of­
entry.

5.
Mode
of
Action
Studies
Though
mechanistic
studies
specifically
designed
to
elucidate
the
mode
of
action
(
MOA)
leading
to
thyroid
tumorigenesis
are
not
available,
there
are
numerous
studies
that
indicate
perturbation
of
thyroid
hormone
homeostasis
is
a
critical
effect
of
iodomethane
exposure.
Alterations
in
serum
T
3
,
T
4
,
and
TSH
levels
have
been
seen
in
several
studies
in
rats,
mice,
and
rabbits.

The
registrant,
Arysta,
has
proposed
perturbations
of
thyroid
hormone
homeostasis
as
the
MOA
operative
in
the
thyroid
tumorigenic
response
to
iodomethane
exposure,
implicating
the
elevated
serum
levels
of
inorganic
iodide
as
a
critical
element
in
the
proposed
MOA.
Iodide
excess
inhibits
the
iodination
of
thyroglobulin
in
the
thyroid
gland
as
well
as
the
release
of
T
4
and
T
3
from
the
gland.
2
Both
effects
could
lead
to
an
increase
in
TSH
levels.
If
sustained,
this
increase
in
TSH
levels
can
result
in
thyroid
cell
hypertrophy,
hyperplasia,
and
eventually
tumor
formation.
Consequently,
excess
iodide
has
been
linked
to
the
development
of
antithyroidal
activity
and
IODOMETHANE
CANCER
ASSESSMENT
DOCUMENT
FINAL
3
USEPA
(
1998)
Assessment
of
Thyroid
Follicular
Cell
Tumors
Office
of
Research
and
Development,
Risk
Assessment
Forum;
EPA
report
no.
EPA/
630/
R­
97/
002
4
"
Mode
of
Action
Study
for
Iodomethane­
Related
Fetotoxicity
in
Rabbits"
(
MRID
46451002),
"
Iodide
in
rat
serum
by
ion
chromatography
study"
and
"
A
24­
Month
Inhalation
Combined
Chronic
Toxicity/
Carcinogenicity
Study
of
Iodomethane
in
Rats."
(
MRID
46512401)

5
"
An
18
month
dietary
carcinogenicity
study
of
miroencapsulated
iodomethane
in
mice."(
MRID
46582801)

23
thyroid
tumor
formation.
3
After
iodomethane
exposures,
dramatic
increases
in
inorganic
iodide
serum
levels
in
conjunction
with
changes
in
thyroid/
pituitary
hormone
serum
levels
have
been
detected
in
the
rat
(
Tables
9a
&
b)
as
well
as
the
rabbit
(
Tables
10a­
d).
4
Similar
to
the
pattern
of
thyroid/
pituitary
hormone
seen
in
rats
and
rabbits,
mice
also
exhibited
hormonal
perturbations
though
no
measures
of
serum
iodide
levels
are
available
for
this
species
(
Table
11).
5
It
is
noteworthy
that
thyroid
follicular
cell
tumors
in
mice
and
rats
are
only
seen
at
doses
eliciting
substantial
sustained
increases
in
TSH
serum
levels
in
rats
and
mice
(
8>
300
and
91%,
respectively).

Data
used
to
demonstrate
that
an
antithyroidal
activity
MOA
is
operative
include
increases
in
cellular
growth,
hormone
changes,
site
of
action
information,
dose
correlations,
reversibility,
lesion
progression,
and
structure
activity
relationships.
With
the
exception
of
reversibility,
the
iodomethane
database
contains
information
on
all
these
elements
of
the
MOA.
Evidence
of
increased
cellular
growth
are
available
in
the
Combined
Chronic
Toxicity/
Carcinogenicity
Study
in
rats,
Carcinogenicity
Study
in
mice,
and
the
MOA
for
fetotoxicity
study
in
rabbits.

In
the
Combined
Chronic
Toxicity/
Carcinogenicity
Study
in
rats,
increases
in
both
absolute
and
relative
(
to
body
weight)
thyroid/
parathyroid
weights
(
883­
197%
and
110­
229%,
respectively)
and
increases
in
the
incidence
of
follicular
cell
hyperplasia
(
30%
vs
0%
control)
were
observed
in
male
rats
exposed
at
the
dose
level
(
60
ppm)
where
thyroid
tumors
were
seen.
Moreover,
T
3
serum
hormone
levels
were
reduced
by
.11­
34%
while
TSH
was
increased
by
.300­
1100%
(
changes
in
T
4
levels
were
inconsistent
throughout
the
study)
[
Table
9b].
No
thyroid
tumors
were
seen
at
dose
levels
that
failed
to
cause
increases
in
thyroid/
parathyroid
weights,
follicular
cell
hyperplasia,
and
sustained
thyroid/
pituitary
hormone
perturbations.
In
terms
of
the
site
of
action,
given
the
essential
role
of
iodine
in
the
proper
function
of
the
thyroid
gland
(
both
iodine
deficiency
and
excess
can
have
profound
effects
on
thyroid
function
and
thyroid
hormone
biosynthesis)
and
the
fact
that
iodomethane
exposure
leads
to
an
excess
accumulation
of
iodine
in
the
thyroid,
it
appears
that
the
proposed
MOA
for
iodomethane's
thyroid
tumorigenic
response
is
mediated
by
an
intrathyroidal
site
of
action
[
Tables
9a
and
10a&
b].
Progression
of
lesions
was
also
demonstrated
in
this
study.
An
increased
incidence
of
thyroid
follicular
cell
hyperplasia
but
not
neoplastic
lesions
was
evident
at
the
interim
histopathological
examination
(
week
52)
while
both
hyperplasia
IODOMETHANE
CANCER
ASSESSMENT
DOCUMENT
FINAL
24
and
neoplastic
lesions
were
observed
at
the
end
of
the
study
(
week
104).

In
the
Carcinogenicity
Study
in
mice,
increases
in
the
absolute
and
relative
(
to
body)
thyroid
weights
were
reported
for
males
at
all
dose
levels
(
8133­
138%
and
152­
157%,
respectively)
in
conjunction
with
an
increased
incidence
of
follicular
cell
hyperplasia
at
the
highest
dose
tested
only
(
12%
vs.
0
in
control).
Interestingly,
though
thyroid/
parathyroid
weights
and
follicular
cell
hyperplasia
incidences
were
increased
at
all
dose
levels
in
females,
no
progression
to
follicular
cell
adenomas
and/
or
carcinomas
was
seen
for
females
while
males
exhibited
a
tumorigenic
response
(
albeit
weak).
A
dose­
related
increase
in
TSH
(
853­
91%)
was
reported
for
males
but
not
females
accompanied
by
a
slight
reduction
in
T
4
(
9#
30%).

Changes
in
hormone
levels
were
also
noted
in
the
MOA
study
for
iodomethane­
related
fetotoxicity
in
rabbits.
When
animals
were
exposed
to
20
ppm
iodomethane
for
4
days,
maternal
TSH
levels
were
increased
by
29­
56%,
T
3
was
decreased
11­
23%,
and
T
4
was
decreased
20­
71%.
Fetal
TSH
was
unaffected
by
maternal
exposure
to
iodomethane
but
T
3
was
decreased
(
919­
29%).
Histopathology
evaluation
revealed
an
increase
in
the
incidence
of
follicular
cell
hypertrophy
in
dams
(
40%
vs
0
controls)
and
fetuses
(
100%
vs
0
control)
after
4
days
of
exposure.
Interestingly,
the
fetal
incidence
of
follicular
cell
hypertrophy
after
a
4
day
recovery
period
was
54%.
Since
exposure
to
iodomethane
in
this
study
was
only
for
four
days,
no
data
are
available
to
ascertain
what
the
impact
of
prolonged
exposure
would
have
been
on
the
rabbit
thyroid.
However,
the
effects
seen
after
such
a
brief
exposure
does
provide
some
insight
into
the
overall
pattern
of
thyroid
toxicity
seen
after
iodomethane
exposure.

Though
there
are
abundant
data
suggesting
that
iodomethane
induces
thyroid
follicular
cell
tumors
through
an
antithyroidal
MOA,
the
fact
that
iodomethane
has
been
shown
to
have
mutagenic
properties
precludes
the
exclusion,
at
this
time,
of
mutagenicity
as
a
contributing
factor
in
thyroid
tumorigenesis.
However,
if
mutagenicity
was
contributing
to
tumorigenesis,
portal­
of­
entry
(
respiratory
tract)
tumors
would
be
expected.
IODOMETHANE
CANCER
ASSESSMENT
DOCUMENT
FINAL
25
TABLE
9a.
Serum
iodide
(
inorganic)
in
rats
following
inhalation
exposure
to
iodomethane:

Exposure
group
(
ppm)
Collection
time
(
hrs)
Inorganic
iodide
(
ng/
ml)
a
0
0
1
3
6
9
24
25
27
30
33
48
17b
17b
19b
22b
39b
19b
14b
14b
4.1b
13b
14b
25
1
3
6
9
24
25
27
30
33
48
5070
±
721
9510
±
3800
25,600
±
1940
18,400
±
1550
1260
±
83.9
5960
±
576
10,800
±
1100
34,100
±
8170
24,700
±
1310
742
±
141
100
1
3
6
9
24
25
27
30
33
48
22,900
±
1620
60,300
±
2860
53,800
±
4480
52,500
±
8230
8170
±
1850
27,200
±
13,700
55,200
±
3050
83,200
±
7840
58,300
±
6520
4500
±
396
a
Mean
±
SD
of
3
rats
b
estimate
at
or
below
limit
of
quantitation;
overall
mean
±
SD
for
control
(
0
ppm)
group
was
17
±
9
ng/
ml
Data
taken
from
Table
V,
p.
23,
Exygen
Study
No.
P0000882
IODOMETHANE
CANCER
ASSESSMENT
DOCUMENT
FINAL
26
TABLE
9b.
Changes
in
serum
thyroid
hormone
levels
in
rats
exposed
to
Iodomethane
by
inhalationa
Parameter
Exposure
concentration
(
ppm)

0
5
20
60
0
5
20
60
Males
Females
Week
26
T3
(
ng/
dL)
57.50
±
5.80
51.40
±
18.63
57.12
±
21.19
38.08
±
16.27
(
66)
b
67.54
±
28.27
55.38
±
17.05
80.12
±
21.93
49.44
±
19.65
(
73)

T4
(
µ
g/
dL)
3.87
±
0.99
3.38
±
0.44
3.24
±
0.47
1.71
±
1.41**
(
44)
2.03
±
0.59
1.68
±
0.57
1.93
±
0.51
1.78
±
0.65
(
88)

TSH
(
ng/
mL)
2.46
±
1.23
3.78
±
1.86
4.92
±
3.87
30.53
±
13.69**

(
1241)
1.76
±
0.62
1.76
±
0.54
2.09
±
0.66
12.92
±
13.36**

(
734)

rT3
(
ng/
mL)
0.13
±
0.05
0.12
±
0.05
0.11
±
0.05
0.15
±
0.03
0.10
±
0.05
0.11
±
0.03
0.15
±
0.05
0.19
±
0.09
(
190)

Week
52
T3
(
ng/
dL)
43.23
±
11.36
38.95
±
15.64
51.34
±
40.35
38.29
±
11.37
(
89)
81.78
±
33.13
78.70
±
20.46
60.10
±
9.84
72.55
±
15.68
(
89)

T4
(
µ
g/
dL)
2.56
±
0.82
2.45
±
0.85
3.44
±
0.69
3.42
±
0.81*
(
134)
2.02
±
0.27
2.16
±
0.45
1.74
±
0.30
2.23
±
0.60
TSH
(
ng/
mL)
2.25
±
0.90
2.26
±
0.64
3.60
±
2.79
9.11
±
11.38
(
405)
2.61
±
0.70
3.33
±
1.91
2.87
±
1.31
5.49
±
6.37
(
210)

rT3
(
ng/
mL)
0.09
±
0.03
0.09
±
0.05
0.09
±
0.04
0.19
±
0.05**
(
211)
012
±
0.04
014
±
0.06
0.09
±
0.02
0.33
±
0.16**
(
275)

Week
104
T3
(
ng/
dL)
49.79
±
21.02
52.77
±
20.97
50.01
±
20.80
44.28
±
15.86
(
89)
72.72
±
32.39
70.90
±
19.28
65.93
±
23.96
64.82
±
22.16
(
89)

T4
(
µ
g/
dL)
2.25
±
0.73
2.27
±
0.73
2.24
±
0.97
2.50
±
0.58
1.55
±
0.99
1.56
±
0.69
1.96
±
0.75
2.47
±
0.98**
(
159)

TSH
(
ng/
mL)
2.38
±
1.13
3.29
±
1.61
3.48
±
1.77
11.29
±
14.92**

(
474)
2.52
±
0.99
2.93
±
1.78
3.78
±
2.94
3.98
±
6.28
(
158)

rT3
(
ng/
mL)
0.03
±
0.03
0.04
±
0.03
0.04
±
0.03
0.07
±
0.05**
(
233)
0.05
±
0.03
0.09
±
0.04
0.20
±
0.12**
0.24
±
0.12**
(
480)

Data
obtained
from
pages
3594­
3599
of
MRID
46512401
a
Values
are
group
means
±
SD
bNumbers
in
parentheses
are
percent
of
control
values
calculated
by
the
reviewer.

*
p
<
0.05;
**
p
<
0.01;
all
T4
and
TSH
as
well
as
T3
and
rT3
at
104
weeks
analyzed
using
Dunnett's
test;
T3
and
rT3
analyzed
using
the
Kruskal­
Wallis
test
at
weeks
26
and
52
IODOMETHANE
CANCER
ASSESSMENT
DOCUMENT
FINAL
27
Table
10a.
Inorganic
Iodide
Concentrations
in
Maternal
Rabbits
(
Does)
after
MeI
administration
via
the
Inhalation
Route
Maternal
Exposure
Gestation
Day/
Time
of
sampling
after
start
of
daily
exposure
Serum
Iodide
Concentrations
(
ng/
mL)

Group
1
(
0
ppm)
Group
2
(
20
ppm
MeI)

GD23
GD23
3
hrs
6.89
±
2.28
7500
±
488*
(
81089X)

GD23
6
hrs
48.6
±
56.6
9570
±
4750*
(
8197X)

GD23­
24
GD24
0
hrs
§

23.5
±
19.7
1740
±
1340
(
874X)

GD24
6
hrs
23.5
±
13.4
14300
±
2360*
(
8609X)

GD23­
25
GD25
12
hrs
14.3
±
6.4
5110
±
1760*
(
8357X)

GD25
18
hrs
19.7
±
11.4
4470
±
3250*
(
8227X)

GD23­
26
GD26
0
hrs
§

5.18
±
0.09
3610
±
1200*
(
8697X)

GD26
6
hrs
10.5
±
7.0
16600
±
6800*
(
81581X)

Excerpted
from
Appendix
I
pp.
438­
453
(
MRID
46451002)
§
t=
0
hrs.
indicates
that
sampling
was
conducted
prior
to
daily
exposure
*
Statistically
different
(
p<
0.05)
from
control
Numbers
presented
parenthetically
represent
change
from
control.
IODOMETHANE
CANCER
ASSESSMENT
DOCUMENT
FINAL
28
Table
10b.
Inorganic
Iodide
Concentrations
in
Rabbit
Fetuses
after
maternal
MeI
administration
via
the
Inhalation
Route
Fetal
Exposure
Gestation
Day/
Time
of
sampling
after
start
of
daily
exposure
Serum
Iodide
Concentrations
(
ng/
mL)

Group
1
(
0
ppm)
Group
2
(
20
ppm
MeI)

GD23
GD23
3
hrs
114
±
14
15100
±
4620*
(
8132X)

GD23
6
hrs
179
±
77
27800
±
9250*
(
8155X)

GD23­
24
GD24
0
hrs
§

155
±
24
8960
±
4830*
(
858X)

GD24
6
hrs
154
±
11
33200
±
11900*
(
8216X)

GD23­
25
GD25
12
hrs
161
±
16
40100
±
15700*
(
8249X)

GD25
18
hrs
217
±
55
32000
±
12800*
(
8147)

GD23­
26
GD26
6
hrs
171
±
66
72600
±
23200*
(
8425X)

Excerpted
from
Appendix
I
pp.
438­
453
(
MRID
46451002)
§
t=
0
hrs.
indicates
that
sampling
was
conducted
prior
to
daily
exposure
*
Statistically
different
(
p<
0.05)
from
control
Numbers
presented
parenthetically
represent
change
from
control.
IODOMETHANE
CANCER
ASSESSMENT
DOCUMENT
FINAL
29
Table
10c.
Rabbit
Maternal
(
Does)
Thyroid/
Pituitary
Hormone
Concentrations
in
Serum
Maternal
Exposure
(
Time
of
Euthanasia
After
Initiation
of
Daily
Exposure)
Hormone
Concentration
Group
1
(
0
ppm)
Group
2
(
20
ppm
MeI)

GD23
(
6
hr)
TSH
(
ng/
mL)
0.5
±
0.10
0.52
±
0.19
T3
(
ng/
dL)
180
±
23.8
173
±
12.3
T4
(
µ
g/
dL)
1.76
±
0.27
1.75
±
0.40
GD24
(
6
hr)
TSH
(
ng/
mL)
0.46
±
0.11
0.62
±
0.04*
(
835%)

T3
(
ng/
dL)
173
±
16.4
158
±
19.7
(
99%)

T4
(
µ
g/
dL)
1.43
±
0.42
1.44
±
0.46
GD
25
(
12
hr)
TSH
(
ng/
mL)
0.56
±
0.05
0.68
±
0.20
(
821%)

T3
(
ng/
dL)
160
±
36.3
136
±
33.6
(
915%)

T4
(
µ
g/
dL)
1.33
±
0.24
0.95
±
0.85
(
929%)

GD26
(
6
hr)
TSH
(
ng/
mL)
0.58
±
0.24
0.58
±
0.15
T3
(
ng/
dL)
122
±
24.2
114
±
25.0
(
97%)

T4
(
µ
g/
dL)
0.60
±
0.38
0.84
±
0.89
(
840%)

GD29
TSH
(
ng/
mL)
0.56
±
0.11
1.05
±
0.65
(
888%)

T3
(
ng/
dL)
168
±
29.7
150
±
18.2
(
911%)

T4
(
µ
g/
dL)
0.77
±
0.35
0.40
±
0.36
(
948%)

Excerpted
from
Appendix
H,
Table
1,
page
380
(
MRID
46451002)
aNumbers
presented
parenthetically
represent
%
change
from
control
*
Statistically
different
(
p<
0.05)
from
control
IODOMETHANE
CANCER
ASSESSMENT
DOCUMENT
FINAL
30
Table
10d.
Rabbit
Fetal
Thyroid/
Pituitary
Hormone
Concentrations
in
Serum
Fetal
Exposure
(
Time
of
Euthanasia
After
Initiation
of
Daily
Exposure)
Hormone
Concentrations
Group
1
(
0
ppm)
Group
2
(
20
ppm
MeI)

GD23
(
0
hr)
TSH
(
ng/
mL)
1.2
±
0.1
1.1
±
0.2
T3
(
ng/
dL)
10.1
±
5.19
8.9
±
5.38
(
912%)
a
T4
(
µ
g/
dL)
0.12
±
0.12
0.07
±
0.02
(
942%)

GD23
(
6
hr)
TSH
(
ng/
mL)
1.2
±
0.4
1.1
±
0.2
T3
(
ng/
dL)
4.5
±
2.55
6.5
±
4.77
(
844%)

T4
(
µ
g/
dL)
0.07
±
0.03
0.10
±
0.05
(
843%)

GD24
(
0
hr)
TSH
(
ng/
mL)
1.5
±
0.2
1.0
±
0.2*
(
933%)

T3
(
ng/
dL)
11.3
±
4.27
10.1
±
6.34
(
911%)

T4
(
µ
g/
dL)
0.09
±
0.05
0.03
±
0.03
(
967%)

GD24
(
6
hr)
TSH
(
ng/
mL)
1.9
±
0.5
1.7
±
0.4
T3
(
ng/
dL)
10.4
±
2.01
13.6
±
4.63
(
831%)

T4
(
µ
g/
dL)
0.05
±
0.04
0.08
±
0.05
(
860%)

GD
25
(
12
hr)
TSH
(
ng/
mL)
1.7
±
0.4
2.7
±
0.6
(
859%)

T3
(
ng/
dL)
13.1
±
6.50
13.3
±
5.76
T4
(
µ
g/
dL)
0.20
±
0.11
0.06
±
0.09*
(
970%)

GD25
(
18
hr)
TSH
(
ng/
mL)
1.5
±
0.2
4.2
±
1.1*
(
8180%)

T3
(
ng/
dL)
12.0
±
2.44
13.2
±
5.61
(
810%)

T4
(
µ
g/
dL)
0.08
±
0.07
0.00
±
0.00
(
9100%)

GD26
(
6
hr)
TSH
(
ng/
mL)
1.9
±
0.9
5.1
±
1.5*
(
8168%)

T3
(
ng/
dL)
15.4
±
3.09
26.6
±
12.62
(
873%)

T4
(
µ
g/
dL)
0.06
±
0.04
0.03
±
0.05
(
950%)

GD29
TSH
(
ng/
mL)
1.1
±
0.2
4.4
±
3.4*
(
8300%)

T3
(
ng/
dL)
23.9
±
4.85
49.4
±
30.17
(
8107%)

T4
(
µ
g/
dL)
0.14
±
0.04
0.10
±
0.15
(
929%)

Excerpted
from
Appendix
H,
Table
2,
page
381
(
MRID
46451002)
aNumbers
presented
parenthetically
represent
%
change
from
control
*
Statistically
different
(
p<
0.05)
from
control
IODOMETHANE
CANCER
ASSESSMENT
DOCUMENT
FINAL
31
TABLE
11.
Serum
hormone
levels
in
male
and
female
mice
fed
microencapsulated
iodomethane
Parameter
Dietary
concentration
(
ppm)

0
60
200
600
Males
T3
(
ng/
dL)
71.49
±
16.686a
70.46
±
17.864
74.86
±
13.762
74.99
±
13.520
T4
(
µ
g/
dL)
2.68
±
0.742
2.60
±
0.976
2.55
±
0.942
1.87
±
0.570**
(
70)
b
TSH
(
µ
g/
mL)
0.45
±
0.140
0.54
±
0.210
0.69
±
0.277*
(
153)
0.86
±
0.468**
(
191)

Females
T3
(
ng/
dL)
62.17
±
17.453
58.76
±
10.346
67.27
±
22.063
68.81
±
18.407
T4
(
µ
g/
dL)
1.82
±
0.996
1.91
±
0.951
1.87
±
0.843
1.76
±
0.753
TSH
(
µ
g/
mL)
0.28
±
0.107
0.45
±
0.306
0.47
±
0.198
0.39
±
0.190
Data
taken
from
Table
32
and
33
(
pp.
265­
266),
MRID
46582801.
aMean
±
standard
deviation
bNumbers
in
parentheses
are
percent
of
control
calculated
by
the
reviewer.

V.
COMMITTEE'S
ASSESSMENT
OF
THE
WEIGHT­
OF­
THE
EVIDENCE
1.
Carcinogenicity
Evidence
of
carcinogenicity
was
seen
in
the
thyroid
glands
of
male
rodents
(
Sprague­
Dawley
rats
and
CD­
1
mice)
in
the
standard
bioassays.
Though
a
slight
increase
in
the
incidence
of
uterine
and
cervical
tumors
was
reported
for
female
mice,
these
lesions
were
not
considered
compound
related
(
see
rationale
below).

Rat
In
Sprague­
Dawley
male
rats,
thyroid
follicular
cell
tumors
(
adenomas
and
carcinomas)
noted
at
the
highest
concentration
tested
(
60
ppm)
were
considered
to
be
treatment
related
since:

<
there
were
significant
positive
trends
for
all
three
types
(
adenomas,
p<
0.01;
carcinomas,
p<
0.05;
combined
adenomas/
carcinomas,
p<
0.01),
as
well
as
significant
differences
in
the
pair­
wise
comparisons
of
the
60
ppm
dose
group
with
the
controls
for
adenomas
(
10/
42,
24%
p<
0.01,
vs
2/
45,
4%
controls)
and
combined
adenomas
and/
or
carcinomas,
(
12/
42,
29%
p<
0.05
vs.
4/
45,
9%
controls)

<
the
incidences
at
the
high
dose
exceeded
the
historical
control
ranges
for
adenomas
(
1.67­
12%)
and
for
carcinomas
(
0.87­
3.85%)
IODOMETHANE
CANCER
ASSESSMENT
DOCUMENT
FINAL
32
The
committee
concluded
that
the
dose
levels
tested
were
adequate
and
not
excessive
in
both
sexes
since
there
was
evidence
of
non­
neoplastic
lesions,
thyroid/
pituitary
hormone
changes,
body
weight
and
body
weight
gain
decreases.

Mice
In
the
CD­
1
mice,
thyroid
follicular
cell
tumors
were
observed
in
males
only.
These
tumors
were
considered
to
be
treatment­
related
because:

<
there
was
a
significant
positive
trend
for
combined
adenomas/
carcinomas
(
p<
0.05)

<
the
increased
incidence
of
thyroid
tumors
is
consistent
with
the
observations
in
the
Sprague­
Dawley
rats
<
the
incidences
exceeded
the
historical
control
range
for
adenomas
(
0­
2%),
although
not
for
carcinomas
(
0­
2%)

<
an
increase
in
thyroid
tumorigenesis
is
consistent
with
substantial
sustained
perturbations
of
thyroid/
pituitary
hormone
homeostasis
as
seen
after
iodomethane
exposure
A
slight
increase
in
the
incidence
of
uterine
and
cervical
fibromas
was
observed
in
female
CD­
1
mice.
Although
significant
positive
trends
for
cervical
fibromas
(
p<
0.05)
and
combined
cervical/
uterine
fibromas
(
p<
0.01)
were
reported,
the
lesions
were
not
considered
to
be
treatmentrelated
for
the
following
reasons:

<
Microscopic
in
size
<
Occurred
only
at
the
terminal
sacrifice
<
Had
no
precursor
lesions
(
hyperplasia)

<
Not
found
in
the
rat
bioassay
<
Fibromas,
consisting
primarily
of
collagen
fibers,
have
not
been
associated
with
chemical
carcinogenicity.

<
Moreover,
these
types
of
lesions
are
not
uncommon
in
the
reproductive
tract
of
female
mice
of
this
age.
 
A
comparison
with
historical
control
data
was
not
appropriate
since
the
number
of
tissue
samples
examined
in
this
study
far
exceeded
the
customary
number
of
sections
evaluated
for
historical
control
data.

The
committee
concluded
that
the
dose
levels
tested
in
this
study
were
adequate
to
assess
the
carcinogenicity
potential
of
iodomethane
based
on
the
increased
incidence
of
non­
neoplastic
lesions
in
the
thyroid,
esophagus,
pharynx,
stomach,
and
pituitary,
decreased
body
weights
(
96­
11%,
p<
0.01)
and
body
weight
gains
(
921­
92%,
p<
0.01),
as
well
as
changes
in
serum
thyroid/
pituitary
hormone
levels.

2.
Mutagenicity
IODOMETHANE
CANCER
ASSESSMENT
DOCUMENT
FINAL
33
Although
the
guideline
mutagenicity
studies
submitted
by
the
registrant
are
negative
for
genotoxicity,
there
is
concern
that
appropriate
measures
to
prevent
compound
volatilization
may
not
have
been
taken.
In
particular,
re­
evaluation
of
the
Bacterial
Reverse
Gene
Mutation
test
(
MRID
45593813)
indicates
that
this
is
a
"
no
test"
since
the
study
report
did
not
describe
what
measures
were
taken,
if
any,
to
keep
the
test
substance
"
in
contact"
with
the
cells.

Numerous
studies
in
the
open
literature
indicate
that
iodomethane
is
a
methylating
agent
and
consequently
a
potential
mutagen.
Evidence
of
this
mutagenic
potential
is
available
from
numerous
in
vitro
assays
and
one
in
vivo
assay
(
e.
g.,
S.
typhimurium,
E.
coli,
CHO
cells,
mouse
lymphoma
assay,
and
an
in
vivo
DNA
adduct
formation
test).

3.
Structure
Activity
Relationship
Methyl
bromide
(
MeBr),
a
monohalogenated
methane
like
iodomethane,
was
considered
with
regards
to
its
SAR
to
iodomethane.
MeBr
was
classified
as
"
not
likely
to
be
carcinogenic
to
humans"
based
on
the
lack
of
tumorigenic
response
in
two
rodent
bioassays
in
spite
of
several
positive
mutagenicity
assays.
Iodinated
glycerol
(
which
contains
3­
iodo­
1,2­
propanediol
as
its
major
component),
a
close
structural
analog
of
iodomethane,
is
an
alkyl
iodide
with
alkylating
and
mutagenic
activities
and
has
been
shown
to
induce
the
same
type
of
thyroid
tumors
as
iodomethane.
However,
iodinated
glycerol
is
a
multi­
target
carcinogen
(
including
port
of
entry)
whereas
iodomethane's
carcinogenic
effect
seems
to
be
confined
to
the
thyroid
gland
in
rodents.
In
contrast,
a
number
of
nongenotoxic
iodinated
compounds
with
little
or
no
structural
similarity
to
iodomethane
(
e.
g.,
amiodarone,
potassium
iodide)
have
been
shown
to
elicit
similar
thyroid
carcinogenic
effects
as
iodomethane
suggesting
that
iodide
may
be
the
key
common
link
for
the
thyroid
activity.

4.
Mode
of
Action
There
is
compelling
evidence
indicating
that
iodomethane
induces
thyroid
follicular
cell
tumors
through
an
antithyroidal
MOA.
Although
iodomethane
has
been
shown
to
be
mutagenic
primarily
in
in
vitro
studies
and
produced
DNA
adducts
in
one
study
in
rats,
the
weight­
of­
evidence
(
WOE)
indicates
that
perturbation
of
thyroid
homeostasis
is
the
key
event
in
the
thyroid
tumorigenic
response
observed
after
iodomethane
exposure.

Among
the
evidence
supporting
an
antithyroidal
MOA
is
the
observation
that
only
male
rodents
exhibit
increases
in
thyroid
tumors.
This
is
a
common
response
pattern
for
classical
antithyroidal
agents.
In
addition,
the
increases
of
cell
growth
in
vivo
(
e.
g.,
increases
in
thyroid
weights
and
hyperplasia)
progressing
to
follicular
cell
tumors
were
only
seen
in
the
presence
of
thyroid/
pituitary
hormone
changes
(
decreased
T
3
and
T
4
in
conjunction
with
profound
TSH
increases)
thus
exhibiting
a
pattern
of
both
dose
and
temporal
concordance.
In
a
1998
review
article,
Hard
states
that
"
genotoxic
chemicals
able
to
induce
thyroid
cancer
in
rodents
have
different
morphological
and
physiological
effects
from
those
of
known
goitrogens."
Characteristics
of
goitrogen­
induced
IODOMETHANE
CANCER
ASSESSMENT
DOCUMENT
FINAL
6
Hard,
G.
C.
(
1998).
Recent
Developments
in
the
Investigation
of
Thyroid
Regulation
and
Thyroid
Carcinogenesis.
Environ.
Health
Perspect.
106(
8):
427­
436.

7
Toxic
Responses
of
the
Endocrine
System
in
Casarett
&
Doull's
Toxicology
The
Basic
Science
of
Poisons.
Fifth
edition
(
1995),
Curtis
D.
Klaassen,
ed.

34
tumors
include:
(
i)
diffuse
follicular
cell
hyperplasia,
(
ii)
increases
in
thyroid
weights
preceding
tumor
formation,
(
iii)
sustained
increases
in
serum
TSH
levels,
and
(
iv)
changes
in
serum
T
4
levels.
In
contrast,
mutagen­
induced
thyroid
tumors
involve
the
formation
of
focal
atypical
hyperplasia
(
originating
from
single
follicles)
and
do
not
involve
changes
in
thyroid/
pituitary
hormone
economy
or
changes
in
thyroid
weights
unrelated
to
tumor
development.
6
The
fact
that
iodomethane
exposure
leads
to
a
dramatic
increase
in
serum
iodide
levels
coupled
with
the
changes
in
thyroid/
pituitary
hormone
levels,
thyroid
weights,
and
diffuse
follicular
cell
hyperplasia
points
to
an
intrathyroidal
site
of
action
further
supported
by
the
fact
that
excess
iodide
is
widely
recognized
as
a
goitrogenic
agent.
7
Evidence
suggesting
that
a
mutagenic
MOA
may
be
operative
in
the
iodomethane
thyroid
tumor
response
include
positive
results
in
in
vitro
gene
mutation
and
chromosome
aberration
assays
as
well
as
formation
of
methyl
DNA
adducts
in
the
liver,
lung,
forestomach
and
stomach
of
rats
(
thyroid
not
examined)
following
oral
or
inhalation
exposure.
In
contrast,
several
lines
of
evidence
indicate
that
mutagenicity
is
not
the
MOA
for
thyroid
follicular
cell
tumor
formation.
For
instance,
the
majority
of
the
neoplastic
lesions
observed
after
iodomethane
exposure
were
benign
and
were
observed
at
the
terminal
sacrifice
unlike
tumors
induced
through
a
mutagenic
MOA.
Other
aspect
that
contradicts
a
mutagenic
MOA
is
that
although
DNA
adducts
are
found
in
multiple
organs
(
e.
g.,
liver,
lungs,
forestomach)
tumors
are
only
seen
in
the
thyroid
in
the
rodent
bioassays.
This
is
consistent
with
the
observation
that
in
standard
rodent
bioassays,
no
thyroid
carcinogen
acting
by
a
mutagenic
MOA
has
been
identified
that
does
not
induce
tumors
at
multiple
sites.
SAR
also
points
to
a
non­
mutagenic
MOA
for
thyroid
tumorigenesis
since
(
i)
methyl
bromide
­
a
methylating
and
mutagenic
agent
­
structurally
related
to
iodomethane
did
not
show
evidence
of
tumorigenesis
in
any
of
the
rodent
bioassays
and
(
ii)
non­
genotoxic
iodinated
compounds
elicit
a
similar
pattern
of
thyroid
tumor
formation
in
the
absence
of
tumors
at
other
sites.
Furthermore,
the
incidence
of
neoplastic
lesions
attributed
to
chlorate
and
perchlorate
­
two
non­
mutagenic
thyroid
carcinogens
with
an
antithyroidal
site
of
action
­
is
similar
to
what
is
observed
after
iodomethane
exposure.
Finally,
the
lack
of
a
tumorigenic
response
at
the
port­
of­
entry
(
respiratory
tract)
in
the
Inhalation
Combined
Chronic/
Carcinogenicity
study
in
rats
also
demonstrates
that
mutagenicity
is
not
contributing
to
the
carcinogenic
profile
of
iodomethane
since
tumors
in
the
respiratory
tract
(
particularly
the
nasal
cavity)
would
be
expected
if
iodomethane
were
acting
through
a
mutagenic
MOA.
VI.
CLASSIFICATION
OF
CARCINOGENIC
POTENTIAL
In
accordance
with
the
EPA's
Final
Guidelines
for
Carcinogen
Risk
Assessment
(
March,
2005),
the
CARC
classified
Iodomethane
as
"
Not
likely
to
be
Carcinogenic
to
humans
at
doses
that
do
not
IODOMETHANE
CANCER
ASSESSMENT
DOCUMENT
FINAL
8
Mileson,
B.
E.
et.
al.
(
2005).
Risk
Assessment
of
Thyroid
Follicular
Cell
Tumors
in
Rats
Following
2­
year
Iodomethane
Exposure
by
Inhalation.

35
alter
rat
thyroid
hormone
homeostasis."
This
was
based
on
the
evidence
that
rats
are
substantially
more
sensitive
than
humans
to
the
development
of
thyroid
follicular
cell
tumors
in
response
to
thyroid
hormone
imbalance.
The
committee
concluded
that
the
key
event
that
influences
the
thyroid
tumor
response
is
the
sustained
stimulation
of
cell
proliferation
by
TSH
consistent
with
the
increase
in
thyroid
follicular
cell
tumors
only.

VII.
QUANTIFICATION
OF
CARCINOGENIC
POTENTIAL
The
point
of
departure
for
the
iodomethane
long­
term
inhalation
risk
assessment
will
be
based
on
salivary
gland
metaplasia.
This
endpoint
is
more
sensitive
than
the
effects
on
thyroid
hormone
homeostasis;
the
human
equivalent
concentration
NOAELs
(
HEC
NOAEL
)
calculated
for
the
effect
are
(
0.89
ppm
and
3.75
ppm,
for
non­
occupational
and
occupational
risk
assessments,
respectively).
In
contrast,
the
HEC
NOAELs
calculated
for
thyroid
hormone
perturbations
using
the
PBPK
model
submitted
by
the
registrant
are
.
6.6
ppm
and
26
ppm
for
non­
occupational
exposures
and
occupational
exposures,
respectively.
8
Consequently,
the
use
of
the
salivary
gland
and
port­
of­
entry
effects
for
risk
assessment
purposes
will
be
protective
of
the
effects
on
thyroid
hormone
homeostasis
which
may
lead
to
other
non­
cancer
adverse
health
outcomes
(
e.
g.,
goiter
and
neurodevelopmental
deficits).
IODOMETHANE
CANCER
ASSESSMENT
DOCUMENT
FINAL
36
VIII.
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(
2005)
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Recent
Developments
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Regulation
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Carcinogenesis.
Environ.
Health
Perspect.
106(
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436.

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Responses
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the
Endocrine
System
in
Casarett
&
Doull's
Toxicology
The
Basic
Science
of
Poisons.
Fifth
edition
(
1995),
Curtis
D.
Klaassen,
ed.

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