Document ID: EPA-HQ-ORD-2006-0187-0122
Agency: epa
Document Type: Supporting & Related Material
Title: 
Posted Date: 2006-04-06T04:00Z

1
NRDC
comments
for
the
HSRB
meeting
April
4­
6,
2006
Jennifer
Sass,
Ph.
D.

Public
health
program
Washington,
DC
Tel:
202­
289­
6868;
www.
nrdc.
org
2
ALDICARB
(
N­
methyl
carbamate)

°
Banned:
Libya,
Tanzania,
Indonesia,

Finland,
Sweden,
St.
Lucia,
Kuwait
°
Restricted:
Morocco,
Sudan,
Togo,

Germany,
Argentina,
Belize,

°
Listed
by
WHO
as
1a,
extremely
hazardous
EPA
used
this
study
as
follows:

EPA
single
chemical
assessment
used
human
study
with
rat
data
to
develop
a
BMD.

UF=
300
(
10X
intra,
3X
inter,
10X
LOAEL
to
NOAEL
EPA
cumulative
assessment
used
human
study
to
calculate
the
ratio
of
rat:
human
ChEi.
This
lead
to
a
2X
inter
UF.
3
Aldicarb
effects
on
humans
0.075
0.025
0.0023
0.05
0.01
0
0.01
0.02
0.03
0.04
0.05
0.06
0.07
0.08
Rhone­
Poulenc
Union
Carbide
Goldman
et
al.

mg/

kg
LOEL
NOEL
EPA
using
R­
P
study
with
LOAEL
(
0.05);
EPA
considered
U­
C
study
ethically
flawed;
EPA
did
not
consider
Goldman
incident
data
4
Incident
data
(
Goldman
et
al,
1990)

Estimated
dosages
ranged
between
0.0023
­

0.06
mg/
kg;
most
were
well
below
0.05
mg/
kg
(
LOAEL)

Goldman
LR,
Beller
M,
Jackson
RJ.
1990.
Aldicarb
food
poisonings
in
California,
1985­
1988:
toxicity
estimates
for
humans.
Arch
Environ
Health,
May­
June,
45(
3):
141­
147.
Erratum
in:
Arch
Environ
Health
1990
Nov­
Dec;
45(
6):
following
380
5
(
Goldman
et
al,
1990)

A
total
of
28
cases,
defined
as
nausea,
vomiting,

diarrhea
within
2
h
of
produce
consumption.

The
lowest
dosage
associated
with
illness
(
0.0023
mg/
kg)
was
a
66­
yr
old
woman,
who
ate
a
contaminated
cucumber.
"
Within
45
minutes
she
experienced
nausea,
vomiting,
sweating,
dizziness,

loss
of
balance,
disorientation,
and
fatigue."

more
severe
illnesses
requiring
hospital
treatment
occurred
only
in
cases
with
estimated
dosages
greater
than
0.01
mg/
kg
body
weight.

One
person
required
atropine
treatment
following
an
estimated
dose
of
0.054
mg/
kg,
what
EPA
has
termed
a
LOAEL
6
Rhone­
Poulenc,
1992
single
oral
dose
double­
blind,
placebo
controlled
study
of
aldicarb
given
to
healthy
male
and
female
subjects.

Doses:
placebo
(
16
males
and
6
females),
0.01
mg/
kg
(
8
males),
0.025
mg/
kg
(
8
males
and
4
females),
0.05
mg/
kg
(
8
males
and
4
females),
and
0.075
mg/
kg
(
4
males).

The
study
reports
that
RBC
ChEi
was
maximal
at
1­
4
hours
after
dosing,
and
was
statistically
significantly
depressed
compared
with
the
placebo
group,
at
all
doses.

°
the
subjects
who
received
0.01
mg/
kg,
the
study
reports
a
marginal
reduction
in
cholinesterase
activity
of
3%
at
1
hr
post­
dose;

°
the
0.025
mg/
kg
group
shown
a
mean
reduction
of
10%;

°
the
0.05
mg/
kg
group
showed
a
mean
reduction
of
30%;

°
the
0.075
mg/
kg
group
showed
a
mean
reduction
of
45%.
7
R­
P
conclude
that
the
clinical
no­
effect
level,
based
on
symptoms
of
sweating
in
the
high
dose
subject,
is
considered
to
be
0.05
mg/
kg.

The
authors
defined
a
treatment­
related
effect
has
having
both
a
pharmacological
and
a
time
relationship
to
treatment.

A
total
of
24
adverse
events
were
reported
by
the
subjects:

°
11
in
the
placebo
group
(
in
6
of
22
subjects;
27%),

°
5
in
the
0.01
mg/
kg
dose
group
(
in
3
of
8
subjects;
38%),

°
3
in
the
0.025mg/
kg
dose
group
(
in
2
of
12
subjects;

17%),

°
1
in
the
0.05
mg/
kg
dose
group
(
in
1
of
12
subjects;
8%),

and
°
4
in
the
0.075
mg/
kg
dose
group
(
in
3
of
4
subjects;
75%).
8
General
statistical
considerations

One
of
the
critical
issues
in
evaluating
the
scientific
validity
of
a
study
design
is
statistical
power.
A
study
with
inadequate
power
to
find
an
effect
is
by
definition
unethical.

There
are
roughly
19
million
children
in
the
United
States
 
5
years
of
age.
If
a
toxicant
harmed
1
child
in
1,000,
that
would
place
19,000
children
at
risk
nationwide.
A
study
with
adequate
power
to
detect
an
increase
in
deficit
from
1%
to
2%
would
require
3,017
subjects
in
each
group
to
yield
a
power
of
0.8,
at
p=

0.05.

Studies
with
sample
sizes
<
50
had
about
a
3%
chance
of
finding
an
effect
if
it
were
present.
9
NRDC
POSITION
°
Studies
should
only
be
considered
where
they
will
a
priori
have
demonstrated
validity
of
study
design,

statistical
power,
and
sample
size
°
Industry
sponsorship
may
bias
study
design,
data
analysis,
or
interpretation.
This
also
applies
to
in­
house
IRB.

°
Study
subjects
are
usually
limited
to
healthy
adults,
often
males,
and
are
not
representative
of
the
general
population
°
Risks
accrue
to
subjects,
while
argued
benefits
accrue
to
society
(
pesticide
residue
in
food
has
no
known
health
benefits)
10
DICHLORVOS
(
DDVP)
(
Organophosphate)

Carcinogenic
in
rats
and
mice
at
multiple
sites
(
Chan
et
al,
1991)

Induces
gene
mutations
and
chromosomal
damage
in
mammalian
cells

Cancer
effects
are
not
revealed
by
measurement
of
ChE

WHO
listed
as
1b,
highly
hazardous

IARC
listed
as
2B,
possible
human
carcinogen

California
prop65
known
human
carcinogen

U.
S.
EPA
group
C,
possible
human
carcinogen

Banned
in
Angola,
Fiji,
Denmark,
United
Kingdom,

Cancelled
in
Sweden

Restricted
in
Kuwai
11
Dichlorvos
MRID442488­
01
7
mg
oral
dose
daily
from
days
1­
18,
all
male
3
control
(
solid
lines),
6
treated
(
broken
lines)

70
75
80
85
90
95
100
105
110
0
2
4
6
8
10
12
14
16
18
20
22
24
26
28
day
of
blood
draw
%

mean
baseline
ChE
Amvac
called
this
a
NOAEL;
EPA
called
it
a
LOAEL
12
EPA
determined:

Human
study
is
well
supported
by
several
animal
studies
and
should
serve
as
the
basis
for
short­
and
intermediate­
term
risks
for
single
chemical
review
(
RBC
ChEi
LOAEL=
0.1
mg/
kg/
day)

MOE=
100
(
intra
10X,
lack
of
NOAEL
3x,
FQPA
3x)

Not
used
for
cumulative
assessment
(
10X
inter)

Scientific
concerns:

One
dose
only
(
0.1
mg/
kg/
day)
and
is
approximate,

since
each
subject
was
given
7
mg,
and
mg/
kg
was
an
average
of
the
subjects

Blood
draws
for
ChEi
measurements
were
made
24
hrs
after
each
dose
13
NRDC
position

There
is
no
value­
added
from
the
human
subjects
test
that
is
not
already
available
from
well­
conducted
animal
studies,
epidemiology,
incident
data,
and
biomonitoring
data

It
is
unethical
to
conduct
a
study
that
is
significantly
scientifically
deficient,
such
as
inadequate
statistical
power
to
detect
an
effect
when
it
may
occur

The
human
subjects
data
are
often
limited
to
healthy
adults,
and
do
not
capture
differences
across
the
population,
chronic
effects,
effects
from
early­
life
stage
exposures.
Applicability
for
"
human"
response
is
extremely
limited.
14
AZINPHOS­
METHYL
(
AZM)

act
on
the
human
system
to
inhibit
acetylcholinesterase;

readily
absorbed
through
the
skin;

induce
systemic
effects
which
include
headache,

dizziness,
weakness,
shaking,
nausea,
stomach
cramps,
diarrhea,
sweating;

may
induce
skin
rashes
and
irritation;
and

may
induce
delayed/
allergic
effects
including
loss
of
appetite,
weakness,
weight
loss,
and
general
malaise.

EPA
proposes
to
use
this
study
to
reduce
the
worker
assessment
(
WOE)
interspecies
factor,
but
not
for
the
cumulative
risk
assessment
(
retain
10X)
15
AZM
ethical
determinations:

test
was
done
on
eight
"
volunteers"
who
were
hospitalized
for
a
month,
were
dosed
with
a
known
poison,
took
repeated
blood
and
urine
tests,
and
gave
up
many
freedoms,
all
for
just
£
1500,
suggesting
participants
were
economically
distressed.

The
consent
form
mentions
no
specific
adverse
effects
that
are
possible.
None
of
the
long
term
chronic
effects
associated
with
OPs
are
mentioned
in
any
form
given
to
subjects.

Although
the
VI
form
mentions
short­
term
acute
effects
that
could
occur,
it
says
they
are
"
not
anticipated"
in
the
study.
This
may
indicate
improperly
making
study
conclusions
a
priori.
16
AZM
ethical
considerations

The
actual
consent
form
signed
by
subjects
misleadingly
states
that
the
study
may
be
disclosed
"
for
medicines
in
the
UK
and
elsewhere,"
when
there
was
no
intention
to
use
the
study
for
medicines.

subjects
apparently
were
not
informed
that
researchers
were
Bayer
contractors

consent
form
required
subjects
to
agree
that
if
injured,

rather
than
suing,
they
would
submit
any
dispute
to
an
arbitrator
(
who
had
to
be
agreed
to
by
the
company)

The
IRB
chair
has
the
same
last
name
as
a
lead
investigator
on
the
study.
17
Scientific
considerations
of
the
AZM
study:

It
tests
just
8
adult
males,
with
one
dose
(
0.25
mg/
kg)

for
28
days
with
in­
hospital
say
throughout

Designed
as
a
"
no­
effect"
(
NOAEL)
study

EPA
and
study
authors
determined
that
the
one
dose
administered
was
a
"
no
effect"
level
18
Adverse
events
reported
in
the
AZM
study:

Adverse
effects:

Total
post
dose
adverse
effects
=
67

17
in
placebo
group
(
25%);
average
of
4.24
different
adverse
effects
per
person

50
in
treatment
group
(
75%):
average
of
6.25
different
adverse
effects
per
person

NOTE:
multiple
complaints
were
never
recorded.

while
only
one
placebo
subject
reported
experiencing
one
single
GI
system
disorder
(
nausea),
the
treatment
group
subjects
(
4
reporting/
8
total
subjects)
reported
an
array
of
GI
disorders
(
nausea,
flatulence,
dyspepsia).
(
Table
P1.2;
p.
P4)
ALL
THESE
ARE
KNOWN
RESULTS
OF
OP
poisoning.

75%
of
treated
subjects
(
N=
6)
report
adverse
effects
(
coughing,

epistaxis,
rhinitis)
versus
25%
of
placebo
subjects
(
N=
1)
(
Table
P1.2;
p.
5)
19
AZM
study
adverse
effects:

although
the
study
reports
that
none
of
the
67
post
dose
adverse
events
were
considered
to
be
related
to
the
test
compound
(
p.
48,
Section
8.4.3),
all
adverse
events
"
resolved
themselves"
by
the
post
study
follow­
up
(
Table
P2.2,
p.
P34).
That
is,
the
treatment
group
who
had
reported
adverse
effects
during
the
treatment
period
seem
to
have
been
cured
when
no
longer
receiving
treatment.
20
AZM
adverse
effects

The
report
makes
the
claim
that
the
adverse
effects
were
not
related
to
treatment
because
they
were
not
correlated
with
"
clinically
relevant
depression
from
mean
baseline
value
of
RBC
or
plasma
cholinesterase,

relating
to
the
time
of
onset
of
adverse
event
in
any
subject."
(
p.
52,
section
8.4.3).

However,
by
their
own
"
retrospective
power
calculation"

they
had
no
statistical
power
to
detect
fluctuations
in
the
ranges
reported
in
the
study
(
i.
e.
within
15%
of
baseline).
21

a
retrospective
power
calculation
(
p.
31­
32)
states
that
the
study
has
an
85%
power
to
detect
a
15%
difference
in
cholinesterase
levels.

Very
few
of
these
%
differences
are
beyond
15%.
(
Fig.

M1.1.1
(
p.
M6),
Table
M2.1
(
p.
M45­
50).

MANY
ADVERSE
EFFECTS
ARE
SEEN
IN
THE
TREATMENT
SUBJECTS;
the
placebo
group
(
N=
4)
had
2
subjects
reported
to
have
adverse
effects,
while
the
treatment
group
(
N=
8)
had
every
single
person
report
adverse
effects
(
Table
P1.1,
page
P3).
Although
nothing
in
this
entire
report
has
any
statistical
significance,
this
may
be
of
considerable
scientific
interest
22
NRDC
POSITION:

Studies
should
only
be
considered
where
they
will
a
priori
have
demonstrated
validity
of
study
design,

statistical
power,
and
sample
size.
Without
good
scientific
design,
it
is
unethical.

Study
subjects
are
usually
limited
to
healthy
adults,

often
males,
and
are
not
representative
of
the
general
population,
so
have
very
questionable
scientific
value.

There
is
no
value­
added
from
human
subjects
test
data
that
are
not
already
available
from
well­
conducted
animal
studies,
epidemiology
studies,
incident
data,
and
biomonitoring
data.

It
is
always
unethical
to
administer
human
subjects
with
toxic
pesticides
that
are
not
intended
to
be
ingested,

particularly
when
robust
data
is
available
from
animal
studies,
epidemiology,
incident
data,
and
biomonitoring
data.