Aldicarb
Human
Volunteer
Study
Inveresk
Clinical
Research
1991­
1992
The
EPA
Human
Studies
Review
Board
Meeting
Rosslyn,
VA
4­
6
April,
2006
Dr.
Neil
Carmichael
Global
Head
of
Toxicology
Bayer
CropScience
4
April
2006
2
Objectives
of
Aldicarb
Human
Study
 
Characterize
the
dose
response
and
time
course
of
ChE
inhibition
following
administration
of
aldicarb
using
a
double
blind
design
 
Demonstrate
the
relative
sensitivity
of
male
and
female
humans
compared
to
animals
 
Address
questions
raised
by
regulatory
authorities
about
aldicarb
toxicity
and
risks
to
humans.
4
April
2006
3
Aldicarb
Ethics
Review
 
Value
of
research
to
society
 
Aldicarb
is
a
carbamate
insecticide,
nematicide,
and
acaricide
used
for
35
years
to
improve
crop
production
 
The
human
data
have
been
published
in
scientific
literature
(
Handbook
of
Pesticide
Toxicology,
2001)
and
presented
in
several
posters
at
SOT
national
meetings
 
Independent
ethical
review
 
IRB
members
independent
of
ICR,
IRB
review
conducted,
lay
summaries
modified
as
requested

Original
protocol
and
lay
summary
submitted
to
the
Ethics
Committee
(
19
Dec,
1991)


Documents
revised
subsequent
to
committee
meeting
to
incorporate
recommendations
(
24
Dec,
1991)


A
modified
Lay
Summary
and
a
letter
to
the
volunteer's
GP
for
the
inclusion
of
female
subjects
was
approved
by
the
Ethics
Committee
(
memo
dated
19
Feb,
1992)
4
April
2006
4
Aldicarb
Ethics
Review
 
Informed
consent
 
Lay
summary
provided
to
candidates;
consent
forms
signed
 
Aldicarb
mentioned
as
a
`
drug'
in
a
few
instances
but
clearly
described
as
an
insecticide/
nematicide
 
Dose
range
given
for
males
in
lay
summary;
doses
specified
for
females
 
Respect
for
potential
and
enrolled
subjects
 
Candidates
free
to
withdraw
at
any
time
 
Privacy
of
subjects
not
compromised
Conclusion:
The
study
was
conducted
ethically
4
April
2006
5
Study
Design
 
Double
blind,
placebo
controlled
 
Aldicarb
was
given
as
a
single
oral
dose
to
healthy
male
and
female
subjects.

 
Dose
selection
based
on
previous
human
studies
and
animal
data.

 
Doses
administered
were:
placebo,
0.01,
0.025,
0.05,
and
0.075
mg/
kg.

 
Full
range
of
appropriate
clinical
measurements
were
made
at
intervals
before
and
after
dosing
 
Samples
were
taken
for
urinalysis,
clinical
chemistry
including
RBC
and
plasma
ChE,
and
hematology
before
and
after
dosing.
4
April
2006
6
Study
Results
 
Dose­
related
ChE
inhibition
was
observed.

 
Recovery
from
ChE
inhibition
was
rapid
even
at
the
highest
dose.

 
No
treatment
related
clinical
signs
were
observed
in
males
or
females
at
0.05
mg/
kg
or
below.

 
A
treatment
related
clinical
effect
was
observed
in
one
male
in
the
highest
dose
group,
based
on
generalized
sweating.

 
Sweaty
palms
observed
sporadically
in
all
dose
groups
and
was
not
clearly
related
to
treatment.

 
Based
on
placebo
control,
less
than
20%
inhibition
of
RBC
ChE
at
0.025
mg/
kg
in
both
sexes
and
no
inhibition
in
RBC
ChE
in
males
at
0.01
mg/
kg
4
April
2006
7
Regulatory
Use
of
Human
Study
 
In
1993,
EPA
accepted
study
for
use
in
the
risk
assessment
process
 
EPA
established
a
RfD
of
0.001
mg/
kg/
day
based
on
a
combination
of
human
and
dog
data
and
a
10X
safety
factor
for
intraspecies
variability
 
WHO
and
EU
established
a
RfD
of
0.003
mg/
kg/
day
based
on
the
human
study
and
a
10X
safety
factor
for
intraspecies
variability
 
Study
has
been
validated
by
two
EPA
SAB/
SAP
meetings
(
1992
and
1999).
4
April
2006
8
BCS
Position
on
Use
of
Human
Study
in
Risk
Assessment
 
The
human
volunteer
study
represents
the
most
relevant
and
appropriate
data
for
setting
the
Reference
Dose
and
the
interspecies
safety
factor
 
Covers
doses
in
the
appropriate
range
(<
0.05
mg/
kg)
for
establishing
the
POD
 
Is
supported
by
a
large
animal
database
which
indicates
consistency
across
species
 
Statistical
analysis
demonstrates
that
at
doses
relevant
for
risk
assessment,
females
are
no
more
sensitive
than
males
4
April
2006
9
General
Comments
 
BCS
recognizes
the
role
of
the
HSRB
in
providing
guidance
and
oversight
to
those
sponsoring
intentional
dosing
studies
for
submission
to
EPA
 
HSRB's
is
charged
with
reviewing
the
ethical
and
scientific
considerations
pertaining
to
study
conduct
including
the
scientific
justification
and
risk/
benefit
questions
 
It
is
inappropriate
for
EPA
to
ask
the
HSRB
to
render
weight­
of­
evidence
(
WOE)
judgments
with
only
a
limited
sampling
and
summarization
of
the
available
information
and
data
