Document ID: EPA-HQ-OPP-2004-0387-0038
Agency: epa
Document Type: Supporting & Related Material
Title: 
Posted Date: 2005-05-12T04:00Z

Human
Health
Hazard
Assessment:
The
Human
Health
Hazard
Assessment:
The
Next
Generation
of
Data
Requirements
Next
Generation
of
Data
Requirements
Vicki
L.
Dellarco,
Ph.
D.

Office
of
Pesticide
Programs
May
2005
Topics

Goals
for
Improving
Human
Health
Hazard
Assessment

Next
Generation
of
Testing
 
ILSI­
Health
&
Environmental
Sciences
Institute's
(
HESI)
Tiered
Toxicology
Testing
Proposal
for
Pesticide
Chemicals
 
EPA's
Computation
Toxicology
Program
 
NAS
proposal

Next
steps
Health
Risk
Assessment:

Areas
of
Increasing
Emphasis

Mechanisms
of
toxicity

Aggregate
&
Cumulative
Risk

Life
stage
sensitivities

Endocrine
disruption
1996
1996
Food
Quality
Food
Quality
Protection
Act
Protection
Act
Challenges
In
Human
Health
Assessment
Source/
stressor
formation
Source
 
to
 
Outcome
Paradigm
Environmental
Concentration
Human
Exposure
Dose
Biological
Event
Effect/
outcome
Goals
in
Human
Health
Hazard
Assessment

Improve
by
providing
better
information
on:

 
Toxicokinetics

refers
to
absorption,
distribution,
metabolism
&

elimination
of
a
chemical
(
ADME)

 
Mechanism
of
toxicity
(
i.
e.,
mode
of
action)

 
Llifestage
sensitivities
Goals
in
Human
Health
Hazard
Assessment

Improve
by
providing
better
information:

 
To
assess
hazard
by
different
durations
&

routes
of
interest
OCCUP
&
NONOCCUP
WATER
FOOD
DERMAL
INHAL.

ORAL
DERMAL
INHAL.

ORAL
DERMAL
INHAL.

ORAL
ORAL
ORAL
ORAL
LONGTERM
>
6
months
INTERMEDIATE
30
days
­

6
months
SHORTTERM
1­
30days
ACUTE
New
Testing
Paradigm
Incorporate
new
concepts
Minimize
redundancy
Incorporate
lessons
learned
Maximize
use
of
each
study
New
testing
approach
should
be
based
on
sound
science
Features
Relevant
Activities

Health
&
Environmental
Sciences
Institute
(
HESI)­­
ILSI
 
Agricultural
Chemical
Safety
Assessment:
A
Multi­
sector
Approach
to
the
Modernization
of
Human
Safety
Requirements

EPA's
Computational
Toxicology
Program

National
Academy
of
Sciences
 
Two­
part
study
to
advance
current
approaches
to
toxicity
testing
to
meet
regulatory
data
needs.
HESI
Technical
Committee
on
Agricultural
Chemical
Safety
Assessment
(
ACSA)

Committee
Objective
 
Reach
consensus
on
a
scientifically
credible
&
viable
approach
for
assessing
the
safety
of
pesticides
more
efficiently,
with
fewer
animals,
&
with
fewer
artifacts
HESI
Technical
Committee
on
Agricultural
Chemical
Safety
Assessment

April
2001
Workshop
 
Recommendation
was
to
develop
a
"
Tiered
Testing
Scheme"


3
Task
Forces
Established
 
ADME
 
Systemic
Toxicity
 
Life
Stages
Multi­
Sector
&
International
Participation

Academia
 
Imperial
College
London,
Johns
Hopkins
University,
Medical
College
of
Wisconsin,
Michigan
State
University,
Mississippi
State
University,
Universitá
di
Padua
(
Italy),
University
of
California
Riverside,
University
of
Nottingham
(
UK),

University
of
Southampton
(
UK)

Government
 
US­­
EPA
(
OPP,
NHEERL,
NCEA)

 
International
Government
­
European
Commission,

European
Food
Safety
Authority,
German
Federal
Institute
for
Risk
Assessment,
Health
Canada,
OECD,
Dutch
RIVM

Agchem/
chemical
companies
 
BASF,
Bayer
CropScience,
Dow
AgroSciences,
DuPont
Crop
Protection,
Monsanto,
Syngenta
Charge
to
Task
Forces:

Design
a
Tier­
Testing
Approach

Ensure
base
set
of
tests
(
Tier
1)
provide
a
sufficient
basis
for
hazard
characterization

Introduce
greater
flexibility

Integrate
more
useful
metabolic/
kinetic
studies

Emphasize
importance
of
reducing
&
refining
animal
usage

Incorporate
improved
understanding
of
exposure
ADME
Tiered
Approach­

Chairs:
Drs.
Hugh
Barton
(
EPA/
NHEERL)
&
Tim
Pastoor
(
Syngenta)

Basic
(
Tier
I)

 
Single
&
repeated
studies
using
multiple
doses
 
Data
for
dose
selection,
half­
life
determinations,
&

identification
of
major
metabolites

Custom
(
Tier
II)

 
Data
for
study
interpretation,
absorbed
dose
estimates,
&

duration/
route
extrapolations

Advanced
(
Tier
III)

 
Data
for
understanding
mode
of
action
&
derivation
of
pharmacodynamic
concordance
Systemic
Toxicity
­
Chairs:
Drs.
Alan
Boobis
(
Imperial
College
London)
&
John
Doe
(
Syngenta)

Tier
1
(
Base
Set)

 
All
organ
systems
evaluated
using
clinical
chemistry,

histopathology,
etc
 
Indicators
for
specialized
endpoints
(
neuro­
&

immunotoxicity

 
Doses
&
dosing
regimen
guided
by
kinetics
&
exposure
predictions

Tier
2
 
If
necessarily,
quantify
specific
effects
more
precisely
&

explore
mechanisms
Systemic
Toxicity
Strategy
Step
1::
Consider
existing
data,

acute
tox,
genetic
tox
Step
2:
Rat
28­
day
study
Step
3:
Dog
90­
day
study
Step
4:
Select
"
relevant"
species
Step
5:

1­
day
RfD
from
1­
exposure
rat

2­
28
days
RfD
from
28­
day
rat

1­
6
months
RfD
from
28­
day
rat

Over
6
months
RfD
from
1­
yr
rat

Carcinogenicity
from
24­
month
rat
Step
5:

1­
day
RfD
from
1­
exposure
dog

2­
28
day
RfD
from
90­
day
dog

1­
6
months
RfD
from
90­
day
dog

Over
6
months
RfD
from
1­
yr
rat
or
90­
day
dog

Carcinogenicity
from
24­
month
rat
Rat
is
"
relevant"
Dog
is
"
relevant"
Life
Stages
­
Chairs:
Drs.
Ralph
Cooper
(
EPA/
NHEERL)
&
Jim
Lamb
(
Weinberg
Group)

Tier
1
 
F1
'
extended'
one­
generation
reproduction
study
in
one
species
(
rat)

 
Developmental
toxicity
rabbit
study
 
Similar
to
current
guidelines
but
dietary
dosing
preferred
&

with
additional
key
markers
of
maternal
toxicity/
exposure

Tier
2
 
If
necessary,
quantify
&
characterize
specific
effects
more
precisely
)
Next
Steps
&
Timeline

White
papers
posted
on
HESI
web
site
 
http://
hesi.
ilsi.
org/
publications/
pubslist.
cfm?
public
ationid=
578

Consensus
paper
&
three
detailed
monographs
to
be
published
as
a
special
issue
of
Critical
Reviews
in
Toxicology

Continue
out
reach
activities
(
for
example)

 
Nov
2005

International
Meeting
on
HESI
projects
for
risk
assessment

American
College
of
Toxicology
Annual
Meeting
View
on
ACSA
Proposal
View
on
ACSA
Proposal
More
Effective
Animal
Usage
Relevant
Exposure
Science­
Based
&
Results
Driven
Integrated
&
Flexible
Evaluation
of
Critical
Toxicities
View
on
ACSA
Proposal
View
on
ACSA
Proposal

More
discussion
&

consensus
building

Carcinogenicity
Testing

Triggers/
criteria
Used
in
Tiered
Testing

Consideration
of
Exposure

Case
Studies
­
Prospective
Analysis
For
example
EPA's
Proposed
Revisions
to
Pesticide
Data
Requirements
Submission
of
ILSI/
HESI
Manuscripts
February
2005
May
2005
10
year
process
nearing
its
end
(
Comprehensive
upgrade
of
data
requirements
to
bring
CFR158
in
line
with
current
practice)
Started
in
2001;
beginning
to
roll
out
its
papers
for
broader
scientific
discussion
EPA's
Part
158
Proposed
Toxicology
Data
Requirements
Concerns
with
Premature
Proposal

Need
to
insure:

 
Adequate
scientific
documentation

Retrospective
analyses
 
May
05
SAP
Meeting
on
Dog
Studies
 
Ongoing
(
cancer
bioassays,
2­
Gen.
Repro,
DNT)

 
Broader
stakeholder,
scientific,
international
input
&
consensus
building
 
Formal
&
broader
peer
review
Steps
for
Making
Decisions
on
Next
Generation
of
Pesticide
Data
Requirements

Engage
&
educate
broader
stakeholder
&
scientific
community

Work
in
several
venues
to
gain
international
harmonization

Modify
&
refine
approach
based
on
additional
input
After
above
steps
are
accomplished

Incorporate
appropriate
changes
into
Part
158
toxicity
data
requirements
via
rule
making
Technology­
based,
hypothesis­
driven
effort
to
increase
the
soundness
of
risk
assessment
decisions
build
capacity
to
prioritize,
screen
&

evaluate
chemicals
by
enhancing
the
predictive
understanding
of
toxicity
pathways
EPA's
Computational
Toxicology
Program
www.
epa.
gov/
comptox
Other
Relevant
Activities
Produce
faster
&
more
accurate
risk
assessments
for
less
cost
relative
to
traditional
means
&
to
classify
chemicals
by
their
potential
to
influence
molecular
&

biochemical
pathways
of
concern
National
Academy
of
Sciences

Project
on
Toxicity
Testing
&
Assessment
 
Part
1

Report
reviewing
selected
aspects
of
several
relevant
reports
provided
by
EPA
&
others
on
this
topic

Anticipated
Summer
2005
 
Part
2
(
funded
separately
at
the
government's
option)

Report
presenting
a
long­
range
vision
&
strategic
plan
for
advancing
the
practices
of
toxicity
testing
and
human
health
assessment
for
environmental
contaminants

Anticipated
March
2007
ACSA
Tiered
Testing
Proposal
EPA
`
s
Computational
Toxicology/
Genomics
Program
Near
Term
Long
Term
Predictive
Toxicity
Approaches
Strategic
Direction
National
Academy
of
Sciences
Project
on
Toxicity
Testing/
Assessment
Tiered
Testing
Proposal:
Spring
Board
to
Next
Tiered
Testing
Proposal:
Spring
Board
to
Next
Generation
of
Pesticide
Data
Requirements
Generation
of
Pesticide
Data
Requirements
Outreach
Consensus
Building
Review
SCIENTIFIC
PROCESS
­
documentation
­
final
framework
­
test
guidelines
RULE
MAKING
PROCESS
­
economic
analysis
2005
Multi­
year
process
The
End