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ILSI Health and
Environmental Sciences
Institute
Health and Environmental Sciences
Institute (HESI) RISK21 Program
Beyond Science and Decisions: From Problem Formulation to Dose-Response - May 29, 2013
Tim Pastoor, PhD, DABT
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The Stimulus for RISK21:
NAS Reports
Toxicity Testing In The 21st Century
“…new methods in computational biology and
a comprehensive array of in vitro tests based
on human biology.”
Science and Decisions: Advancing Risk
Assessment
• Design of risk assessment
• Uncertainty and variability
• A unified approach to dose-response
assessment
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RISK21 Principles
• Start with problem formulation
• Begin with exposure estimates rather
than toxicity
• Use prior knowledge
• Seek enough precision to make a
decision
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The RISK21
Roadmap 0.01
0.1
1
10
100
Esti
ma
te
of
To
xic
ity (
mg
/kg
)
Lo
w
Hig
h
Mod
0.0001 0.01 0.1 1 10
Estimate of Exposure (mg/kg)
0.001 100 High Mod Low
Problem Formulation:
•What is it?
•Where used?
•How used?
•How much?
•What do we already know?
Biomonitoring
Probabilistic
Deterministic
Worst
case
Mode of Action
In vivo
In vitro
QSAR TTC
The Matrix
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Tiered Approach for Exposure Assessment
Minimal information, such as physicochemical properties
and use knowledge. Estimate may include all, one, or
any combination of the following:
Environmental background: Monitoring databases
Consumer Uses: Consumer banding lookup tables
Industrial Uses: Worker banding lookup tables and
estimates from water solubility and saturation vapor
pressure
Use exposure model(s) with population, exposure
route, environmental fate, volume, release, and
specific-use information
Detailed use knowledge. Use
measurements specifically relevant to use
Estimate based on samples from
exposed individuals
Incre
asin
g r
esourc
es &
refinem
ent
Biomonitoring
Probabilistic
Deterministic
Worst Case
3
2
1
0
• Purpose: Creation of a tiered system for human exposure estimates (“Exposure
Profiles”) to estimate the range of likely exposure to a given chemical.
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0
200,000
400,000
600,000
800,000
1,000,000
1,200,000
0.0001 0.001 0.01 0.1 1 10 100
Cu
mu
lati
ve
Fre
qu
en
cy
Parts per Billion
PDP 2000-2012: Pesticides in Water Samples
Quintile: 1st 2nd 3rd 4th 5th Max: 29.7ppb
n= 1,175,362 samples
Mean: 0.003ppb
USDA Pesticide Data Program (PDP)
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Tiered Approach for Toxicity Estimate
Structure & activity relationships
plus existing databases such as
Threshold of Toxicological
Concern (TTC)
Predictive assays plus in vitro to in
vivo extrapolation (IVIVE)
Apical endpoints
Dose-response for mode of
action, Key Events Dose-
Response Framework (KEDRF)
Incre
asin
g r
esourc
es &
refinem
ent
Mode of Action
In vivo
In vitro
QSAR TTC
3
2
1
0
• Purpose: Creation of a tiered system for human toxicity estimates (“Toxicity
Profiles”) to estimate the range of likely PODs/RVs for a given chemical.
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8
0.001
0.01
0.1
1.0
Esti
mate
of
To
xic
ity (
mg
/kg
/d)
Lo
w
Hig
h
Mod
10
0.0001 0.01 0.1 1 10
Estimate of Human Exposure (mg/kg/d)
0.001 100 High Mod Low
100
Toxicity range
Exposure range
Plotting exposure and toxicity information on the
RISK21 matrix using ranges
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“Pseudomethrin” case study Problem Formulation
Use pyrethroid-impregnated bed nets to
protect against mosquito bites
Pseudomethrin is a candidate pyrethroid for
this use
11pyrethroids registered
Determine reasonable certainty of no harm
for…
Bed-net dipping
Sleeping under treated net
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10
Pseudomethrin tox range
based on Cramer class III
0.01
0.1
1
10
Esti
mate
o
f To
xic
ity (
mg
/kg
)
Lo
w
Hig
h
Mod
100
0.0001 0.01 0.1 1 10
Estimate of Exposure (mg/kg)
0.001 100 High Mod Low
Pseudomethrin exposure
range of 0.003– 0.02 mg/kg
based on WHO model for
sleeping
Sleeping scenario: Tier 0
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11
0.01
0.1
1
10
Esti
mate
o
f To
xic
ity (
mg
/kg
)
Lo
w
Hig
h
Mod
100
0.0001 0.01 0.1 1 10
Estimate of Exposure (mg/kg)
0.001 100 High Mod Low
“Mix” of toxicity and
exposure probability
estimates indicating position
of the situation
Tier 0 does not give assurance of safety; shape of probability mix indicates refinement of toxicity would be more relevant for Tier 1
Sleeping scenario: Tier 0
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0
2
4
6
8
10
12
14
16
Pyrethroid Chronic NOELs N
OA
EL (
mg/k
g b
w p
er
day)
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13
Pseudomethrin tox
probability range of 0.5 –
500 mg/kg based on “read
across” +
0.01
0.1
1
10
Esti
mate
o
f To
xic
ity (
mg
/kg
)
Lo
w
Hig
h
Mod
100
0.0001 0.01 0.1 1 10
Estimate of Exposure (mg/kg)
0.001 100 High Mod Low
Pseudomethrin exposure
probability range of 0.003–
0.02 mg/kg based on WHO
model
Tier 1: Use read across to estimate toxicity, exposure estimate unchanged
Sleeping scenario: Tier 1
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14
0.01
0.1
1
10
Esti
mate
o
f To
xic
ity (
mg
/kg
)
Lo
w
Hig
h
Mod
100
0.0001 0.01 0.1 1 10
Estimate of Exposure (mg/kg)
0.001 100 High Mod Low
“Mix” of toxicity and
exposure probability
estimates indicating position
of the situation
Tier 1: Sleeping scenario acceptable
Sleeping scenario: Tier 1
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15
The RISK21
Roadmap 0.01
0.1
1
10
100
Esti
mate
o
f To
xic
ity (
mg
/kg
)
Lo
w
Hig
h
Mod
0.0001 0.01 0.1 1 10
Estimate of Exposure (mg/kg)
0.001 100 High Mod Low
Problem Formulation:
•What is it?
•Where used?
•How used?
•How much?
•What do we already know?
Biomonitoring
Probabilistic
Deterministic
Worst
case
Mode of Action
In vivo
In vitro
QSAR / TTC
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HESI RISK21
For more information, contact:
Michelle Embry ([email protected])
Nancy Doerrer ([email protected])
Jennifer Young ([email protected])
Alan Boobis ([email protected])
Tim Pastoor ([email protected])
http://www.hesiglobal.org