health and environmental sciences institute (hesi) risk21 ... for risk/workshop/ws6... · tim...
TRANSCRIPT
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
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
RISK21 Principles
• Start with problem formulation
• Begin with exposure estimates rather
than toxicity
• Use prior knowledge
• Seek enough precision to make a
decision
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
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.
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)
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.
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
“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
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
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
0
2
4
6
8
10
12
14
16
Pyrethroid Chronic NOELs N
OA
EL (
mg/k
g b
w p
er
day)
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
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
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
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