Transcript Beyond Science and Decisions

Beyond Science and
Decisions
TCEQ Workshop I
Austin, Texas
March 16-18, 2010
Bob Benson
EPA Region 8
March 17, 2010
Bob Benson’s House
Science and Decisions:
Advancing Risk Assessment
Chapter 5
Toward a Unified Approach to
Dose-Response Assessment
A Perspective from an EPA
Regional Scientist
Disclaimer: The views in this presentation do
not reflect the views and policies of the US EPA
Problems Identified by NAS Panel
Cancer Assessments:
• Inter-human variability in risk either not
addressed (animal studies) or
incompletely addressed (epidemiological
studies)
• Uncertainty in risk not characterized
• Low dose, non-linear assessments (RfD
approach) do not present a risk measure
(risk below RfD = 0)
Problems Identified by NAS Panel
Non-Cancer Assessments:
• Possibility for low dose linearity not
addressed
• No risk measure presented. Risk below
RfD = 0. HI, RfD, MOE of limited utility for
risk-benefit analyses.
• Uncertainty not distinguished from
variability
Characteristics of the NAS
Recommended Dose-Response
Framework
• Use spectrum of evidence from human,
animal, mechanistic, and other relevant
studies (in absence of chemical
specific information use defaults based
on evidence from other chemicals)
• Adopt risk-specific Reference Dose
• Use distributions rather than point
values for uncertainty factors
Risk Specific Reference Dose
• Dose that corresponds to a particular risk
specified to be de minimus (for example, 1
in 100,000) at a defined confidence level
(for example, 95%) for the endpoint of
concern. It can be derived by applying
human variability and other adjustment
factors (for example, for interspecies
differences) represented by distributions
rather than default uncertainty factors.
Using a risk standard of 1 in
100,00 is too low to be practical
for hazardous waste sites in EPA
Regions
What does a 1 in 100,000
probability of a 10% increase
in liver weight mean?
What is the cost (willingness
to pay) to correct the
condition?
Characteristics of the NAS
Recommended Dose-Response
Framework
• Quantitative consideration of human
variability
• Quantitative consideration of
uncertainty
• Evaluate background exposure and
background disease process to select
modeling approach (linear or nonlinear)
Consideration of Background Exposure
0.2%
2.7%
2%
95%
Hiking
Drinking water
Soil
Diet
Contributions of Exposure Pathways from Cadmium for Crested
Butte Residents who also recreate at Standard Mine
Summary of Cancer Risk from Arsenic to an Adult
Fisherman Compared to Risk to a Resident
5.0E-04
Receptor
Soil*
Air
Water
Diet**
Adult Fisherman
3E-07
--
1E-07
1E-05
Adult Resident
1E-06
4E-06
1E-05
4E-04
Water
Air
4.0E-04
Soil
Risk Value
Diet
3.0E-04
2.0E-04
1.0E-04
0.0E+00
Adult Fisherman
Adult Resident
-- = incomplete pathway
*Risks from exposure to sediment have been summarized in the "soil" category for the fisherman.
**Risks from exposure to diet have been summarized for fish tissue for the fisherman.
Characteristics of the NAS
Recommended Dose-Response
Framework
• Extrapolate from human POD to low
dose where response = 1 in 100,000
• Default extrapolation using linear
model in most cases (slope = 1)
Current Uncertainty Factors
used to derive a RfD
•
•
•
•
Subchronic to chronic
Data base deficiency
Animal to human extrapolation
Inter-human variability
Source of distributions to
replace uncertainty factors
• Distributions from an analysis of
uncertainty factors from a random
sampling of IRIS files
• Distributions from an analysis of data from
pharmaceuticals
Is it an advance to replace point
values for uncertainty factors
with a distribution that is not
derived from the chemical of
concern?
Alternative Source of distributions
to replace uncertainty factors
• Distributions in internal dose (PK) in lab
animals and humans with the chemical of
interest
• Distributions in PD in lab animal and
humans (Tox Testing in 21st Century)
A Proposal for CostBenefit Analyses
Many EPA statutes require cost-benefit
analyzes in the rule making.
BMD10 = 3.62
BMDL10 = 2.78
RfD = BMDL10/10x10 = 0.03
Response at RfD = 0 to 1 in 1,000 (95% UCL)
Multistage Model with 0.95 Confidence Level
0.8
Multistage
BMD Lower Bound
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0
BMDL BMD
0
100
200
300
400
dose
19:56 02/23 2010
500
600
700
800
BMD10 = 80.3
BMDL10 = 65.8
RfD = BMDL10/10x10 = 0.7
Response at RfD = 0 to 1 in 1,000 (95% UCL)
Log-Logistic Model with 0.95 Confidence Level
0.7
0.6
Log-Logistic
BMD Lower Bound
0.5
0.4
0.3
0.2
0.1
0
BMDL BMD
0
5
10
15
20
dose
20:28 02/16 2010
25
30
35
40
Thank You!
What about thresholds?
Toxicologists: A threshold exists!
There must be an exposure below
which no biologically significant
response occurs
Statisticians: A threshold can’t be
verified!
A response follows a linear relationship.
Any exposure greater than 0 will cause some
response. The slope isn’t always equal to 1.