Beyond Science and Beyond Science and DecisionsDecisions

TCEQ Workshop ITCEQ Workshop I

Austin, TexasAustin, Texas

March 16-18, 2010March 16-18, 2010

Bob BensonBob Benson

EPA Region 8EPA Region 8

March 17, 2010March 17, 2010

Bob Benson’s House

Science and Decisions:Science and Decisions:Advancing Risk AssessmentAdvancing Risk Assessment

Chapter 5Chapter 5Toward a Unified Approach to Toward a Unified Approach to Dose-Response AssessmentDose-Response Assessment

A Perspective from an EPA A Perspective from an EPA Regional ScientistRegional Scientist

Disclaimer: The views in this presentation do Disclaimer: The views in this presentation do not reflect the views and policies of the US EPAnot reflect the views and policies of the US EPA

Problems Identified by NAS PanelProblems Identified by NAS PanelCancer Assessments: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 PanelProblems Identified by NAS PanelNon-Cancer Assessments: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 Characteristics of the NAS Recommended Dose-Response Recommended Dose-Response

FrameworkFramework

• 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 DoseRisk 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 Using a risk standard of 1 in 100,00 is too low to be practical 100,00 is too low to be practical

for hazardous waste sites in EPA for hazardous waste sites in EPA RegionsRegions

What does a 1 in 100,000 What does a 1 in 100,000 probability of a 10% increase probability of a 10% increase

in liver weight mean?in liver weight mean?

What is the cost (willingness What is the cost (willingness to pay) to correct the to pay) to correct the

condition?condition?

Characteristics of the NAS Characteristics of the NAS Recommended Dose-Response Recommended Dose-Response

FrameworkFramework

• Quantitative consideration of human variability

• Quantitative consideration of uncertainty

• Evaluate background exposure and background disease process to select modeling approach (linear or non-linear)

Consideration of Background ExposureConsideration of Background Exposure

Hiking

Drinking water

Soil

Diet

0.2%

2.7%2%

95%

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 Summary of Cancer Risk from Arsenic to an Adult Fisherman Compared to Risk to a ResidentFisherman Compared to Risk to a Resident

Receptor Soil* Air Water Diet**

Adult Fisherman 3E-07 -- 1E-07 1E-05

Adult Resident 1E-06 4E-06 1E-05 4E-04

-- = 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.

0.0E+00

1.0E-04

2.0E-04

3.0E-04

4.0E-04

5.0E-04

Adult Fisherman Adult Resident

Ris

k V

alu

e

Water

Air

Soil

Diet

Characteristics of the NAS Characteristics of the NAS Recommended Dose-Response Recommended Dose-Response

FrameworkFramework

• 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 Current Uncertainty Factors used to derive a RfDused to derive a RfD

• Subchronic to chronic

• Data base deficiency

• Animal to human extrapolation

• Inter-human variability

Source of distributions to Source of distributions to replace uncertainty factorsreplace 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 Is it an advance to replace point values for uncertainty factors values for uncertainty factors with a distribution that is not with a distribution that is not derived from the chemical of derived from the chemical of

concern?concern?

Alternative Source of distributions Alternative Source of distributions to replace uncertainty factorsto 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 Cost-A Proposal for Cost-Benefit AnalysesBenefit Analyses

Many EPA statutes require cost-benefit Many EPA statutes require cost-benefit analyzes in the rule making.analyzes in the rule making.

BMDBMD1010 = 3.62 = 3.62

BMDLBMDL1010 = 2.78 = 2.78

RfD = BMDLRfD = BMDL1010/10x10 = 0.03/10x10 = 0.03

Response at RfD = 0 to 1 in 1,000 (95% UCL)Response at RfD = 0 to 1 in 1,000 (95% UCL)

0

0.1

0.2

0.3

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0.5

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0.7

0.8

0 100 200 300 400 500 600 700 800

Fra

ctio

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ffe

cte

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dose

Multistage Model with 0.95 Confidence Level

19:56 02/23 2010

BMDBMDL

MultistageBMD Lower Bound

BMDBMD1010 = 80.3 = 80.3

BMDLBMDL1010 = 65.8 = 65.8

RfD = BMDLRfD = BMDL1010/10x10 = 0.7/10x10 = 0.7

Response at RfD = 0 to 1 in 1,000 (95% UCL)Response at RfD = 0 to 1 in 1,000 (95% UCL)

0

0.1

0.2

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0 5 10 15 20 25 30 35 40

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dose

Log-Logistic Model with 0.95 Confidence Level

20:28 02/16 2010

BMDL BMD

Log-LogisticBMD Lower Bound

Thank You!Thank You!

What about thresholds?What about thresholds?

Toxicologists: A threshold exists!Toxicologists: A threshold exists!

There must be an exposure below There must be an exposure below which no biologically significant which no biologically significant

response occursresponse occurs

Statisticians: A threshold can’t be Statisticians: A threshold can’t be verified!verified!

A response follows a linear relationship. A response follows a linear relationship. Any exposure greater than 0 will cause some Any exposure greater than 0 will cause some response. The slope isn’t always equal to 1.response. The slope isn’t always equal to 1.