Transcript SOT - Alliance for Risk Assessment

Case Study: Risk – Risk Comparison
n-Propyl Bromide vs. Perchloroethylene in Dry Cleaning
Harvey Clewell
The Hamner Institutes for Health Sciences
Research Triangle Park, NC
Risk Comparison: Perchloroethylene (Perc)
vs. n-Propyl Bromide (nPB)
Issue: EPA regulation of Perc use in dry cleaning is leading to
substitution of Perc with nPB
Comparative Toxicity
Endpoint
Neurotoxicity
Developmental Toxicant *
Carcinogenic Potency
Exposure (TWA)
ACGIH TLV
Perc
nPB
reversible
irreversible
no
yes
1.5x10^3/ppm
2x10^3/ppm **
40 ppb ***
Up to 54 ppm **
25 ppm
10 ppm
* CalEPA Prop 65 listing
* * Not yet regulated by EPA
** * EPA regulatory limit
Case Study on Risk – Risk Comparison
• Goal: Develop a methodology for comparing risks of
alternative materials
• Assure hazardous materials are not replaced with more
toxic alternatives
• Challenge: current risk assessment paradigms are ill-suited
for such situations
• conservative assumptions/analyses
• Ad hoc uncertainty factors
• Approach: review original data on each chemical, and
conduct parallel analyses comparing best estimates rather
than biased (health-protective) estimates
Differences Between Conservative Risk Assessments
and Risk – Risk Comparisons
Single-chemical
risk assessment
Risk-Risk
Comparison
BMDL
BMD
3
1
95% UCL
MLE
Linear vs threshold
Bias toward linear
default
Weight of
evidence
Database limitations
UF up to 10
Read-across
Point of departure
UFanimal to human dynamics
Potency
Elements of Risk – Risk Comparison
• Characterization of best estimate and range of estimates
• Consistent with OMB Principles for Risk Assessment
• Unbiased characterization of uncertainty
• Probability distributions of predicted risks
• CSAFs in place of UFs
• Semi-quantitative documentation of expert judgment
• Decision (probability) trees (Clewell et al. 2008)
• Rodricks plots (Rodricks et al. 1987)
Decision Analysis Framework
for Methylene Chloride
Species
Pharmacokinetics
Dose Response
Model
Applied
MLE
Species
Internal
Dose
Animal
Bioassay
PB-PK
LMS
Risk
per
Dose
Other
Unit
Risk
Human
Pharmacokinetics
Species to Human
Pharmacodynamics
Applied
Body
Surface
Human
Internal
Dose
Human
Exposure
PB-PK
Source: Clement and Tatman, 1990
Target
Dose
Body
Weight
Methylene Chloride
Human
Tree Diagram Species to Human Pharmacokinetics
Pharmacodynamics
Species
Pharmacokinetics
Body Surface
0.3
Applied
0.2
Body Weight
0.7
Weighted average
of unit risk = 2.1x10-7
Body Surface
0.2
PB-PK
0.8
Body Weight
0.8
Source: Clement and Tatman, 1990
PB-PK
0.7
Applied
0.3
PB-PK
0.7
Applied
0.3
PB-PK
1.0
Applied
0.0
PB-PK
1.0
Applied
0.0
Unit
Pathway Risk
MFO
0.2
GST
0.7
DCM
0.1
5.64e-5
1.45e-6
1.45e-6 OLD EPA
3.48e-6
MFO
0.2
GST
0.7
DCM
0.1
4.46e-6
MFO
0.2
GST
0.7
DCM
0.1
1.06e-5
MFO
0.2
GST
0.7
DCM
0.1
8.4e-7
1.15e-7
1.15e-7 FDA
2.75e-7
5.55e-7 NEW EPA
6.38e-6
n/a
4.38e-8 USAF
5.04e-7
n/a
Unit Risk Distribution for DCM
0.5
Marginal Weighting
0.4
Weighted Average
0.3
of Unit Risk = 2.1x10
-7
0.2
0.1
0
0.44
1.2
2.8
5.0
5.6
8.4
15
-7)
Unit
Risk
(x10
Source: Clement and Tatman, 1990
35
45
64
110
560
Relative Impact of Decisions on Risk
20
18
16
Weighted Average
-7
Unit Risk (x10 )
14
12
of Unit Risk = 2.1x10
-7
10
8
6
4
2
0
Pathway
Source: Clement and Tatman, 1990
Pharmacodynamics
Human
Pharmacokinetics
Mouse
Pharmacokinetics
Relative Impact of Mode of Action Decision vs.
Model Uncertainty on Risk
10
9
8
-7
Unit Risk (x10 )
7
Weighted Average
of Unit Risk = 1.1x10
6
-7
5
4
3
2
1
0
Pathway
A2
Source: Clement and Tatman, 1990 Lung GST
Kf
Liver GST
VMax
Liver MFO
A1
Lung MFO
Example of Rodricks Plot
Comparison of NOAEL/LOAELs for DEHP. Dashed lines indicate less confidence
and bolder lines indicate greater confidence. Broader solid lines identifies the
preferred POD based on confidence.
1000
NOAEL/LOAEL (mg/kg/day)
100
10
1
0.1
0.01
0.001
NOAEL
Source: Gentry et al. 2011
LOAEL