1. Case Study: Risk – Risk Comparison n-Propyl Bromide vs
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

2. 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
Perc
nPB
Neurotoxicity
reversible
irreversible
Developmental Toxicant * no
yes
Carcinogenic Potency
1.5x10^3/ppm
2x10^3/ppm **
Exposure (TWA)
40 ppb ***
Up to 54 ppm **
ACGIH TLV
25 ppm
10 ppm
* CalEPA Prop 65 listing
* * Not yet regulated by EPA
** * EPA regulatory limit 1

3. 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 2

4. Differences Between Conservative Risk Assessments and Risk – Risk Comparisons
Single-chemical risk assessment
Risk-Risk Comparison
Point of departure
BMDL
BMD
UFanimal to human dynamics 3 1
Potency
95% UCL
MLE
Linear vs threshold
Bias toward linear default
Weight of evidence
Database limitations
UF up to 10
Read-across

5. 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) 4

6. Decision Analysis Framework for Methylene Chloride
Unit
Risk
Animal
Bioassay
Species
Internal
Dose
per
MLE
LMS
Other
Applied
PB-PK
Dose Response
Model
Pharmacokinetics
Species to Human
Pharmacodynamics
Human
Exposure
Target
Body
Surface
Weight
Source: Clement and Tatman, 1990

7. Methylene Chloride Tree Diagram Unit Human Risk Pathway Pharmaco-
n/a
8.4e-7
4.38e-8
5.04e-7
Weighted average
of unit risk = 2.1x10-7
MFO
0.2
GST
0.7
DCM
0.1
PB-PK
Applied
0.3
Body Surface
Body Weight
1.0
0.0
0.8
Unit
Risk
Pathway
Human
Pharmaco-
kinetics
Species to Human
Pharmacodynamics
Species
Pharmacokinetics
OLD EPA
FDA
NEW EPA
USAF
Source: Clement and Tatman, 1990

8. Unit Risk Distribution for DCM
Unit Risk (x10-7)
Source: Clement and Tatman, 1990

9. Relative Impact of Decisions on Risk
Source: Clement and Tatman, 1990

10. Relative Impact of Mode of Action Decision vs.
Model Uncertainty on Risk
Source: Clement and Tatman, 1990
Lung GST
Liver GST
Liver MFO
Lung MFO

11. Example of Rodricks Plot
Need to change title from “biological plausibility” to “confidence”. This figure demonstrates that as we increase our confidence and certainty in the endpoint observed.being an “adverse” effect. This figure demonstrates that decreasing uncertainty that the NOAEL is in the range of 1-10 mg/kg/day, with the lowest LOAEL in the range of mg/kg/day. What else do we want to say about this figure and doe we need text boxes beside the lines like Clewell et al
Source: Gentry et al. 2011