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

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

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

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

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

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

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

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

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

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

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 10-25 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. 2008. Source: Gentry et al. 2011