1. Risk Assessment of Exposure to Trihalomethanes: Use of Biomonitoring Equivalents and Biomonitoring Data from NHANES Lesa L. AylwardRichard A. Becker Sean M. Hays Chris R. KirmanAmerican Chemistry Council

2. Purpose and Approach  Conduct an internal dose-based risk assessment of potential non-cancer risks from population THM exposures  Use internal dose measures for both Dose-response – Biomonitoring Equivalents (BEs) Exposure metrics – NHANES blood THM data  Use IPCS Tier 1 approach (assumption of dose addition) for screening THM mixtures in blood

3. “Biomonitoring Equivalent” Concentration of biomarker that is consistent with existing exposure guidance or reference values such as RfDs, TDIs, etc. Rat Dose NOAEL/LOAEL “Safe” Human Dose – RfD BE RfD Human Blood Level 3

4. THMs Non-Cancer Critical Effects (USEPA 2001, 2005)  Critical effect: Risk of fatty liver degeneration in rats and dogs Quantal measure: yes/no Point of Departure: BMDL 10  Non-alcoholic fatty liver disease prevalent in adult US population (~10%)  PBPK models available for humans and experimental species

5. BE Derivation for THMs BMDL 1 0

6. Low-Dose Extrapolation: 2 Approaches

7. NHANES 2003-2004 Blood THM Data  Population representative sampling  Allows assessment of simultaneous internal blood concentrations of all four THMs on an individual-by-individual basis  Highly transient biomarkers

8. Hazard Quotient/Hazard Index  Compare estimated dose to RfD to estimate a “Hazard Quotient” (HQ):  Compare measured biomarker concentration to BE RfD :  Sum across THMs (IPCS Tier 1 approach): 8

9. Hazard Indices and Quotients Across Individuals Based on NHANES Data 0 0 0 0

10. Estimated Percentiles: Risk of Fatty Liver

11. Issues in Interpretation  Highly transient biomarker: comparison to steady-state avg. blood conc. (BE POD, BE RfD ) How representative are spot blood samples of long term avg. conc.? Is this better/worse/complementary to external exposure-based assessments?  POD: quantal risk of fatty liver (y/n) vs. background prevalence of fatty liver and pre- fatty liver changes Continuous metric for POD (e.g., severity, liver enzyme changes) might allow evaluation of risks to “sensitive” or at-risk populations

12. Issues in Interpretation (cont’d)  Low-dose extrapolation procedure: How does MOA for hepatic fatty liver occurrence inform selection? MOA: Cytotoxicity due to reactive metabolite production Related to peak, or elevated, metabolism rates rather than low-level production of metabolites? Interaction of this mechanism with underlying pre-pathologic conditions in humans?