1. hEX-Tox paper reading 2015. 4. 14. Tue Hye Young Choi

2. The Purpose of reading 2015-04-14hEX-Tox PR2

3. Introduction and Background Biomonitoring the measurement of parent chemical or metabolite in a biological sample BE (biomonitoring equivalent) the concentration of a chemical (or metabolite) in a biological medium consistent with defined exposure guidance values 2015-04-14hEX-Tox PR3

4. Key Concepts and Methods Derivation of BE Values 2015-04-14hEX-Tox PR4 Prof. Choi, US EPA(1997) SourceTarget organ 체외 ( 환경 ) 체내 ( 세포벽 통과 ) 체내 ( 위 등 ) External dose Internal dose

5. Key Concepts and Methods Derivation of BE Values ① In case of available Human PK data (pathway 1) 2015-04-14hEX-Tox PR5 External dose ex) DEHP in dust (unit : ng/g of dust) Internal dose ex) MEHP in urine (unit : ng/mL of urine) Human PK model Human

6. Key Concepts and Methods Derivation of BE Values ② In case of available Animal PK data (pathway 2) 2015-04-14hEX-Tox PR6 at POD Internal dose Exposure guidance value ⇒ BE Animal PK model Uncertainty Factors Human Animal Point of departure ex) BMDL, LOAEL, NOAEL

7. Key Concepts and Methods Derivation of BE Values 2015-04-14hEX-Tox PR7 BE POD Final BE value

8. Key Concepts and Methods BE derivation process ① Identification of the Target Organ and any Available Understanding Regarding the Mode of Action for Toxicity. ② Identification of Potential Biomarkers. ③ Identify and Assess Available Pharmacokinetic Data and Models in Humans and the Relevant Animal Species. ④ Calculating BEs for Biomarkers in Urine ⑤ Confidence Rating ⑥ Discussion of Variability and Uncertainty 2015-04-14hEX-Tox PR8

9. Key Concepts and Methods Communication and Interpretation using BE Values 2015-04-14hEX-Tox PR9

10. Case Studies Toluene 2015-04-14hEX-Tox PR10 38 ppm BE POD : 135 ㎍ /L in blood BE : 40 ㎍ /L in blood

11. Case Studies 2,4-dichlorophenoxyacetic acid 2015-04-14hEX-Tox PR11 Animal POD (NOAEL) : 5 mg/kg/day Human POD : 0.5 mg/kg/day UF : 10 Be adults,POD : 30,000 ㎍ /g of crea. UF : 100 BE : 300 ㎍ /g of crea.

12. Case Studies Cadmium 2015-04-14hEX-Tox PR12 POD : 200 ㎍ /g of renal cortex BE POD : 6.3 ㎍ /g of crea. BE : 2 ㎍ /g of crea. UF

13. Case Studies Acrylamide 2015-04-14hEX-Tox PR13 POD : 0.004 μmol AA or GA in serum NOEL : 0.2 mg/kg/day POD animal : 0.13 μmol AA or GA in serum BE POD AAVal : 25.3 fmol/mg of globin GAVal : 39.8 fmol/mg of globin BE AAVal : 8 fmol/mg of globin GAVal : 13 fmol/mg of globin

14. Interpretation of Biomonitoring Data using BE Values 2015-04-14hEX-Tox PR14

15. Interpretation of Biomonitoring Data using BE Values 2015-04-14hEX-Tox PR15

16. Future Challenges As part of the evolution, there is a natural fit for the BEs to be developed along with such exposure guidance values. No existing exposure guidance values, but available toxicity and pharmacokinetic data. set of conservative uncertainty factors to derive a provisional BE POD and BE Lacking in pharmacokinetic data, but existing exposure guidance values. Provide the means to develop a provisional BE. Derivation of a BE involves a careful evaluation of the mode of action and the most relevant internal dose metric and the biomarkers The BE approach helps identify such situations and focus research efforts on issues that will enhance the value of collected biomonitoring data 2015-04-14hEX-Tox PR16

17. Future Challenges As part of the evolution, there is a natural fit for the BEs to be developed along with such exposure guidance values. No existing exposure guidance values, but available toxicity and pharmacokinetic data. set of conservative uncertainty factors to derive a provisional BE POD and BE Lacking in pharmacokinetic data, but existing exposure guidance values. Provide the means to develop a provisional BE. Derivation of a BE involves a careful evaluation of the mode of action and the most relevant internal dose metric and the biomarkers The BE approach helps identify such situations and focus research efforts on issues that will enhance the value of collected biomonitoring data 2015-04-14hEX-Tox PR17

18. Conclusions The BE process seeks to translate those risk assessments so that biomonitoring data can be interpreted in the context of those existing risk assessments. Framework for potentially improving risk assessments by focusing on mode of action and relevant internal dose metrics. framework for identifying the most relevant chemical specific biomarker(s). risk prioritization and calculating about margin of safety. Other approaches : ‘reverse dosimetry’ modeling 2015-04-14hEX-Tox PR18

19. 감사합니다. 2015-04-14hEX-Tox PR19