1. Why is Risk Assessment Necessary? All agents can harm us; the question is to what degree we need to distinguish risk from hazard »risk=probability of hazard under given conditions …. Without risk assessment »no discussion of relative degree of harm from agents »no control over new agents

2. Definition and Terms Adverse Effect: functional impairment or pathological lesion resulting in increased morbidity or mortality in the whole organism Acceptable Daily Intake: the amount of a chemical which is likely to be of no appreciable risk of adverse effect during a lifetime »usually expressed in mg/kg/day »several other similar quantities No Observed Adverse Effect Level (NOAEL) Lowest Observed Adverse Effect Level (LOAEL)

3. Risk Assessment Dose-Response Characterization Animal Toxicology Clinical Studies Epidemiology Cell/Tissue Experiments Computational Methods Monitoring/ Surveillance Research Needs Hazard Characterization Exposure Characterization Risk Characteri- zation Control Options Non-risk Analyses Risk Management Collaboration External Input into Research/ Assessment Other Federal Agencies States/Local Agencies Academia Industry Public Interest/Environmental Groups DecisionsDecisions Scientific Research/ Data Collection

4. Aspects of Health Risk Assessment Hazard Identification »focus on statistical issues »pairwise comparisons »trend tests Dose-Response Analysis »focus on pattern of response as a function of dose »extrapolation is very important »focus on models and variance

5. Strength of Evidence Carcinogen Non-Carcinogen Epidemiology Dose-Response Replication Study Type Similar Agents Genetic Changes Rare Tumor Confounding Selection Bias Conflicting Studies Common Tumor Epigentic Origin Poor Dose Measure Toxicology Multiple Species Multiple Sites Uncommon Tumor Dose-Response Single Species Single Site Common Tumor Extremely High Dose Mechanism Genetic Changes

6. Dose-Response Assessment Potency as a function of exposure

7. Dose-Response Assessment Shape as a function of exposure

8. Response Dose Statistically Significantly Different From Control NOAEL LOAEL NOAEL vs. LOAEL

9. Benchmark Dose Step 1 »Fit a model to the data [p=f(dose)] »Find the dose corresponding to a chosen level of risk (e.g. 10%) »0.10=f(ED 10 ) »ED->Effective Dose Step 2 »Find a lower bound (95%) on the ED 10 »This is the 10% benchmark dose (BD 10 )

10. 10% Benchmark Dose Sample Data - Butadiene Mammary Gland Tumors in Female Mice 10 0 1 2 3 0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 ED 10 =13.14 ppm BD 10 =5.43 ppm 95% Upper Bound on Dose-Response Curve

11. Converting NOAEL/LOAEL/Benchmark Dose to a Standard Extrapolation »species (1-10) »variability (1-10) »lower risk??? Quality »database (1-10) »endpoint (1-10)

12. Critical Dose NOAEL LOAEL Effective Dose Benchmark Dose Risk from Mechanistic Model

13. Converting to a Standard Action Dose = Critical Dose Product of Modification Factors

14. DibenzodioxinsDibenzofurans Biphenyls (PCBs) O O O Dioxin-like compounds Naphthalenes N N O Azoxybenzenes

15. Effects of Dioxins Biological response to Dioxins »Modulation of gene expression »Modulation of steroid hormones and receptors »Modulation of growth factors and receptors Adverse Health effects »Cancer (IARC Class 1) »Immunosuppression »Reproductive effects »Developmental effects

16. Dose-Response for TCDD Mechanistic Models Empirical Models NOAELs/LOAELs Modifying Factors

17. GI Tract Rapidly PerfSlowly PerfFatKidneyLiver Venous Blood Arterial Blood Cap Space Lumen Urine Feces ORAL DOSE Distribution and Metabolism

18. Liver Capillary Blood TCDD TCDD+AhAh.TCDD CYP1A1 CYP1A2 E 2 OH E 2 ER ER.E 2 Metabolism Cell Lysis + - Bound TCDD (CyP1A2) + + + Liver Interstitium Growth Peptide + + EGFR Growth Signal DNA Damage Metabolite Biochemical and Molecular Events

19. Normal Cell Initiated Cell Malignant Cell Birth (Growth Signal) Mutation (DNA Damage) Mutation Birth/Death (Tissue Size) Birth/Death (Tumor Size) Death/Differentiation Cancer Model

20. Normal Cells Initiated Cells Malignant Cells Birth CYP1A2 Free EGF-R PBPD Model Two Stage Model - Dioxin

21. Low Dose Risks

22. Empirical Cancer Modeling P(d)  1  e  0  1 d  2 d 2  3 d 3 Background Linear Quadratic Cubic

23. Rodent Cancers

24. Non-Cancer Endpoints Hill model R(d)  b  vdvd n k n  d n Background Max Effect Shape ED 50

25. Criteria For Inclusion 4 or more doses An estimated maximum effect Dose and Response Types of data »raw »summary with s.e. 52 Datasets used

26. Sample Results

27. Shape Over all Endpoints Values for the shape parameter Center area is approximately linear No clear indication of a threshold 0.5124 0 2 4 6 8 10 12 14 16 19% 36% 45% Linear

28. Epidemiology Data

29. ED 01 ’s Across Endpoints Based upon daily doseBased upon body burden 0.01110010000 0 5 10 15 20 0 5 10 15 20 0.01110010000 Human DataOther Data Mechanistic Model ng/kg/day ng/kg body burden

30. Beyond 1% response 1% added risk marks the edge of the observable response region this is not in a zero response region to get into a zero response region, we must use some other factors IPCS has published factors for going from no-observed-effect levels (NOELs) and from lowest-observed-effect levels (LOELs) to find an acceptable risk

31. Uncertainty Factor Considerations the use of a range of LOAELs instead of a NOAEL the possible differences between humans and experimental animals in susceptibility to these compounds the potential differences in susceptibilities within the human population differences in half-lives of elimination for the compounds of a complex TEQ mixture chose to use 10

32. Toxic Equivalency Factors A large class of chemicals act like dioxin Try to find factors which make the effects for a given level of dose the same Factors based on a number of biological measurements TEQ=sum TEF*Dose

34. Lowest Effect Levels

35. Tolerable Daily Intake Critical Dose/Modifying Factor Critical Doses »minimum 14 pg/kg/day TEQ »maximum 40 pg/kg/day TEQ »ED01 range 3 to >100 pg/kg/day TEQ Modifying Factor »10 TDI »1-4 pg/kg/day TEQ

36. Final Message Dioxins and related compounds can cause hazardous effects in mammals including humans Thresholds are not apparent Exposures should be limited, preferably to below 1 pg/kg/day but 4 pg/kg/day is acceptable considering difficulty in reducing exposure

37. Acknowledgements George Lucier Mike Kohn Mel Anderson Bill Farland Lynn McGrath Linda Birnbaum Mike DeVito many others USEPA WHO/IPCS NRMC-England Australian Health Centers for Disease Control German Cancer Research Center