1. Risk Assessment Nov 7, 2008 Timbrell 3 rd Edn pp 16-21 Casarett & Doull 7 th Edn Chapter 7 (pp 107-128)

2. The Risk Assessment Paradigm Hazard Evaluation Dose-Response Evaluation Exposure Assessment Risk Characterization Risk = Probability (of adverse outcome) Hazard ≠ Risk National Research Council's 1983 report Risk Assessment in the Federal Government: Managing the Process, called the "Red Book"

3. US EPA

4. Dr. Costa

5. 1938 Food, Drug and Cosmetic Act Requires that “safe tolerances” be set for “unavoidable poisonous substances”. Miller Amendment (1954)  Chemical pesticides and other residues tolerated at levels at which evidence can show that they “do not cause any deleterious effects ” Food Additives Amendment (1958) GRAS List Generally Regarded As Safe Delaney Clause

6. The Delaney Clause No Food Additive Shall be Deemed to be Safe if it is Found to Induce Cancer when Ingested by Man or Animals, or if it is Found, After Tests which Are Appropriate for the Evaluation of the Safety of Food Additives, to Induce Cancer in Man or Animals

7. Carcinogens No safe dose Single molecule Cancer Acceptable dose: dose that causes 1 in 10 6 lifetime risk of cancer Need to define Potency Dose-response

8. Dose-Response Dose Increasing Response 0 No Threshold Slope = Potency

9. Modeling the dose-response One hit – linear model Multi-hit –Logit, Probit, Weibull, Gamma –Armitage-Doll Multistage Model (biologically- based) –Linearized Multistage (LMS) Model P(D) = 1 – exp(-q 0 - q 1 D - q 2 D 2 - …- q n D n ) P(D) = q 0 - q 1 D q 1 = q* = potency, units (dose) -1 e.g. (mg/kg/day) -1

10. Methylene Chloride CH 2 Cl 2 Human cancer risk derived from bioassay with B6C3F1 female mice (Reitz et al., 1989) ModelCancer risk for 1 μg/m 3 Probit< 10 -15 Logit2.1 x 10 -13 Weibull9.8 x 10 -8 LMS4.1 x 10 -6 Concentration in airIncidence of lung tumors 03/45 200016/46 400041/46 Animal data:

11. Carcinogens No safe dose Acceptable dose: dose that causes 1 in 10 6 lifetime risk of cancer All carcinogens ? Flash-back to Dr. Rusyn’s material

12. Peroxisome Proliferators  A wide range of classes of chemicals: lipid lowering drugs, plasticizers, food flavors, industrial solvents, herbicides  Cause marked increases in size and number of peroxisomes  Potent rodent liver carcinogens  Human exposure is from therapeutic, environmental, industrial and other sources  No clear epidemiological evidence for or against carcinogenicity in humans

13. So, we have a chemical that is a non-genotoxic RODENT carcinogen! If we would regulate this chemical, would it help to improve the quality of HUMAN life?

14. Is there a “safe” dose ? For effects other than cancer:

15. Dose-Response Dose Increasing Response 0 Threshold

16. Non-carcinogens No Observed Adverse Effects Level NOAEL

17. ACCEPTABLE DAILY INTAKE (ADI) or TOLERABLE DAILY INTAKE (TDI) The amount of a substance that can be ingested over a lifetime without significant health risk ADI = NOAEL Safety Factor(s) Poor quality of data Safety Factor = 10 x 10 [x 10] [x 10] Inter-species Animal-to-humanIntra-speciesParticularly variabilityinter-individual severe effect variability Units:mg/kg/day Based on most sensitive species and most sensitive end- point

18. Extrapolations From short-term studies to lifetime exposure From high doses in animal studies to low doses in environmental exposure From animals to humans

19. Scale from animal to human Scale according to body weight (BW) Scale according to surface area – (BW) 2/3 Scale according to relative metabolic rates – (BW) 3/4 Biological modeling – physiologically- based (PBPK)

21. Variability - Uncertainty

22. Factors in determining acceptable dose Species differences, gender, age, body weight Approach has been chemical by chemical. Multiple chemical exposure - combined risk assessment approach. Multiple sources of exposure need to be accounted for.

23. 1996 Food Quality Protection Act Amendment to FDCA, removes application of Delaney Clause to pesticides and pesticide residues The “Risk Cup”

24. The Risk Cup Food Quality Protection Act (1996) “Assess the risk of the pesticide chemical residue [to infants and children] based on…available information concerning the cumulative effects of infants and children of such residues and other substances that have a common mechanism of toxicity”

25. Interactions Additivity Synergism Potentiation Antagonism

26. Interactions can be expected between chemicals that Act by binding to the same receptor Act through the same mechanism Require the same enzyme for activation/detoxication

27. Combinations Binary mixtures Ternary mixtures Four-, five-component mixtures Six, seven, eight….... Complex mixtures

28. Additivity Chemicals A, B, C…N are all toxic Potency of mixture = Sum of potencies * concentrations of constituents Effect total = Potency A * Dose A + Potency B * Dose B + Potency C * Dose C +…..+Potency N * Dose N

29. Synergism The whole is greater than the sum of the individual constituents Effect total >> Potency A * Dose A + Potency B * Dose B … +… + Potency N * Dose N

30. Potentiation One constituent A is toxic, the other B is not. Effect of the combination A + B is greater than the effect of the active constituent Effect total >> Potency A * Dose A where Potency B = 0

31. Antagonism Effect of the whole is less than the sum of the effects of the individual components Effect total << Potency A * Dose A + Potency B * Dose B … +… + Potency N * Dose N