1. Risk Assessment II Dec 9, 2009

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

3. Dose-Response Dose Increasing Response 0 Threshold

4. Non-carcinogens No Observed Adverse Effects Level NOAEL

5. 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 inter-individual severe effect variability Units:mg/kg/day Based on most sensitive species and most sensitive end- point

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

7. 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)

9. Variability Inter-individual variation in –Exposure –Metabolism –Repair capacity –Sensitivity –… Uncertainty: Factors that we do not know or understand fully (yet) True magnitude of –Exposure –Metabolism –Repair capacity –Sensitivity How to extrapolate from test animals to humans, high to low doses… How to combine risks

10. Carcinogens: There exists a “measurable” risk from any exposure, eg 4.1 x 10 -6 cancer risk for exposure to 1 μg/m 3 of CH 2 Cl 2 for a lifetime Non-carcinogens: A “safe” dose can be determined Pathogens: An “infectious dose” can be determined - ID 50,, - Dose that produces 1 in 10 4 risk of infection Each is considered in isolation Approach has been chemical by chemical. Multiple chemical exposure requires combined risk assessment approach. Multiple sources of exposure need to be accounted for.

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

12. The Risk Cup Food Quality Protection Act (1996) –Amendment to Food Drugs and Cosmetics Act (1906, 1938) “Assess the risk of the pesticide chemical residue [to infants and children] based on…available information concerning the cumulative effects on infants and children of such residues and other substances that have a common mechanism of toxicity”

13. Interactions Additivity Synergism Potentiation Antagonism

14. 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

15. 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

16. 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

17. 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

18. 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

20. Competing risks Drinking water disinfectant by-products ↔ infectious diseases

21. Comparison of Risks Disability Adjusted Life Years One DALY = 1 lost year of healthy life Disability is weighted by a factor that reflects the severity of the disease on a scale from 0 (perfect health) to 1 (equivalent to death). WHO Global Burden of Disease analysis http://www.who.int/healthinfo/global_burden_disease/en/index.html

23. Some examples of weighing factors Asthma -- 0.043 Blindness – 0.600 Cancer: Liver – 0.20 Cancer: Trachea, bronchus and lung 0.15 –Metastatic 0.75 Cirrhosis of the liver - 0.330 Cleft palate - Cases 0.103 Diarrheal diseases - 0.105 Malaria - 0.191

24. USA, Both sexes, National Center for Health Statistics Life expectancy at birth Year of birth Age at death Year of birth Age at death 190047.3198073.7 195068.2199075.4 196069.7200077.0 197070.8200577.8 200777.9