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Risk Assessment II

Risk Assessment II. Dec 9, 2009. For effects other than cancer:. Is there a “safe” dose ?. Dose-Response. Increasing Response. 0. Dose. Threshold. Non-carcinogens N o O bserved A dverse E ffects L evel NOAEL. ACCEPTABLE DAILY INTAKE (ADI) or TOLERABLE DAILY INTAKE (TDI)

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Risk Assessment II

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  1. Risk Assessment II Dec 9, 2009

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

  3. Dose-Response Increasing Response 0 Dose 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-human Intra-species Particularly 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)

  8. 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

  9. Carcinogens: There exists a “measurable” risk from any exposure, eg 4.1 x 10 -6 cancer risk for exposure to 1 μg/m3 of CH2Cl2 for a lifetime Non-carcinogens: A “safe” dose can be determined Pathogens: An “infectious dose” can be determined - ID50, , - Dose that produces 1 in 104 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.

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

  11. 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”

  12. Interactions • Additivity • Synergism • Potentiation • Antagonism

  13. 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

  14. Additivity • Chemicals A, B, C…N are all toxic • Potency of mixture = Sum of potencies * concentrations of constituents • Effecttotal = PotencyA * DoseA + PotencyB * DoseB + PotencyC * DoseC +…..+PotencyN * DoseN

  15. Synergism • The whole is greater than the sum of the individual constituents Effecttotal >> PotencyA* DoseA + PotencyB* DoseB… +… + PotencyN* DoseN

  16. 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 Effecttotal >> PotencyA* DoseA where PotencyB = 0

  17. Antagonism • Effect of the whole is less than the sum of the effects of the individual components Effecttotal << PotencyA* DoseA + PotencyB* DoseB… +… + PotencyN* DoseN

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

  19. 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

  20. 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

  21. Life expectancy at birth USA, Both sexes, National Center for Health Statistics

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