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Risk Assessment

Risk Assessment. Dec 3 - 5, 2007. Toxicology – the dismal science Toxicology + Risk Assessment = the predictive science. The Risk Assessment Paradigm. National Research Council's 1983 report Risk Assessment in the Federal Government: Managing the Process , called the "Red Book" .

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Risk Assessment

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  1. Risk Assessment Dec 3 - 5, 2007

  2. Toxicology – the dismal science • Toxicology + Risk Assessment = the predictive science

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

  4. Food and Drug Administration(FDA) • Food and Drugs Act (1906) prohibits interstate commerce in misbranded and adulterated foods, drinks and drugs.

  5. “Anyone who says saccharin is injurious to health is an idiot” Theodore Roosevelt (26th President of the USA, 1901-1909)

  6. 1938 Food, Drug and Cosmetic Act • Requires that “safe tolerances” be set for “unavoidable poisonous substances”. • 1940 FDA transferred from USDA to Federal Security Agency, first Commissioner of Food and Drugs appointed • 1944 Public Health Service Act • 1968 FDA placed in Public Health Service

  7. Miller Amendment (1954) Chemical pesticides and other residues tolerated at levels at which evidence can show that they “do not cause any deleterious effects”

  8. 1958 Food Additives Amendment Generally Regarded As Safe • GRAS List • Delaney Clause

  9. The Delaney ClauseNo 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

  10. Carcinogens • No safe dose • Acceptable dose: dose that causes 1 in 106 lifetime risk of cancer

  11. Dose-Response Increasing Response 0 Dose No Threshold

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

  13. Dose-Response Increasing Response 0 Dose Threshold

  14. Non-carcinogens No Observed Adverse Effects Level NOAEL

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

  16. Extrapolations • From short-term studies to lifetime exposure • From animals to humans

  17. 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)

  18. 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.

  19. 1996 Food Quality Protection Act • Amendment to FDCA, removes application of Delaney Clause to pesticides and pesticide residues • The “Risk Cup”

  20. 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”

  21. Interactions • Additivity • Synergism • Potentiation • Antagonism

  22. 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

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

  24. 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

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

  26. 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

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

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

  29. “Acceptable” risks • Carcinogens: 1 in 106 over lifetime • Occupational exposures: 1 in 103 – 1 in 104 over working lifetime • Enteric diseases: 1 in 104 per year

  30. Comparison of Risks Disability Adjusted Life Years

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