1. Risk Assessment
Dec 4 -6, 2006

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, )

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 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

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

11. Dose-Response
Increasing Response
Dose
No Threshold

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

13. Dose-Response
Increasing Response
Dose
Threshold

14. Non-carcinogens No
Observed
Adverse
Effects
Level
NOAEL

15. ADI = NOAEL Safety Factor(s) Poor quality of data
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 = x [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 Effecttotal >> PotencyA* DoseA where PotencyB = 0
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

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

30. “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

31. Comparison of Risks
Disability
Adjusted
Life
Years