1. Risk Assessment Dec 7, 2009 Timbrell 3rd Edn pp 16-21
Casarett & Doull 7th Edn Chapter 7 (pp )

2. 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

3. US EPA

4. Dr. Costa

5. Carcinogens Dose-response No safe dose Single molecule Cancer
Acceptable dose: dose that causes 1 in 106 lifetime risk of cancer
Need to define Potency
Dose-response

6. Dose-Response
Increasing Response
Slope = Potency
Dose
No Threshold

7. 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(-q0 - q1D - q2D2 - …- qnDn)
P(D) = q0 - q1D
q1 = q* = potency, units (dose) -1
e.g. (mg/kg/day) -1

8. Incidence of lung tumors
Methylene Chloride CH2Cl2 Human cancer risk derived from bioassay with B6C3F1 female mice (Reitz et al., 1989)
Model
Cancer risk for 1 μg/m3
Probit
<
Logit
2.1 x 10-13
Weibull
9.8 x 10 -8
LMS
4.1 x 10 -6
Animal data:
Concentration in air
Incidence of lung tumors
3/45
2000
16/46
4000
41/46

9. Carcinogens No safe dose
Acceptable dose: dose that causes 1 in 106 lifetime risk of cancer
Does this apply to all carcinogens ?
Flash-back to Dr. Rusyn’s material

10. 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

11. 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?

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. 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 high doses in animal studies to low doses in environmental 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. 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

19. 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.

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

21. 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”

22. Interactions
Additivity
Synergism
Potentiation
Antagonism

23. 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

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