Transcript Dose-Response

Risk Assessment
Nov 7, 2008
Timbrell 3rd Edn pp 16-21
Casarett & Doull 7th Edn Chapter 7 (pp 107-128)
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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Hazard Evaluation
Dose-Response Evaluation
Exposure Assessment
Risk Characterization
Risk = Probability (of adverse outcome)
Hazard ≠ Risk
US EPA
Dr. Costa
1938 Food, Drug and Cosmetic Act
• Requires that “safe tolerances” be set for
“unavoidable poisonous substances”.
Miller Amendment (1954)
Chemical pesticides and other residues
tolerated at levels at which evidence can show
that they “do not cause any deleterious effects”
Food Additives Amendment (1958)
• GRAS List
Generally
Regarded
As
Safe
• Delaney Clause
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
Carcinogens
• No safe dose
• Single molecule
Cancer
• Acceptable dose: dose that causes
1 in 106 lifetime risk of cancer
• Need to define Potency
Dose-response
Dose-Response
Increasing Response
Slope = Potency
0
No Threshold
Dose
Modeling the dose-response
• One hit
– linear model
• Multi-hit
– Logit, Probit, Weibull, Gamma
– Armitage-Doll Multistage Model (biologicallybased)
– 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
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
< 10 -15
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
0
2000
4000
3/45
16/46
41/46
Carcinogens
• No safe dose
• Acceptable dose: dose that causes
1 in 106 lifetime risk of cancer
• All carcinogens ?
Flash-back to Dr. Rusyn’s material
Peroxisome Proliferators
 A wide range of classes of chemicals:
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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
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?
For effects other than cancer:
Is there a “safe” dose ?
Dose-Response
Increasing Response
0
Threshold
Dose
Non-carcinogens
No
Observed
Adverse
Effects
Level
NOAEL
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
Inter-species
Animal-to-human
variability
x
10
[x 10]
Intra-species
inter-individual
variability
[x 10]
Particularly
severe effect
Units: mg/kg/day
Based on most sensitive species and most sensitive endpoint
Extrapolations
• From short-term studies to lifetime
exposure
• From high doses in animal studies to low
doses in environmental exposure
• From animals to humans
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 – physiologicallybased (PBPK)
Variability - Uncertainty
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.
1996 Food Quality Protection Act
• Amendment to FDCA, removes application
of Delaney Clause to pesticides and
pesticide residues
• The “Risk Cup”
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”
Interactions
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Additivity
Synergism
Potentiation
Antagonism
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
Combinations
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Binary mixtures
Ternary mixtures
Four- , five-component mixtures
Six, seven, eight….
...
Complex mixtures
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
Synergism
• The whole is greater than the sum of the
individual constituents
Effecttotal >> PotencyA* DoseA +
PotencyB* DoseB… +…
+
PotencyN* DoseN
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
Antagonism
• Effect of the whole is less than the sum of
the effects of the individual components
Effecttotal << PotencyA* DoseA
+ PotencyB* DoseB… +…
+ PotencyN* DoseN