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Section F
Dose-Response Relationships
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Dose Response
! Dose-response assessment
- How does the adverse health effect respond to dose?
! Requires quantitative toxicity data
! Involves extrapolation of animal data to human
exposure levels
- Issues
! Exposure-response, not dose-response,
relationship
Association vs. cause/effect
! Plausible biologic mechanism
! 3
Two Types of “Traditional” Dose-Response
Relationships
! Graded or continuous dose response
- In individuals
! Quantal dose response
- All or none in populations
! Conceptually similar
- Typically sigmoidal
- Differ in nature of endpoint measured
4
Graded or Continuous Dose Response
! Reflects a dose-dependent increase in severity of
response
! Applies to continuous variables
- Body weight, etc.
- Blood/serum enzyme activity
! Percent inhibition of activity of an enzyme
- Chlorpyrifos (orgnophosphate insecticide)
inhibition of cholinesterase activity
(neurotoxicity)
! Increase in liver enzyme in serum (reflecting
hepatotoxicity)
- Increase in ALT (alanine aminotransferase)
reflecting carbon tetrachloride (CCL4)
hepatotoxicity
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Graded or Continuous Dose Response
6
Quantal Responses
! All or none responses in a population—responders and
non-responders
! Types of responses
- Tumor incidence
- Lethality
! Quantal responses can best be represented in terms of a
normal distribution
- Assumption: quantal dose-responses usually show
normal distribution when expressed as the frequency
of response
! For example: percent response at each dose
minus the percent response at the immediately
lower dose
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Quantal Response
8
Normal Distribution: Quantal Dose-Response
Relationship
9
Replot in Probit Units
! Convert percent response to normal equivalent
deviation (NED) from the mean
- Later, add 5 to avoid negative numbers
1 SD
68.3
%
Response
NED
Probit
0.1
–3
2
2.3
–2
3
–1
4
0
5
+1
6
97.7
+2
7
99.9
+3
8
15.9
50
84.1
2 SD
95.5
%
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Probit Transformation
! An adjustment of quantal response to an assumed
response representative of a normal distribution
(sigmoidal curve to straight line)—for example, the graph
below:
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Dose-Response Relationship
! Two previous curves are examples of traditional dose
responses (monotonic)
! Non-traditional dose response curves (non-monotonic)
- U-shaped dose response—essential nutrients
- Hormesis—hormones/hormonally active chemicals;
various other chemicals
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U-Shaped Dose-Response Relationship
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Hormetic Dose-Response Relationship
! Hormesis: concept that xenobiotics may cause
stimulatory (beneficial?) effects at low dose but adverse
effects at high dose
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