Seminário Nacional do Benzeno (5 e 6 dez/12) - AVALIAÇÃO DO RISCO CARCINOGÊNICO À SAÚDE HUMANA: MODELOS E ASPECTOS REGULATÓRIOS INTERNACIONAIS

1. Brazilian Benzene Seminar
Brasilia, Brazil
December 6, 2012
Low Dose Extrapolation for
Carcinogens – U.S. EPA Perspective
Rita Schoeny, Ph.D.
Senior Science Advisor,
Office of Science Policy, Office of Research and Development
U.S. EPA
1

2. Disclaimer
 The views expressed in this presentation
are those do the author and do not
represent the policy of the U.S. EPA.
I am still a Federal employee
2

3. Cancer Guidelines: What’s Different
from 1986?
 Analyze data before invoking default options.
 Mode of action is key in decisions
 Weight-of-evidence narrative replaces the
previous “A-B-C-D-E” classification scheme.
 Two step dose response assessment
 Model in observed range
 Extrapolate from point of departure
 Consider linear and non-linear extrapolation
 Address differential risks to children
12/10/12 3

4. High dose data – what do they
tell us?
Response
Dose
4

5. Possibilities
Response
Dose
Interspecies
5

6. Two Step Approach
 Model data in
the observed
range – to a
point of
Response (Tumor or Nontumor Data)
e)
os
nD
i to
e Lim x
Environmental nc Empirical
Exposure Levels
of Interest Co
nf
ide ma
te) Range of
Observation departure
sti
%
95
E
st
al
e
tr
ow
en
(L
Extrapolate
(C
x
x 
below the POD
10%
ault Range of
ar Def
Line Extrapolation
x x
0%
LED10 ED10
UF x NOAEL
Nonlinear Default
Dose x LOAEL
6

7. Extend the Observed Range Using
Precursor Data
 Objective of choosing POD is to set it as
close to environmental levels as
Supported by data
Appropriate to model
 Cancer Guidelines say precursor data
are useful for this
 Must have MOA
Section
3.2.2
7

8. Mode of Action: Bladder Tumors, Key Events
Cytotoxicity and Regenerative Hyperplasia
DMAIII Measurable Key
Metabolite Events in Target
SEM Tissue
Urothelial
Toxicity
BrdU
Sustained BrdU Labeling
Labeling
Regenerative
Proliferation
Hyperplasia Tumor

9. Cacodylic Acid: BMDs and BMDLs
Feeding Drinking water
10% 1% 10% 1%
Endpoint Duration Duration
BMD BMDL BMD BMDL BMD BMDL BMD BMDL
(mg/kg/d) (mg/kg/d) (mg/kg/d) (mg/kg/d) (mg/kg/d) (mg/kg/d) (mg/kg/d) (mg/kg/d)
104 104
Tumor weeks 7.74 5.96 6.80 2.22 weeks 1.92 1.21 0.88 0.14
10
weeks 1.36 1.04 0.42 0.32
104
Hyperplasia weeks 1.63 1.04 0.74 0.14
104
weeks 1.97 1.61 0.93 0.66
BrdU 10 weeks 0.65 0.29 0.54 0.07 Not determined. Available data not suitable for modeling.
labeling
3
weeks 0.68 0.18 0.31 0.02
Cytotoxicity No reliable dose-response data available
10 weeks 0.02 0.008 0.002 0.0007
9

10. What Else Could Be Used?
 Pre-neoplastic lesions (e.g. altered
enzyme foci)
 Mutations?
 Chromosomal changes?
 DNA damage?

11. So Many Models!
Response (Tumor or Nontumor Data)
)
se
Do
o n
it
m
Li
en
ce x
Environmental Empirical
e)
id
nf
at
Exposure Levels Co Range of
m
sti
of Interest % Observation
95
lE
st
ra
e
nt
ow
e
(L
(C
x
x
10%
ult
efa Range of
earD
Lin Extrapolation
x x
0%
LED10 ED10
UF x NOAEL
Nonlinear Default
Dose x LOAEL

12. Linear or Non-linear?
Two Step Dose Response Process
Response (Tumor or Nontumor Data)
e)
os
D
on
it
Another Question First
m
Li
ce
en x
e)
Environmental fid Empirical
at
on
im
Exposure Levels C Range of
st
%
95
lE
of Interest Observation
st
ra
e
nt
o w
e
(L
(C
x
x
10%
lt
fa u
De Range of
e ar
Lin Extrapolation
x x
0%
LED10 ED10
UF x NOAEL
Nonlinear Default
Dose x LOAEL
12

13. Is There Something Better?
Analyze the available data
Is there too much uncertainty or is
Invoke a
critical information lacking? Y default option*
N
Conduct risk assessment
13

14. Source
Exposure
PBPK
Tissue dose
BBDR
Mode of action
Biologically Based
Dose Response
Model
Response
14

15. BBDR – Based on Knowledge of Key
Events
dosimetry Key event B1
Key event B2
Key event A1 Mode of
Action Assessment
endpoint
Key event A2
Key event A3
15

16. Applied
M ul
Dose of Phenobarbital tipl
ed
and ose
(PBPK)
tim -resp
e-c ons
our
ses es
16

17. Reality check (I)
 There are always data gaps
Arsenic
Formaldehyde
TCDD
phenobarbital
 A BBDR model is a description of biological
structure with embedded empirical linkages
that cover the parts of the overall exposure-
dose-response linkage for which data are
missing.
17

18. Reality check (II)
 As research improves our understanding of
the overall exposure-dose-response linkage,
the sophistication of the description of the
mode of action increases.
 Corresponding iteration of the BBDR model
leads to more accurate predictions of dose-
response and time-course behaviors.
 Will always be some degree of residual
uncertainty.
 But is the default more uncertain?
18

19. And if no BBDR?
Two Step Dose Response Process
Response (Tumor or Nontumor Data)
e)
os
D
on
it
m
Li
Linear or Non-linear
ce
en x
e)
Environmental fid Empirical
at
on
im
Exposure Levels C Range of
st
%
95
lE
of Interest Observation
st
ra
e
nt
o w
e
(L
(C
x
x
10%
lt
fa u
De Range of
e ar
Lin Extrapolation
x x
0%
LED10 ED10
UF x NOAEL
Nonlinear Default
Dose x LOAEL
19

20. Mutagenesis Paradigm
Mutagens/Spontaneous
DNA Damaged DNA
Damage Sensing
Cellular Response
DNA Repair Incorrect No repair
Repair/Replication
Repaired DNA Mutant DNA Dead Cell
Demarini 70
20

21. Threshold?
 Demonstrated  Based on MOA
By inspection of the Mutagenic MOA
dose response has been linear
curve But should consider
Fitting models and biology of mutation
checking goodness
of fit
Statistical tests for
one model or
another
Does mutagenic MOA
mean low dose linear?
BBDR should be first
choice 21

22. In vitro Mutation Dose-Response: MMS & MNU
Doak et al., 2007
HPRT MF
MMS
MMS
NOEL = 1 µg/ml
MNU
MNU
No NOEL
2011 EMS Annual Meeting Pottenger 22

23. In vitro Mutation Dose-Response:
ENU Johnson et al., 2009
HPRT MF
ENU threshold dose-response (Lutz & Lutz model)
Slide from Pottenger 23

24. RfV = POD / UF
UFs Health IPCS RIVM ATSDR EPA
Canada
Interhuman 10 10 10 10 1-10
(3.16 X 3.16
Animal to 10 10 10 10 1-10
human (2.5 X 4)
Subchronic 10 NA 1-10
to chronic 1-100 1- 100
LOAEL to 10 10 1-10
NOAEL
Incomplete NA NA 1-10
database 24

25.  Example: Inhalation, RfCs – use RfC methodology
guidance (U.S. EPA 1994) in determining
interspecies UF. (Generally use UF = 3 when
dosimetric adjustment of animal data).
 Example: Methylmercury PK UF of 3 (based on
analyses of interindividual variability) and default PD
UF of 3
 U.S. EPA Risk Assessment Forum working on
Guidance for Data-derived Extrapolation Factors.
Divides UFA into toxicokinetic and toxicodynamic
components
Same for UFH
25

26. Take Home Message
 MOA informs dose response
assessment
 DNA damage is not mutation
 Mutation is not cancer
 Some genotoxicity endpoints may be
reasonable biomarkers
May be useful for extending the lower end of
dose response curve
Useful in MOA
26

27. 27

28. NRC 2009 Silver Book 1
 Framing questions
and design step.
 Risk Assessment is
not an end in itself.
 Characterize
uncertainty and
variability
 Default before data?
These are strictly my own opinions
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29. NRC 2009 Silver Book 2
 Dose response
Additivity to background is a major theme
○ How differentiate between exogenous and
endogenous damage?
○ DNA adducts biomarkers, could have major role
○ Does this mean linear all the time?
EPA has expressed preference for BBDR
○ Low dose data for adduct formation
○ Low dose data for mutation
○ Low dose data for other markers
Again my own opinions
29

30. Breaking Down the Dichotomy
Cancer Non-Cancer
 Threshold
 Non-Threshold
 Reversible
 Irreversible
 Safety Value
 Risk value
 RfD/RfC
 Slope Factor
 ADI/TDI
 Unit Risk
 MRL
 Risk-Specific Dose
30

31. Postulated Mode Of Action
ve CYP2E1 etabolism Chloroform
M
Ox idati
Ph o s
g e ne
Sustained Toxicity
Regenerative Cell Proliferation
Key Events
Tumor Development
31

32. Postulated Mode Of Action
Metabolism CP
Cyt p 450s
Phosp
h
Acrole oramide m
in ustard
, PAM
DNA damage
Tumor
Development Mutations
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