Seminário Nacional do Benzeno (5 e 6 dez/12) - NOVOS PARADIGMAS PARA O GERENCIAMENTO DO RISCO CARCINOGÊNICO - rita schoeny

1. Brazilian Benzene Seminar
Brasilia, Brazil
December 5, 2012
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.
Some of this is EPA policy
2

3. So What Is EPA Policy?
 Science Policy
 Defaults, methods, Guidelines
 Used when there are data or methodology gaps
 Peer reviewed
 Lots of documentation, which is publicly available
 Policy based on science
 May be set by EPA Executive Level
 Generally involves regulations or other risk
management choices; science is peer reviewed, action
involves public comment; May be subject to Federal
Advisory Committee Act
 Lots of documentation; may be docket; publicly
available
3

4. Examples
 Science policy
 Cancer Guidelines 2005
 Set a reference dose for effects which are likely to
have a threshold
 Quantitative adjustment to cancer risk for early life
exposure
 Animal data are relevant to humans unless
demonstrated otherwise
4

5. Examples
 Policy set on science
 Drinking Water Regulations are set as close as
feasible to a Maximum Contaminant Level Goal
 Consideration of residual risk after setting and
air regulation requiring Maximum Achievable
Control Technology
○ What we are currently doing for electrical power
plants
 Cost / benefit choices
5

6. SDWA ‗96
Does the contaminant adversely affect Regulate with
public health?
NPDWR
Is the contaminant known or likely to occur in
PWSs with a frequency and at levels posing a
threat to public health?
These are questions,
Will regulation of the contaminant present a demonstrations of risk
meaningful opportunity for health risk reduction?
6

7. ‘83 Risk Assessment Paradigm ‘12?
Risk Assessment Risk Management
Statutory, legal
Mode of considerations
Dose Response
Action Assessment Politics
Risk
Hazard Risk Management
Identification Characterization Options
Social
Factors
Exposure Available
Assessment Technology
Economics
7

8. A lot has changed since ‗83
Exposure
Science in the
21st Century:
A Vision and A
Strategy
IPCS FRAMEWORK FOR ANALYSING THE
RELEVANCE OF A CANCER MODE OF ACTION
FOR HUMANS
8

9. NRC Silver Book
Recommendation
 NRC Silver Book recommendation (Chapter
8 ―Improving Utility of Risk Assessment‖)
 To make risk assessments most useful for risk
management decisions, the committee
recommends that EPA adopt a framework for risk-
based decision-making . . . that embeds the Red
Book risk assessment paradigm into a process
with initial problem formulation and scoping,
upfront identification of risk-management options
and use of risk assessment to discriminate among
these options.
9

10. Draft HHRA Framework
Silver Book on Utility
“Risk assessments
Planning & Scoping
and Problem Formulation should not be
Conceptual Analysis
conducted unless it is
clear that they are
Confirmation of Utility
Model Plan
Risk Assessment
designed to answer
Public/
Community/ specific questions, and
Effects Assessment
Stakeholder Exposure
Hazard Identification that the level of
Assessment
Involvement Dose Response
technical detail and
Risk Characterization
uncertainty and
variability analysis is
appropriate to the
Informing Decisions decision context” (NRC
2009, p. 247).
10

11. 12/10/2012 11

12. 12

13. NRC Scheme for Biomarkers
(Schulte, 1989)
13

14. A Generalized Conceptual Model
(adapted from USEPA, 2002; 2003)
Sources Stressors Exposure Pathways/Routes Receptors Endpoints Risk Metrics
Activities that
generate/release
Stressors or Chemical,
types of stressor physical or
releases biological
agents Physical processes
that cause or interactions by which
an effect a stressor is brought
into to contact with Populations
receptor and/or
lifestages
exposed to Measures of
the stressor stressor
effects or
biological
systems Metrics by
affected which risk is
quantified
(e.g., disease
cases, hazard
quotients,
magnitude of
effect)

15. Sources Stressors Exposure Receptors Endpoints Risk
Pathways/ Metrics
Drinking water
disinfection Routes
Variable
mixture
nitrosamines;
dependent on Conceptual Model
treatment & Nitrosamines in Drinking Water
source water. Ingestion of
nitrosamine
mixture in
drinking water Consumers of
drinking
water;
includes
sensitive
populations
& life stages
Cancer,
any site or
type
Combined
risk of cancer
from subset
nitrosamines
in mixture

16. 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
12/10/2012 16

17. Risk Assessment Science
Use Data Before Invoking Defaults
Analyze the available data
Is there too much uncertainty or Invoke a
is critical information lacking? default option
Y
N
Conduct risk assessment
17

18. 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
12/10/2012 18

19. Human Animal Indirect,
Other
IARC US EPA NTP
Sufficient -- --
Carcinogenic to
Strong human Carcinogenic to Known to Be Human
humans
mechanistic humans Carcinogen
(Group 1)
Limited Sufficient data
-- Probably
carcinogenic to
Sufficient Strong humans
(Group 2A)
Inadequate Limited Strong
Likely to be
Sufficient -- carcinogenic to Reasonably
humans Anticipated to Be
Limited Limited -- Possibly Human Carcinogen
carcinogenic to
Strong & same humans
class as other (Group 2B)
Inadequate Inadequate carcinogens
Strong/ Inadequate
convincing Information to Assess
Inadequate Limited -- Not classifiable Suggestive Not classified
19
Zeise EEA Copenhagen Sept 3, 2010

20. 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
12/10/2012 20

21. Mode of Action and Cancer
Assessment
 MOA is the keystone to all aspects of
the assessment process
True for other endpoints
and is the major factor in
harmonization among risk
assessments
21

22. Why Do You Care about
MOA ?
 MOA is key in Hazard Identification
 Helps describe circumstances under which
agent is carcinogenic (High dose? Route?)
 Relevance of data for humans
 MOA determines choice of Low Dose
Extrapolation
 Life stage risk
R esponse (T u m o r o r N on tu m o r D ata)
e)
os
D
on
it
m
Li
ce x
en
e)
E n v iro n m e n ta l E m p iric a l
fid
at
E x p o s u re L e v e ls on R ange of
ti m
C
5%
Es
o f In te re s t 9
O b s e rv a tio n
st
al
tr
e
ow
en
(L
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x
x
10%
lt
fau
De R ange of
ear E x tra p o la tio n
L in
x x
0%
L E D 10 E D 10
MOE x N O AEL
N o n lin e a r D e fa u lt
D ose x LO AEL
22

23. 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
23

24. Mode of Action Exposure
 ―. . . a sequence of key Key event
events and processes,
starting with interaction of an
agent with a cell, proceeding
through operational and
anatomical changes, and
resulting in cancer Key event
formation. . . Mode of action is
contrasted with ―mechanism of
action,‖ which implies a more
detailed understanding and
description of events, often at the
molecular level, than is meant by
mode of action‖
Key event
Toxicity 24

25. Mode of Action Frameworks
U.S. EPA IPCS
 Postulated mode of action
 Hypothesized MOA: summary (theory of the case)
description and identification  Key events
of key events  Concordance of dose-
 Experimental support: response relationships
 Strength, consistency,  Temporal association
specificity of association  Strength, consistency and
 Dose-response specificity of association of
concordance tumour response with key
 Temporal relationship
events
 Biological plausibility and
 Biological plausibility and coherence
coherence  Other modes of action
 Consideration of the  Uncertainties,
possibility of other MOAs Inconsistencies, and Data
 Relevance to humans Gaps
 Assessment of postulated
mode of action
25

26. MOA/Human Relevancy ILSI/IPCS
NO
Is the weight of evidence Proceed with
sufficient to establish a mode risk assessment
of action (MOA) in animals?
YES
Can human relevancy of the MOA be
YES reasonably excluded on the basis of
MOA not fundamental, qualitative differences in
Relevant key events between
animals and humans?
NO
Can human relevancy of the MOA be
reasonably excluded on the basis of NO
YES
MOA not quantitative differences in either Proceed with
Relevant kinetic or dynamic factors between Risk assessment
animals and humans?
26

27. Key Event
 A “key event” is an empirically observable
precursor step that is itself a necessary
element of the mode of action or is a
biologically based marker for such an
element.
Key event is necessary, but not sufficient
If a key event doesn‘t occur, there is no
cancer
If one key event occurs, there may or may
not be cancer
27

28. Postulated Mode Of Action
Chloroform
Sustained Toxicity
Regenerative Cell Proliferation
Key Events
Tumor Development
28

29. Postulated Mode Of Action
Metabolism CP
DNA damage
Tumor
Development Mutations
29

30. Mode of Action Framework
 Hypothesized MOA: summary description
and identification of key events
 Experimental support:
 Strength, consistency, specificity of association
 Dose-response concordance
 Temporal relationship
 Biological plausibility and coherence
 Consideration of the possibility of other
MOAs
 Relevance to humans
12/10/2012 30

31. Based on ―Hill Criteria‖ for
Causality
―None of my nine viewpoints
 Experimental support: can bring indisputable
 Strength, consistency, evidence for or against the
cause-and-effect hypothesis
specificity of and none can be required
association as a sine qua non. What
they can do, with greater or
 Dose-response less strength, is to help us
concordance to make up our minds on
the fundamental question —
 Temporal relationship is there any other way of
explaining the set of facts
 Biological plausibility before us, is there any other
and coherence answer equally, or more,
likely than cause and
effect?‖ Hill (1965)
12/10/2012 31

32. Experimental Support for
MOA
 Strength, consistency, specificity of association
 What is the level of statistical and biological
significance for each event and for cancer?
 Do independent studies and different
experimental hypothesis-testing approaches
produce the same associations?
 Does the agent produce effects other than those
hypothesized?
 Is the key event associated with precursor
lesions?
Section
2.4.3.2
12/10/2012 32

33. Experimental Support for
MOA
 Dose Response Concordance
○ Is precursor induced at lower dose than
tumors?
○ If greater incidence of the precursor
occurs, does incidence of tumor
increase?
○ If the precursor event is more severe is
there an increase in tumor incidence?
12/10/2012 33

34. Experimental Support for
MOA
 Temporal Relationship
○ Do the precursor events occur
before tumors are observed?
○ Is this observed in independent
studies?
12/10/2012 34

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

36. Association of Key Precursor Events & Bladder Tumors in F344 Rats
Temporal
Dose Metabolism Transitional
Urothelial Regenerative Urothelial
(mg/kg DMAVDMAI Cell
II Toxicity Proliferation Hyperplasia
bw/day) Carcinoma
0.2 + +
(2 ppm) (wk 3-0.03 ± (wk 10-6/10, - - -
Dose Response Concordance
0.01 uM) grade 3 or 4)
+ +
1 (wk 3-2/7, grade slight
(10 ppm) (wk 3-0.12 ±
3) (wk- 10; 8/10, (wk 10-1.5X inc)
- -
0.02 uM)
grade 3 or 4)
+ +
4
(wk 3-0.28 ±
(wk 3-7/7, grade + + -
(40 ppm) 3) (wk 10-5/10, (wk 10-4.3X inc) (wk 10- 4/10)
0.09 uM)
grade 3 or 4)
+
(6 hrs-6/7, grade 3) + +
9.4 + (24 hrs-4/7, grade 3 (wk 1- 2.2X inc)
+ (papilloma first
(100 ppm) (wk 3-0.55 ± or 4) (wk 8-7/10) obs at wk 107;
(wk 2 6/10, grade
(wk 2-3.9X inc) (wk carcinoma first
0.15 uM) (wk 10-9/10)
5)(wk 10-0/10, grade 10-4.2X inc) obs at wk 87)
4 or 5)
12/10/2012 36

37. Experimental Support for
MOA
 Biological plausibility and coherence
○ Does the MOA make sense given what
is known about carcinogenesis in
general, and for the case specifically?
○ Are carcinogenic effects and events
consistent across structural analogues?
○ Is the database on the agent internally
consistent in supporting the MOA,
including relevant non-cancer
toxicities?
12/10/2012 37

38. Nuclear Receptor Workshop
Possible Key Strength Consistency Specificity Temporal Biological Biological Coherence Key Event
Events Reproducibility Gradient Plausibility (Causal)
Dose- Associated
Response (Marker?)
Modulatory
?
Neither
CAR activation High, Required High High Earliest Not Yes High Causal
for tumors1,2 2 In vivo Knock out event, in determine Fits in a (DWolf)
Bear in mind studies1,2 studies1,2 vivo and in d logical (RPeffer)
that both ref #1 In vitro nuclear vitro14 (any sequence (RBars)
& #2 involve translocation3,4 Perhaps data?) No (RSchoeny)
initiation with PB- data that I (CElcombe)
den and a induced am aware Causal, under
rather short activation of. the
period of of the Only in experimental
treatment with phosphatas vitro (93, conditions
pb, 32 wk in e that 58) outlined in
ref #1 & 30 wk appears to Ref #1 & #2
in ref #2, we facilitate (JGoodman)
do not know the
what would translocati
happen in car on of CAR
ko mice if they from the
were treated cytoplasm
with pb for 2 to the
years nucleus is
(JGoodman) the very
earliest
event?
12/10/2012 38

39. MOA/Human Relevancy ILSI/IPCS
NO
Is the weight of evidence Proceed with
sufficient to establish a mode risk assessment
of action (MOA) in animals?
YES
Can human relevancy of the MOA be
YES reasonably excluded on the basis of
MOA not fundamental, qualitative differences in
Relevant key events between
animals and humans?
NO
Can human relevancy of the MOA be
reasonably excluded on the basis of NO
YES
MOA not quantitative differences in either Proceed with
Relevant kinetic or dynamic factors between Risk assessment
animals and humans?
39

40. Concordance Analysis of Key Events:
Cytotoxic Mode of Action
Key Event Rodents Humans Concordance analysis
Presence of of key events is for
Yes Yes
metabolite the MOA and not
Persistent Yes Possible necessarily
cytototoxicity
chemical specific
Persistent Chemical specific and
regenerative Yes Possible
generic information
proliferation
relevant to adverse
Tumors Yes Possible outcome is useful

41. α2μ Globulin and Male Rat
Kidney Tumors
Chemical-
a2u-Globulin a2u -Globulin
"Complex"
Renal Reabsorption Renal Reabsorption
Nucleus Nucleus
Heterolysosome Amino Acids Heterolysosome
Circulation Circulation

42. α2u-Globulin
 The main story
 Protein produced by male rats
 MOA– functional changes in epithelial cells of
proximal tubules
•Hyaline droplets accumulate
•Tubule cell degeneration
•Regenerative cell proliferation
•Expansion of initiated renal
tubule cells
12/10/2012 42

43. Human Relevance of α2u-globulin
nephropathy – U.S. EPA
Humans do not possess a protein that is similar to α2u in
abundance or binding characteristics; thus, humans would not
be at risk of developing a chemically induced protein-mediated
nephrotoxic response.
Borghoff SJ and Lagarde WH, Toxicol Appl Pharmacol. 1993 Apr;119(2):228-35.
If male rat kidney tumors develop
In the absence of female rat kidney tumors
Male rats have increased hyaline droplets
Hyaline droplets contain a2u-Globulin
Characteristic nephrotoxicity
The male rat kidney tumors are not relevant for human health
risk and would not be included in a risk assessment.

44. Is the MoA for phenobarbital plausible in
humans?
Key event in MoA Plausible in humans?
Activation of CAR
Induction of CYP2B Increase via CAR can occur
Hypertrophy Yes
Cell proliferation Not likely, based on in vitro
and in vivo data
Inhibition of apoptosis Possible but not likely, based on
limited in vitro data
Selective clonal expansion Possible but not likely, none reported
Occurrence of liver tumors No, based on
epidemiological data

45. 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
12/10/2012 45

46. MOA and Kids
 Supplemental Guidance for Assessing
Susceptibility from Early-Life Exposure
to Carcinogens
 Effects observed in childhood
 Early life exposures that contribute to later
life effects
 MOA determines whether quantitative
adjustment is made
46

47. Supplemental Guidance
 Use age-specific values for
exposure and potency
 When data permit, develop
separate potency estimates
for childhood exposure
 In risk characterization, mutagenic MOA risk
is increased by age-dependent adjustment
factor (used with exposure info for age
group)
○ <2 yrs old, 10 fold
○ 2 to < 16yrs, 3 fold
 No MOA, linear extrapolation without ADAF;
non-linear MOA, no ADAF
47

48. Framework for Determining  This may actually get
a Mutagenic Mode of published at some
Action for Carcinogenicity point in time
Using EPA‘s 2005 Cancer
Guidelines and Supplemental
Guidance for Assessing
Susceptibility from Early-Life
Exposure to Carcinogens
48

49. Framework on Default MOA
 ― It should also be noted that there is no
‗default MOA.‘ The Cancer Guidelines offer
some default procedures to use when no
MOA can be determined.‖
•No MOA is not the same as a Mutagenic MOA
Determination of mutagenic MOA is as
scientifically rigorous as any other MOA
I found nothing in IPCS on a default MOA
49

50. To boldly go where no regulatory
toxicologist has gone before . . .
Mutagenicity is the induction of permanent,
transmissible changes in the amount,
chemical properties, or structure of the
genetic material. These changes may involve a
single gene or gene segment, a block of genes, parts of
chromosomes, or whole chromosomes. Effects on whole
chromosomes may be structural and/or numerical (e.g.,
aberrations and/or aneuploidy).
50
50
12/10/2012

51. Boldly part 2
Genotoxicity is the induction of alterations to
genetic material. It is a broader term than
mutagenicity in that genotoxicity refers to potentially
harmful effects on genetic material, which are not
necessarily persistent and transmissible. Genotoxicity
may be mediated directly or indirectly by chemical or
physical agents, and may or may not be associated with
mutagenicity. Tests for genotoxicity include tests for
mutagenicity, as well as other tests which provide an
indication of induced damage to DNA. For example, such
tests may include unscheduled DNA synthesis (UDS),
sister chromatid exchange (SCE), mitotic recombination,
DNA adduct formation, or DNA strand breaks.
51
12/10/2012

52. What does this definition
do?
 Distinguishes between genotoxic and
mutagenic (U.S. EPA Guidelines refer to
―mutagenic MOA‖; Europe deals with
genotoxic).
 Includes numeric changes in chromosome
as mutagenic
 But not likely to be linear at low dose
 Includes agents that generate reactive
oxygen species (ROS)
 But need to consider low dose response
52

53. Framework: Multi-step
Process
 Risk assessment
is an iterative
process
 Visualize the Framework as series of
linear steps
 Assemble data
 Assess, weigh data quality
 WOE for mutagenicity
 WOE for MOA
53

54. Step 2: Evaluate Data
Quality
 Look at primary papers
 Judge against current
acceptability criteria
 Cites publications for evaluating quality (e.g.
Cimino 2006, OECD, ICH, IWGT, DHHS
2006)
 Keep, but weigh
54

55. Step 3 Gene- tox Tests Measure
Different Events
Genotoxicity Assays
Mouse Chromosome Ames Bacterial
Type of Damage
Lymphoma Aberrations CHO cells Mutagenicity
Point mutation Yes No Yes
Oligonucleotide
insertion or deletion
Yes No Yes
Allele Loss Yes No No
Small Chromosome
alteration
Yes ? No
Large Chromosome
alteration
Yes Yes No
Aneuploidy ? Yes No
Adapted from M. Moore (2004)
Cancer Hazard ID TERA’s Dose-Response Assessment Boot Camp 55
55

56. Step 3: WOE for Mutagenic
Activity
 Categorize data – suggest use of our table in
Appendix A.
 Put in all data with notes on quality
 Use consistent terms for assay types or
endpoints: positive, negative, inconclusive,
contradictory
 Present summary of
database
56

57. Concen- Cytotoxicity Duration of Results With Results Without Conform to Ref
In vitro Assays trations observed Exposure metabolic metabolic relevant
Test System activation (+ S9) activation (- S9) guideline
Gene Mutation
Bacterial
Salmonella, reverse mutation
E. coli, reverse mutation
Mammalian
CHO gene mutation, hprt locus
Mouse L5178Y, tk locus
Chromosome
Mutation
Micronucleus assay
Chromosomal aberrations
DNA Effects
Mammalian
Unscheduled DNA synthesis
Sister chromatid exchanges
Comet assay
DNA adduct analysis
Lower Eukaryote
Saccharomyces cerevisiae, gene
conversion
57

58. WOE for Mutagenic Activity
 Conclusions across endpoints: some
endpoints carry more weight than others
○ e.g. Sperm head morphology may be caused
by modification of protein structure
○ Morphologic cell transformation does not
measure mutation
 WOE for mutagenic activity: negative, data
are inadequate, data are of questionable
quality, data are equivocal, data are positive
58

59. Apply MOA Framework
Mutagenicity + carcinogenicity ≠ Mutagenic MOA
Mutagenic Carcinogen
Initiating Multiple events
Tumor
Mutation
Nonmutagenic Carcinogen
Toxicity
Altered Gene Initiating Multiple events
Expression Mutation
Tumor
Cell Proliferation
59

60. Data Preference: WOE Mutagenic MOA
 Cancer-relevant oncogene or tumor suppressor gene
mutations detected in target tissue after chemical exposure.
 Surrogate gene mutations detected in target tissue after
chemical exposure.
 Chemical-specific DNA adducts (known to be mutagenic
adducts) in target tissue after chemical exposure.
 Primary DNA damage in target tissue after chemical
exposure.
 Gene mutations or chromosome aberrations in surrogate
tissues after in vivo exposure.
 DNA adducts or other measures of DNA damage and/or
repair or in surrogate tissues after in vivo exposure.
 Mutations, cytogentic damage, DNA adducts and/or primary
DNA damage in vitro.
60
12/10/2012

61. What Has a Mutagenic MOA?
Cyclophosphamide
Cytotoxic, alkylating
Alkylating
Cytotoxic
61

62. Source
Application to Levels of
Organization Based on
Source to Outcome
Environmental
Contaminant
Exposure
Molecular Initiating Event Cellular Effects Individual Population Community
Toxicity Pathway
Mode of Action
Adverse Outcome Pathway
Source to Outcome Pathway
62

63. Application to Levels of
Organization Based on Source
to Outcome
Source
Community
Environmental
Contaminant
Population
Exposure Individual
Molecular Initiating Event Cellular Effects
Toxicity Pathway
Mode of Action
Adverse Outcome Pathway
Source to Outcome Pathway
63

64. 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
12/10/2012 64

65. High dose data – what do they
tell us?
Response
Dose
65

66. Take home message
 In science, data before defaults
 Scientifically based low dose
extrapolation before defaults
 Science may inform policy; policy should
never affect science
66

67. Possibilities
Response
Dose
Interspecies
67

68. Two Step Approach
 Model data in the
observed range – to a
R e s p o n s e (T u m o r o r N o n tu m o r D a ta )
it
o
n
D
o
se
)
point of departure
im
L
ce x
 Extrapolate below the
en
e)
E nv ironm e ntal d E m pirical
fi
at
n
E xpo sure Lev els C
o im
R ange of
st
of In terest 5% O b serv ation
lE
t9
tr a
es
w
POD
en
o
(L
(C
x
x
1 0%
lt
fa u R ange of
r De
ea
L in E xtrapo lation
x x
0%
L E D 10 E D 10
UF x NOAEL
N on lin ear D efau lt
D o se x LOAEL
68

69. 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
69

70. 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
70

71. Linear or Non-linear?
Two Step Dose Response Process
R e sp on se (Tum o r o r No n tu m o r D ata )
e)
os
D
on
it
Another Question First en
ce
Li
m
x
e)
E n v iro n m e n ta l E m p iric a l
fid
at
E x p o s u re L e v e ls on R ange of
t im
C
Es
o f In te re s t 5% O b s e rv a tio n
t9
al
es
tr
ow
en
(L
(C
x
x
1 0%
lt
fa u
De R ange of
e ar
L in E x tra p o la tio n
x x
0%
L E D 10 E D 10
UF x NOAEL
N on lin ear D efau lt
D ose x LOAEL
71

72. 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
72

73. Specify the sequence(s) of key
events
dosimetry Key event B1
Key event B2
Key event A1 Mode of
Action Assessment
endpoint
Key event A2
Key event A3
73

74. Source
Exposure
PBPK
Tissue dose
BBDR
Mode of action
Biologically Based
Dose Response
Model
Response
74

75. Applied
Dose of Phenobarbital
(PBPK)
75

76. 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.
76

77. 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?
77

78. And if no BBDR?
Two Step Dose Response Process
R e sp on se (Tum o r o r No n tu m o r D ata )
e)
os
D
on
it
m
Linear or Non-linear
Li
ce x
en
e)
E n v iro n m e n ta l E m p iric a l
fid
at
E x p o s u re L e v e ls on R ange of
t im
C
Es
o f In te re s t 5% O b s e rv a tio n
t9
al
es
tr
ow
en
(L
(C
x
x
1 0%
lt
fa u
De R ange of
e ar
L in E x tra p o la tio n
x x
0%
L E D 10 E D 10
UF x NOAEL
N on lin ear D efau lt
D ose x LOAEL
78

79. 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
79

80. Threshold?
 Demonstrated  Based on MOA
 By inspection of the  Mutagenic MOA has
dose response 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 80

81. In vitro Mutation Dose-Response: MMS & MNU
Doak et al., 2007
HPRT MF
MMS
MMS
NOEL = 1 mg/ml
MNU
MNU
No NOEL
2011 EMS Annual Meeting Pottenger 81

82. In vitro Mutation Dose-Response:
ENU Johnson et al., 2009
HPRT MF
ENU threshold dose-response (Lutz & Lutz model)
Slide from Pottenger 82

83. 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
83

84. Take home message 2
 In science, data before defaults
 Scientifically based low dose
extrapolation before defaults
 Science may inform policy; policy should
never affect science
84

85. 85

86. 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
86

87. 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
87

88. 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
88