Download - 08 rita schoeny
NEW PARADIGMS FOR ASSESSING AND
MANAGING CHEMICAL CARCINOGENS
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
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Disclaimer
The views expressed in this presentation are those do the author and do not represent the policy of the U.S. EPA.
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Some of this is EPA policy
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So What Is EPA Policy?
Science Policy Defaults, methods, Guidelines Used when there are data or methodology gapsPeer reviewedLots of documentation, which is publicly available
Policy based on scienceMay be set by EPA Executive LevelGenerally 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
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Examples Science policy
Cancer Guidelines 2005Set a reference dose for effects which are likely to
have a thresholdQuantitative adjustment to cancer risk for early life
exposureAnimal data are relevant to humans unless
demonstrated otherwise
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
plantsCost / benefit choices
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SDWA ‘96
Will regulation of the contaminant present a meaningful opportunity for health risk reduction?
Is the contaminant known or likely to occur in PWSs with a frequency and at levels posing a threat to public health?
Does the contaminant adversely affect public health?
Regulate with NPDWR
These are questions, demonstrations of risk
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Risk Assessment Risk Management
’83 Risk Assessment Paradigm ’12?
Hazard Identification
Dose ResponseAssessment
Exposure Assessment
Risk Characterization
Risk Management Options
Statutory, legalconsiderations
Politics
Social Factors
Economics
Available Technology
Mode of Action
A lot has changed since ‘83
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IPCS FRAMEWORK FOR ANALYSING THE RELEVANCE OF A CANCER MODE OF ACTION
FOR HUMANS
Exposure Science in the 21st Century: A Vision and A Strategy
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.
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Con
firm
atio
n of
Util
ity
Planning & Scopingand Problem Formulation
Informing Decisions
ConceptualModel
AnalysisPlan
ExposureAssessment
Public/ Community/ Stakeholder Involvement
Effects AssessmentHazard Identification
Dose Response
Risk Characterization
Risk Assessment
Draft HHRA FrameworkSilver Book on Utility“Risk assessments should not be conducted unless it is clear that they are designed to answer specific questions, and that the level of technical detail and uncertainty and variability analysis is appropriate to the decision context” (NRC 2009, p. 247).
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NRC Scheme for Biomarkers (Schulte, 1989)
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A Generalized Conceptual Model (adapted from USEPA, 2002; 2003)
S ources Exposure Pathways/RoutesS tressors EndpointsReceptors Risk Metrics
Activities that generate/release
Stressors or types of stressor releases
Chemical, physical or biological agents that cause an effect
Physical processes or interactions by which a stressor is brought into to contact with
receptor Populationsand/or lifestagesexposed tothe stressor
Measures of stressor effects or biological systems affected
Metrics by which risk is quantified(e.g., disease cases, hazard quotients, magnitude of
effect)
Drinking water disinfection
Variable mixturenitrosamines; dependent on treatment & 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 subsetnitrosamines in mixture
Sources Stressors Exposure Receptors Endpoints Risk Pathways/ Metrics Routes
Conceptual Model Nitrosamines in Drinking Water
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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
Risk Assessment Science
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Analyze the available data
Is there too much uncertainty or is critical information lacking?
Invoke a default option
N
Y
Use Data Before Invoking Defaults
Conduct risk assessment
04/12/2023 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
Evidence Maps to Cancer ClassificationsHuman Animal Indirect,
OtherIARC US EPA NTP
Sufficient -- --Carcinogenic to
humans (Group 1)
Carcinogenic to humans
Known to Be Human Carcinogen
Limited Sufficient
Strong human mechanistic data
-- Probably carcinogenic to
humans (Group 2A)
Likely to be carcinogenic to
humansReasonably
Anticipated to Be Human Carcinogen
Inadequate
Sufficient Strong
Limited Strong
Possibly carcinogenic to
humans (Group 2B)
Sufficient --
Limited Limited --
Inadequate Inadequate
Strong & same class as other carcinogens
Strong/ convincing
Inadequate Information to Assess
Inadequate Limited -- Not classifiable Suggestive Not classified 19
Zeise EEA Copenhagen Sept 3, 2010
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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
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Mode of Action and Cancer Assessment MOA is the keystone to all aspects of
the assessment process
True for other endpointsand is the major factor in harmonization among riskassessments
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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
MOE
Dose
Resp
on
se
(T
um
or
or
No
ntu
mo
r D
ata
)
0%
10%
EnvironmentalExposure Levels
of Interest
LED10 ED10
Nonlinear Default
EmpiricalRange of Observation
Range ofExtrapolation
x
x
xx
x
x NOAEL
LOAEL
x
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Cancer
Breaking Down the Dichotomy
Non-ThresholdIrreversibleRisk value
Slope Factor Unit Risk Risk-Specific Dose
Non-Cancer
ThresholdReversibleSafety Value
RfD/RfC ADI/TDI MRL
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Exposure
Toxicity
Key event
Key event
Key event
“. . . a sequence of key events and processes, starting with interaction of an agent with a cell, proceeding through operational and anatomical changes, and resulting in cancer 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”
Mode of Action
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Mode of Action Frameworks
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
Postulated mode of action (theory of the case) Key events Concordance of dose-response relationships Temporal association Strength, consistency and specificity of association of tumour response with key events Biological plausibility and coherence Other modes of action Uncertainties, Inconsistencies, and Data Gaps Assessment of postulated mode of action
U.S. EPA IPCS
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MOA/Human Relevancy
ILSI/IPCS
YES
NO
NO
YESMOA notRelevant
YESMOA notRelevant
NOProceed withRisk assessment
Proceed withrisk assessment
Is the weight of evidence sufficient to establish a mode of action (MOA) in animals?
Can human relevancy of the MOA be reasonably excluded on the basis of fundamental, qualitative differences in key events between animals and humans?
Can human relevancy of the MOA be reasonably excluded on the basis of quantitative differences in either kinetic or dynamic factors between animals and humans?
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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
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ChloroformCYP2E1
Phosgene
Regenerative Cell Proliferation
Postulated Mode Of Action
MetabolismOxidative
Sustained Toxicity
Tumor Development
Key Events
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Postulated Mode Of Action CPMetabolism
Phosphoramide mustard, PAM
Acrolein
DNA damage
Mutations
Tumor Development
Cyt p 450s
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Mode of Action Framework
Hypothesized MOA: summary description and identification of key events
Experimental support:Strength, consistency, specificity of associationDose-response concordanceTemporal relationshipBiological plausibility and coherence
Consideration of the possibility of other MOAs
Relevance to humans
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Based on “Hill Criteria” for Causality
Experimental support:Strength, consistency,
specificity of association
Dose-response concordance
Temporal relationshipBiological plausibility
and coherence
“None of my nine viewpoints can bring indisputable evidence for or against the cause-and-effect hypothesis and none can be required as a sine qua non. What they can do, with greater or less strength, is to help us to make up our minds on the fundamental question — is there any other way of explaining the set of facts before us, is there any other answer equally, or more, likely than cause and effect?” Hill (1965)
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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?
Section2.4.3.2
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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?
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Experimental Support for MOA Temporal Relationship
○Do the precursor events occur before tumors are observed?
○ Is this observed in independent studies?
Mode of Action: Bladder Tumors, Key EventsCytotoxicity and Regenerative Hyperplasia
DMAIII
Metabolite
Hyperplasia
UrothelialToxicity
RegenerativeProliferation
Tumor
Sustained BrdU Labeling
Measurable Key Events in Target Tissue
BrdULabeling
SEM
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Dos
e R
espo
nse
Con
cord
ance
Temporal
Dose (mg/kg bw/day)
Metabolism DMAVDMAIII
Urothelial Toxicity
Regenerative Proliferation
Urothelial Hyperplasia
Transitional Cell
Carcinoma
0.2(2 ppm)
+(wk 3-0.03 ± 0.01 uM)
+(wk 10-6/10, grade 3 or 4)
- - -
1(10 ppm)
+(wk 3-0.12 ± 0.02 uM)
+(wk 3-2/7, grade 3) (wk- 10; 8/10, grade 3 or 4)
slight(wk 10-1.5X inc) - -
4(40 ppm)
+(wk 3-0.28 ± 0.09 uM)
+(wk 3-7/7, grade 3) (wk 10-5/10, grade 3 or 4)
+(wk 10-4.3X inc)
+(wk 10- 4/10) -
9.4(100 ppm)
+(wk 3-0.55 ± 0.15 uM)
+(6 hrs-6/7, grade 3) (24 hrs-4/7, grade 3 or 4)(wk 2 6/10, grade 5)(wk 10-0/10, grade 4 or 5)
+(wk 1- 2.2X inc) (wk 2-3.9X inc) (wk 10-4.2X inc)
+ (wk 8-7/10)(wk 10-9/10)
+ (papilloma first obs at wk 107; carcinoma first obs at wk 87)
Association of Key Precursor Events & Bladder Tumors in F344 Rats
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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?
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Possible Key Events
Strength ConsistencyReproducibility
Specificity Temporal Biological GradientDose-Response
Biological Plausibility
Coherence Key Event(Causal)Associated(Marker?)Modulatory?Neither
CAR activation High, Required for tumors1,2
Bear in mind that both ref #1 & #2 involve initiation with den and a rather short period of treatment with pb, 32 wk in ref #1 & 30 wk in ref #2, we do not know what would happen in car ko mice if they were treated with pb for 2 years(JGoodman)
High2 In vivo studies1,2
In vitro nuclear translocation3,4
HighKnock out studies1,2
Earliest event, in vivo and in vitro14
Perhaps PB-induced activation of the phosphatase that appears to facilitate the translocation of CAR from the cytoplasm to the nucleus is the very earliest event?
Not determined(any data?) No data that I am aware of.Only in vitro (93, 58)
Yes HighFits in a logical sequence
Causal(DWolf)(RPeffer) (RBars)(RSchoeny)(CElcombe)Causal, under the experimental conditions outlined in Ref #1 & #2(JGoodman)
Nuclear Receptor Workshop
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MOA/Human Relevancy
ILSI/IPCS
YES
NO
NO
YESMOA notRelevant
YESMOA notRelevant
NOProceed withRisk assessment
Proceed withrisk assessment
Is the weight of evidence sufficient to establish a mode of action (MOA) in animals?
Can human relevancy of the MOA be reasonably excluded on the basis of fundamental, qualitative differences in key events between animals and humans?
Can human relevancy of the MOA be reasonably excluded on the basis of quantitative differences in either kinetic or dynamic factors between animals and humans?
Concordance Analysis of Key Events: Cytotoxic Mode of Action
Key Event Rodents Humans
Presence of metabolite Yes Yes
Persistent cytototoxicity
Yes Possible
Persistent regenerative proliferation
Yes Possible
Tumors Yes Possible
Concordance analysis of key events is for the MOA and not necessarily chemical specific
Chemical specific and generic information relevant to adverse outcome is useful
α2μ Globulin and Male Rat Kidney Tumors
a2u
-Globulin
Renal Reabsorption
Nucleus
Heterolysosome Amino Acids
Circulation
Chemical-a2u -Globulin "Complex"
Renal Reabsorption
Nucleus
Circulation
Heterolysosome
04/12/2023 42
α2u-Globulin The main story
Protein produced by male ratsMOA– functional changes in epithelial cells of
proximal tubules
• Hyaline droplets accumulate • Tubule cell degeneration• Regenerative cell
proliferation• Expansion of initiated renal tubule cells
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 developIn the absence of female rat kidney tumorsMale rats have increased hyaline dropletsHyaline droplets contain a2u-GlobulinCharacteristic nephrotoxicity
The male rat kidney tumors are not relevant for human health risk and would not be included in a risk assessment.
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
04/12/2023 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
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MOA and Kids
Supplemental Guidance for Assessing Susceptibility from Early-Life Exposure to CarcinogensEffects observed in childhoodEarly life exposures that contribute to later
life effectsMOA determines whether quantitative
adjustment is made
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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
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Framework for Determining
a Mutagenic Mode of
Action for CarcinogenicityUsing EPA’s 2005 Cancer
Guidelines and Supplemental
Guidance for Assessing
Susceptibility from Early-Life
Exposure to Carcinogens
This may actually get published at some point in time
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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
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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).
04/12/202351
Boldly part 2Genotoxicity 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.
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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 mutagenicBut not likely to be linear at low dose
Includes agents that generate reactive oxygen species (ROS)But need to consider low dose response
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Framework: Multi-step Process Risk assessment
is an iterative process
Visualize the Framework as series of linear stepsAssemble dataAssess, weigh data qualityWOE for mutagenicityWOE for MOA
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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
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Step 3 Gene- tox Tests Measure Different EventsStep 3 Gene- tox Tests Measure Different Events
Genotoxicity Assays
Type of Damage
Mouse Lymphoma
ChromosomeAberrations CHO cells
Ames Bacterial Mutagenicity
Point mutation Yes No YesOligonucleotide insertion or deletion
Yes No Yes
Allele Loss Yes No NoSmall Chromosome alteration
Yes ? No
Large Chromosome alteration
Yes Yes No
Aneuploidy ? Yes No
Adapted from M. Moore (2004)
Cancer Hazard ID 55TERA’s Dose-Response Assessment Boot Camp
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Step 3: WOE for Mutagenic Activity Categorize data – suggest use of our table in
Appendix A.Put in all data with notes on qualityUse consistent terms for assay types or
endpoints: positive, negative, inconclusive, contradictory
Present summary of
database
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In vitro AssaysTest System
Concen-trations
Cytotoxicity observed
Duration of Exposure
Results With metabolic activation (+ S9)
Results Without metabolic activation (- S9)
Conform to relevant guideline
Ref
Gene MutationBacterial Salmonella, reverse mutation
E. coli, reverse mutation
Mammalian CHO gene mutation, hprt locus
Mouse L5178Y, tk locus
Chromosome Mutation
Micronucleus assayChromosomal aberrations
DNA EffectsMammalian
Unscheduled DNA synthesis
Sister chromatid exchanges
Comet assay
DNA adduct analysis
Lower Eukaryote
Saccharomyces cerevisiae, gene conversion
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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 mutationWOE for mutagenic activity: negative, data
are inadequate, data are of questionable quality, data are equivocal, data are positive
Apply MOA Framework
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Mutagenicity + carcinogenicity ≠ Mutagenic MOA
Initiating
Mutation
Multiple events
Toxicity
Altered Gene Expression
Cell Proliferation
InitiatingMutation
Multiple events
Tumor
Mutagenic Carcinogen
Nonmutagenic Carcinogen
Tumor
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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.
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What Has a Mutagenic MOA? Cyclophosphamide
Alkylating
Cytotoxic
Cytotoxic, alkylating
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Mode of Action
Adverse Outcome Pathway
Source to Outcome Pathway
Toxicity Pathway
Source
EnvironmentalContaminant
Exposure
Molecular Initiating Event Cellular Effects Individual Population Community
Application to Levels of Organization Based on
Source to Outcome
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Application to Levels of Organization Based on Source
to Outcome Source
EnvironmentalContaminant
Exposure
Cellular Effects
Individual
Population
Community
Mode of Action
Adverse Outcome Pathway
Source to Outcome Pathway
Toxicity Pathway
Molecular Initiating Event
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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
65
High dose data – what do they tell us?
Res
pons
e
Dose
Take home message
In science, data before defaults Scientifically based low dose
extrapolation before defaults Science may inform policy; policy should
never affect science
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67
PossibilitiesR
espo
nse
Dose
Interspecies
68
Two Step Approach
Model data in the observed range – to a point of departure
Extrapolate below the POD
UF
Dose
Res
pons
e (T
umor
or
Non
tum
or D
ata)
0%
10%
EnvironmentalExposure Levels
of Interest
LED10 ED10
Nonlinear Default
EmpiricalRange of Observation
Range ofExtrapolation
x
x
xx
x
x NOAEL
LOAEL
x
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Extend the Observed Range Using Precursor Data Objective of choosing POD is to set it as
close to environmental levels as Supported by dataAppropriate to model
Cancer Guidelines say precursor data are useful for this
Must have MOA
Section3.2.2
70
Endpoint Duration
Feeding
Duration
Drinking water
10% 1% 10% 1%
BMD (mg/kg/d)
BMDL(mg/kg/d)
BMD(mg/kg/d)
BMDL(mg/kg/d)
BMD(mg/kg/d)
BMDL(mg/kg/d)
BMD(mg/kg/d)
BMDL(mg/kg/d)
Tumor 104 weeks 7.74 5.96 6.80 2.22 104
weeks 1.92 1.21 0.88 0.14
Hyperplasia
10weeks 1.36 1.04 0.42 0.32
104 weeks 1.63 1.04 0.74 0.14
104 weeks 1.97 1.61 0.93 0.66
BrdU labeling
10 weeks 0.65 0.29 0.54 0.07 Not determined. Available data not suitable for modeling.
Cytotoxicity
3 weeks 0.68 0.18 0.31 0.02
No reliable dose-response data available
10 weeks 0.02 0.008 0.002 0.0007
Cacodylic Acid: BMDs and BMDLs
Linear or Non-linear?
71
UF
Dose
Re
sp
on
se
(T
um
or
or
No
ntu
mo
r D
ata
)
0%
10%
EnvironmentalExposure Levels
of Interest
LED10 ED10
Nonlinear Default
EmpiricalRange of Observation
Range ofExtrapolation
x
x
xx
x
x NOAEL
LOAEL
x
Two Step Dose Response Process
Another Question First
Is There Something Better?
72
Analyze all data before using defaults
Is there too much uncertainty or is critical information lacking? Invoke a
default option*
N
Y
Analyze the available data
Conduct risk assessment
73
Specify the sequence(s) of key events
dosimetry Key event B1
Key event B2
Key event A1
Key event A2
Key event A3
Assessment endpoint
Mode of Action
Exposure
Tissue dose
Mode of action
Response
Source
PBPK
BBDR
74
Biologically Based Dose Response Model
75
(PBPK)
AppliedDose of Phenobarbital
Multiple dose-responses
and time-courses
76
Reality check (I) There are always data gaps
ArsenicFormaldehydeTCDDphenobarbital
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.
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?
And if no BBDR?
78
UF
Dose
Re
sp
on
se
(T
um
or
or
No
ntu
mo
r D
ata
)
0%
10%
EnvironmentalExposure Levels
of Interest
LED10 ED10
Nonlinear Default
EmpiricalRange of Observation
Range ofExtrapolation
x
x
xx
x
x NOAEL
LOAEL
x
Two Step Dose Response Process
Linear or Non-linear
Mutagenesis Paradigm
DNA Damaged DNA
Mutagens/Spontaneous
Damage Sensing
Cellular Response
DNA Repair
Repaired DNA
IncorrectRepair/Replication
Mutant DNA
No repair
Dead Cell79
Demarini 70
Threshold? Demonstrated
By inspection of the dose response curve
Fitting models and checking goodness of fit
Statistical tests for one model or another
Based on MOAMutagenic MOA has
been linearBut should consider
biology of mutation
Does mutagenic MOA mean low dose linear?BBDR should be first choice 80
MMS
MNU
2011 EMS Annual Meeting Pottenger 81
In vitro Mutation Dose-Response: MMS & MNUDoak et al., 2007
MMS
MNU
HPRT MF
NOEL = 1 mg/ml
No NOEL
Johnson et al., 2009
ENU threshold dose-response (Lutz & Lutz model)
In vitro Mutation Dose-Response: ENU
HPRT MF
Slide from Pottenger 82
Take Home Message
MOA informs dose response assessment
DNA damage is not mutation Mutation is not cancer Some genotoxicity endpoints may be
reasonable biomarkersMay be useful for extending the lower end of
dose response curveUseful in MOA
83
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
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
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
88
Cancer
Breaking Down the Dichotomy
Non-ThresholdIrreversibleRisk value
Slope Factor Unit Risk Risk-Specific Dose
Non-Cancer
ThresholdReversibleSafety Value
RfD/RfC ADI/TDI MRL