Peter W' Preuss, Ph'D'

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Human Health Risk Assessment at EPA Background,
Current Practice, Future Directions
Presentation for the Board of Scientific
Counselors for Human Health Risk Assessment
October 2, 2007

• Peter W. Preuss, Ph.D.
• Director, National Center for Environmental
  Assessment

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Risk Paradigm Alignment in ORD
National Center for Computational Toxicology
Application of computational tools and models to
improve understanding of toxicity and risks posed
by environmental agents.
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Risk Assessment Linkages
Risk Assessments and Management
Application
Regulatory Programs, Regions
Dose-Response Assessments (IRIS,Criteria Docs)
Communication, support
Assessments
NCEA
Needs
Methods, Models, Data
Risk Assessment Methods, Models for Extrapolation
Guidelines for Interpretation
NCEA RAF
Synthesis and Guidance
Comp. Tox Labs (EPA, others) NCER
Toxicity Testing, Epidemiology
Research on Exposure
Research on Mode of Action (TK/TD),
dose-response, etc
Primary Research
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NCEA and Risk Assessment at EPA
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NCEA and Risk Assessment at EPA
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Human Health Risk Assessment is

• Fundamental to EPAs approach to analysis of
  potential risk from exposure to environmental
  contaminants
• Essential for EPA regulatory decision-making
• Evolving in the face of new understandings about
  uncertainty, mode of action, metabolism,
  susceptibility, etc.
• Addressing emerging science and new science
  challenges

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Human Health Risk Assessment at EPA

• Beginnings of the field of risk assessment
• Emphasis on oral route per FDA precedent
• General acceptance of Safety Factors (10x10)
• Beginnings of cancer guidelines

1970s

• Adopt NRC RA/RM paradigm
• EPA publishes five risk assessment guidelines
  
• First paper on Reference Dose
• Integrated Risk Information System (IRIS)

1980s

• Inhalation RfC methodology
• Oral RfD methodology
• Applications of PBPK models
• BBDR models developed
• BMD models developed and applied

1990s

• Risk Assessment Forums recommendations for RfD
  and RfC
• Examination of non-cancer methods
• Susceptible populations
• Cumulative assessment approaches
• Probabilistic approaches
• Uncertainty analysis

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Federal Agencies States Public
Oversight, Interest, and Influences
NAS Reports
Scientific community
Industry Trade associations
Executive branch
U.S. international agreements
Public interest groups Environmental
organizations Advocacy groups
Court-ordered schedules
Statutory mandates/schedules Congressional
concerns
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Human Health Risk Assessment Multi-Year
Plan August 2007
LTG 1 Integrated Risk Information System (IRIS)
and other priority health hazard assessments
Agency, state and local risk assessors use the
state-of-the-science health hazard assessment
information provided on priority substances in
their decisions and actions to protect human
health from risks posed by environmental
pollutants. LTG 2 State-of-the-science risk
assessment models, methods, and guidance EPA
programs, states and other risk assessors use the
risk assessment models, methods, and guidance
provided to enhance, through the incorporation of
contemporary scientific advances, the quality and
objectivity of their assessments and
decision-making on environmental health risks.
Executive Lead Peter Preuss Center
Director, ORD-NCEA Science Lead John
Vandenberg Associate Center Director,
ORD-NCEA Author Leads Bruce Rodan Assistant
Center Director, ORD-NCEA Stan
Barone Acting Assistant Center Director,
ORD-NCEA
LTG 3 Air Quality Criteria Documents (now called
Integrated Science Assessments) As mandated in
the Clean Air Act, the ambient air criteria
pollutants are reviewed and AQCDs revised to
reflect the best available scientific information
on identifiable effects on public health and the
environment from exposure to the pollutant, and
this information is used by the EPA Office of Air
and Radiation in their review and promulgation of
the National Ambient Air Quality Standards
(NAAQS) to protect public health with an adequate
margin of safety.
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Logic Model for the Human Health Risk Assessment
- Multi-Year Plan
Environmental Indicators Impact Matrix
measuring incorporation of RA-H outputs into
agency risk assessment practices and decisions,
including use in agency site assessments, RODs
and regulations, and the benefits resulting from
this use of sound science, evaluated through
independent external scientific review, such as
the EPA BOSC, CASAC, SAB and NAS.
Outreach and Effective Transfer Output via the
IRIS database, NCEA websites, peer reviewed
agency and journal publications, and
participation at scientific society and regional
risk assessment meetings. Input through
Congressional mandate, annual programmatic
reviews, Federal Register solicitation, public
meetings and external peer consultation.
Resources We apply our human resources and
expertise in the diverse scientific fields
contributing to risk assessment practice,
supplemented through extramural funding and
contractor support, and incorporating
stakeholder, public and peer review input
Research Activities to compile, analyze and
summarize the state of the science on
environmental health hazards posed to humans by
substances of priority concern to agency
decision-makers, along with the models, methods,
guidance and technical support necessary to
enhance the quality of these analyses
Clients to risk assessors and managers in EPA
client Offices and Regions dealing with air,
water, land, and enforcement, in addition to
other state and local risk assessors, the public
and international organizations
Short-term Outcomes so that they have high
quality health hazard information under the
Integrated Risk Information System (IRIS) and
Integrated Science Assessment( ISA) Documents
based on sound scientific models, methods, and
guidance
Immediate Outcomes leading to enhanced
risk-based decision-making and reduced
environmental pollution of the air, water, land
and food to levels without appreciable risk to
the public
Outputs to provide human health hazard
assessments and quantitative risk information in
a form most appropriate for decision-making,
supported by peer reviewed agency reports,
journal articles, and technical presentations
Long Term Outcomes ... resulting in improved
health, well-being and prosperity of communities
through science-based environmental decision
making.
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RA LTG 1 Annual Performance Goals
LTG 1 Integrated Risk Information System (IRIS)
and other priority health hazard assessments
Agency, state and local risk assessors are
provided state-of-the-science health hazard
assessment information on priority substances
included in planned Agency decisions and actions.
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IRIS assessments
Complete health hazard assessments for
interagency review or external peer
review. 16 IRIS hazard/DR
assessments 25 new/ 25 revised PPRTVs
Complete health hazard assessments for
interagency review or external peer
review. 16 IRIS hazard/DR assessments Post
4 completed hazard/DR assessments 50
new/revised PPRTVs
Complete health hazard assessments for
interagency review or external peer
review. 16 IRIS hazard/DR assessments Post
6 completed hazard/DR assessments 50
new/revised PPRTVs
Complete health hazard assessments for
interagency review or external peer
review. 16 IRIS hazard/DR assessments Post
10 completed hazard/DR assessments 50
new/revised PPRTVs
Complete health hazard assessments for
interagency review or external peer
review. 16 IRIS hazard/DR assessments Post
14 completed hazard/DR assessments 50
new/revised PPRTVs
Complete health hazard assessments for
interagency review or external peer
review. 16 IRIS hazard/DR assessments Post
16 completed hazard/DR assessments 50
new/revised PPRTVs
Complete health hazard assessments for
interagency review or external peer
review. 16 IRIS hazard/DR assessments Post
16 completed hazard/DR assessments 50
new/revised PPRTVs
Provisional Toxicity Values
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Human Health Risk Assessment LTG 2 Annual
Performance Goals
Quantitative RA models tools Provide models
and tools for improving quantitative
dose-response relationships, characterizing human
exposures and reducing uncertainty in risk
assessments
Quantitative RA advances, including central
tendency uncertainty Develop mathematical
models to address an expanded range of data sets,
including measures of central tendency and
uncertainty analysis, accompanied by
dissemination for use in quantitative risk
assessment, including categorical regression,
2-stage clonal, and acute models to incorporate
current standards of RA science into EPA
practice methods for central tendency and
uncertainty in RA modeling dissemination through
the BMD software BMD guidance harmonization of
uncertainty factors and age group designations
for childrens exposure assessment.
Integrating RA advances into quantitative
frameworks Integrate PBPK, exposure, microbial
and biological modeling advances into
quantitative risk frameworks, thereby applying
mathematical modeling and data advances to
biological systems, including application of
uncertainty analysis in PBPK modeling
quantitative basis for interspecies scaling and
defaults exposure factors, dermal methods, and
exposure assessment guidelines and microbial RA
models.
Mode of Action to refine RA extend beyond the
range of data Incorporate mode of action
advances to improve approaches for cancer and
non-cancer RA, facilitating quantitative
estimates of risk within the range of data and at
environmental exposure levels, including
dose-response and extrapolation implications of
MoA in peroxisome proliferation, bladder tumors,
mutagenesis, chemical mixtures and
immunosuppression, culminating in a summary of
conceptual MoA models and their application to
dose-response modeling.
Guidance on RA models uncertainty analysis
Apply uncertainty analyses in
biologically-based risk assessment models,
accompanied by the development of risk assessment
guidance to disseminate information, including
tools to characterize uncertainty and variability
in PBPK models lifestage data and its
application to childrens RA and RfC methods
guidance, less than lifetime RA guidance, and
microbial RA guidance.
Expanding single substance RA to complex
environmental mixtures
Synthesis of progress to improve risk assessment
application for hazard and exposure
information Synthesize qualitative and
quantitative information contributing to
uncertainty in RA for exposure and susceptibility.
Integrating synthesizing progress in RA models
methods Integrate and synthesize
improvements in dose-response methods and models
in risk assessment,
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Human Health Risk Assessment LTG 3 Annual
Performance Goals Measures
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NCEA Human Health Assessment

• Conducting human health risk assessments and
  management of the Agencys Integrated Risk
  Information System (IRIS) (e.g.,
  tetrachloroethylene, methyl tertiary butyl ether,
  ethylene oxide, trichloroethylene TCE,
  acrylamide, formaldehyde and 72 others)
• Producing Integrated Science Assessments
• Ozone -- completed February 2006 proposed NAAQS
  June 2007
• Lead -- completed September 2006 proposed NAAQS
  fall 2007
• Particulate Matter -- completed October 2004
  completed NAAQS fall 2006
• Nitrogen Oxides -- underway
• Sulfur dioxide -- underway
• Carbon Monoxide -- completed June 2000

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NCEA Other Human Health Assessments

• Other types of assessments products include
• Provisional peer reviewed toxicity values
  (PPRTVs) for site specific purposes
• These are hazard and dose response assessments
  principal for OSWER where no IRIS, ATSDR, or Cal
  EPA values exist.
• Technical expertise in risk assessment is also
  requested for major disasters and emergencies.
  Examples include
• World Trade Center
• Hurricane Katrina and Rita recovery and cleanup
• DC WASA lead issue

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NCEA Human Health Assessment (continued)

• Providing risk assessment research, methods,
  guidelines, training materials, and technical and
  regulatory support to EPAs Program Offices and
  Regional Offices and the public
• Uncertainty analysis
• Identification of possible modes of action
• Physiologically-Based Pharmacokinetics (PBPK)
  Modeling
• Approaches to quantification
• Approaches for Assessing Risk of Environmental
  Exposures to Age-Susceptible Populations
  (children, elderly)
• Less than Lifetime Assessments

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• LTG 1 Integrated Risk Information System (IRIS)
  and other priority health hazard assessments

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Integrated Risk Information System

• IRIS provides qualitative and quantitative
  health effects information on over 540
  substances
• Many high-profile, first applications of risk
  assessment guidelines and science policy

• Reference Dose (RfD)/Reference Concentration
  (RfC) for non- cancer effects
• Cancer risk Hazard characterization, oral slope
  factors, and oral and inhalation unit risks
• Improvements in transparency, consistency, and
  timeliness
• EPA and OMB/Interagency group discussing revised
  IRIS process for the development of human health
  assessments
• Proposed process will be subjected to both Agency
  comment and public comment

www.epa.gov/iris
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Integrated Risk Information System (IRIS) Program

• Develops EPA positions on potential human health
  effects from exposure to various chemical
  substances found in the environment
• Follows EPA guidelines for health risk assessment
• Follows IRIS standard operating procedures that
  are updated yearly
• Fosters consistent risk assessments across EPA
  Programs and Regions

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IRIS Agenda Development

• Nominations solicited by ORD Assistant
  Administrator from AAs and RAs of the Program
  Offices and Regions that use IRIS values in their
  assessments and from the public
• Priority-based annual selection of substances for
  IRIS (re)assessment
• Criteria
• Statutory, regulatory, or programmatic need
• New science or methodology available to develop
  an assessment or update an older assessment
• Public, state, other user need
• Assessment available or in progress in EPA or
  other federal agency (leverages resources)
• Availability of EPA resources to conduct
  assessments
• 2007 agenda lists 75 assessments in progress

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2007 IRIS AGENDA

• acetaldehyde
• acrolein
• acrylamide
• acrylonitrile
• aldicarb/aldicarb sulfoxide
• aldicarb sulfone
• arsenic
• asbestos
• benzene (acute)
• benzo(a)pyrene
• beryllium (cancer effects)
• bromobenzene
• butyl benzyl phthalate
• cadmium
• carbon tetrachloride
• cerium
• chloroethane
• chloroform (inhalation route)
• chloroprene

• dibutyl phthalate
• 1,2-dichlorobenzene
• 1,3-dichlorobenzene
• 1,4-dichlorobenzene
• 1,2-dichloroethylene
• di(2-ethylhexyl)adipate (DEHA)
• di(2-ethylhexyl)phthalate
• 1,4-dioxane
• ethanol
• ethyl tertiary butyl ether
• ethylbenzene
• ethylene dichloride
• ethylene glycol monobutyl ether
• (cancer effects)
• ethylene oxide
• (cancer effects noncancer acute)
• formaldehyde
• hexachlorobutadiene
• hexachloroethane

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2007 IRIS AGENDA

• RDX (hexahydro-1,3,5-dintirotriazine)
• 2-hexanone
• hydrogen cyanide
• hydrogen sulfide
• isopropanol
• kepone
• methanol
• methyl tert-butyl ether (MTBE)
• methylene chloride
• (dichloromethane)
• mirex
• naphthalene (inhalation route)
• nickel (soluble salts)
• nitrobenzene
• PAH mixtures
• pentachlorophenol
• perfluorooctanoic acid -
• ammonium salt (PFOA)

• phosgene (acute exposure
• platinum
• polybrominated diphenyl ethers
• polychlorinated biphenyls (PCBs)
• (noncancer endpoints)
• propionaldehyde
• refractory ceramic fibers
• styrene
• 2,3,7,8-TCDD (dioxin)
• 1,1,2,2-tetrachloroethane
• tetrachloroethylene
• tetrahydrofuran
• thallium
• trichloroacetic acid
• 1,1,1-trichloroethane
• trichloroethylene
• 1,2,3-trichloropropane
• 2,2,4-trimethylpentane
• uranium compounds

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Current Process for Assessment Development and
Review

• Annual FR Notice of IRIS agenda data call
• Literature search and review
• EPA develops draft assessment
• Internal peer review, IRIS Agency Review
• Interagency review
• External peer review with public comment period
• Interagency and Agency review of response to
  comments
• Final EPA and OMB approval and posting on IRIS
  database

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Outline of IRIS Process
Final Agency and Inter-agency Review
External Peer Review Public Comment
Scoping meeting
IRIS Track Entry
Develop Draft Tox Review/ IRIS Summary
Option for NCEA and ORD AA Briefing
ORD AA Briefing
FRN Annual IRIS Agenda
Peer Review Plan
FR Notice Communication materials
Internal Peer Consultation
FRN Request for Nominations
OMB/ Interagency Review
Communication Materials
Submit peer review file to IRIS helpdesk
NCEA Center Dir Briefing
Final Assm Posted on IRIS
Agency Review
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IRIS Users

• EPA Program Offices and Regional Offices
• Regulatory and site-specific evaluations
• Other Federal agencies
• State and local agencies
• International agencies
• Public - including academia, regulated
  industries, environmental organizations,
  individuals
• Usage 21,000 hits/day

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2006 IRIS Web Site Hits
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Basic Principles of Risk Assessment at EPA

• The starting point for risk assessment is a
  critical analysis of available scientific
  information.
• Quantitative estimates of risk are, to the extent
  possible,
• Biologically-motivated,
• Data-driven.
• When there is insufficient data, default methods
  are used that
• Protect public health,
• Ensure scientific validity (i.e., scientifically
  plausible and extensively peer reviewed), and
• Create an orderly and predictable process.
• Implementation of these principles
  involvesextensive peer review.

U.S. EPA 2005, Cancer Guidelines NRC 1994,
Science and Judgment in Risk Assessment
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NCEA IRIS Example Products
IRIS Track IRIS Chemical Assessment Tracking
System is available. This report shows the user
where the chemical assessment is in its
development.
Assessments Final Perchlorate, Toluene,
n-Hexane Interagency/External Review Draft
Polybrominated Diphenyl Ethers,
1,4-Dichlorobenzene, 2,2,4-Trimethylpentane,
Dibutyl Phthalate, Nitrobenzene, Bromobenzene,
Dioxinand16 or more sent each year as an annual
output. Trichloroethylene (TCE) Issue Papers
NCEA provided four papers on key science issues
to the National Academy of Science in preparation
for an NAS consultation to support the current
human health assessment. National Academy of
Sciences Consultations on recurring risk
assessment issues and the direction of risk
assessment
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Example NCEAs TCE Health Assessment Challenges
In Assessing TCE

• TCE is inherently complex toxicologically, with
  multiple metabolites and multiple potential modes
  of action.
• Rapid absorption via inhalation and ingestion,
  with distribution to blood-rich organs and
  storage in fat
• Metabolized by two competing pathways
• P450-mediated oxidative pathway
• Metabolites CH, TCA, DCA
• Glutathione-S-transferase conjugative pathway
• Metabolites DCVG, DCVC
• Toxicity generally attributed to metabolites
  rather than parent compound.
• ORDs work in computational toxicology can
  provide significant insight into which pathways
  are really being turned on and about other things
  that are happening at the cellular level.

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MOAs and Metabolic Scheme of TCE
TCE
Focus of liver carcinogenicity
Focus of mouse lung carcinogenicity
Oxidation
Conjugation
Focus of kidney toxicity
--
Source Dobrev, Andersen, and Yang 2002, with
modifications based on Lash et al. 2000a.
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Liver Tumors A Postulated Mode of Action
PPARa and other MOAs for TCA, DCA and CH
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Kidney Tumors Postulated Mode of Action

• Multiple potential modes of action via reactive
  GSH metabolites
• Genotoxicity VHL marker
• Dose-dependent MOAs
• Example DCVC
• High doses lead to acute tubular necrosis
• Low doses changes in homeostasis leading to
  altered gene expression and growth

Source Lash et al., 2000
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Biologically-Based Dose-Response for Formaldehyde
Cancer Risk Assessment
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Use of All Historical Controls has Significant
Impact on Relevance of Mutagenic Component
Biologically-Based Dose-Response for Formaldehyde
Cancer Risk Assessment
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4-orders of magnitude increase in human risk with
alternative model parameters
Biologically-Based Dose-Response for Formaldehyde
Cancer Risk Assessment
a Our CIIT used CIIT parameter estimates but
differed from CIIT in human background cancer
data, use of weekly average DPX, and human body
weight data.
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5. Example of MLE instability Simulated data
Proposed Estimates of Risk and Uncertainty Bounds
When MLE of linear term is equal to zero (left
column), the MLE risk is not stable. It changes 5
orders of magnitude when just one animal is moved
between two tumor groups. Even when MLE risk
is not near zero (right column), it can be
unstable. The proposed strategies allow
identifying such cases.
Simulated data with risk at .001ppm
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• Simulated Data Example
• Original
  data One tumor moved
• Estimate of expected risk 6.9E-5
  7.0E-5 95th
  Confidence limit 1.9E-4
  2.0E-4
• Estimate of expected risk 2.9E-5
  3.1E-5 95th
  Confidence limit 1.5E-4
  1.7E-4
• Both strategies provide stable results and close
  estimates

Bayesian estimate
Bootstrap estimate
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Uncertainty Analysis Papers

• 7 papers on uncertainty topics in cancer risk
  assessment, including
• Uncertainty in Cancer Risk Assessments Broad
• View and Biological Assumptions and Models
• Identifiability and Prediction in a Multi-stage
  Clonal
• Expansion Model
• Multiple modes of action
• A Systems Biology Approach for Meta-Analysis
  of
• Biological Data
• Impact of Datasets, Parameter, and Modeling
• Approaches
• A Roadmap for practical improvements.

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Critical Analysis of Available Scientific
Information
Organ-Specific RfDs
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• LTG 2 State-of-the-science risk assessment
  models, methods, and guidance

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HHRA LTG2- Methods, Models Guidance
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Major Recurring Science Issues

• Use of data from human studies in health
  assessments
• Accounting for less-than-lifetime exposure
  durations
• Qualitative and quantitative use of mode of
  action data in noncancer and cancer assessments
• Benchmark dose modeling and selection of the
  benchmark response
• Evaluation and use of PBPK models
• Accounting for life-stage and subpopulation
  susceptibility in uncertainty factors
• Use of data-derived uncertainty factors
• Characterization of uncertainty in noncancer and
  cancer analysis
• Quantitation of uncertainty
• Use of time-to-tumor modeling for cancer
  assessments

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Exploratory Review of the Scientific Foundation
for Estimating Uncertainty in EPA Reference Values

• Continuing scientific and methodological advances
  have raised questions about how current
  procedures could be improved
• Advances have included
• increased chemical specific data and the
  willingness of stakeholders/agencies to provide
  these data
• improved methodologies such as benchmark dose
  modeling
• development of physiologically-based
  pharmacokinetic (PBPK) models
• development of biologically-based dose-response
  models (BBDR)
• increased computing power to facilitate
  probabilistic assessment to convey the
  uncertainties in different parameters and results
  
• As the data have improved, the limitations of
  current methodologies have become more apparent

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Use of MOA Framework in Risk Assessment
MOA can not be determined
MOA sufficiently supported in animals?
Use linear extrapolation as a default.
Yes
No
No further analysis of tumors.
MOA relevant to humans?
Yes
Model using MOA or use RfD/RfC method as default.
Adjustments for susceptible
Flag lifestage(s) or population(s) that could be
susceptible based on MOA
Nonlinear
Determine extrapolation based on information
about specific MOA.
Use the same linear extrapolation for all
lifestages, unless have chemical-specific
information on lifestages or populations.
Linear, but nonmutagenic MOA
Linearity due to mutagenic MOA
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Mode-of-Action
Issues

• MOA sufficiently supported in animals?
• Identification of key events and testable
  hypotheses
• Evidence necessary to draw conclusions and rule
  out alternatives
• Separation of chemical-induced events from
  natural progression of cancer
• Integration of multiple MOAs
• MOA relevant to humans?
• Repeat a-d
• Yes/no answer or dose-response dependent
• If dose-response dependent, then what kinetic and
  dynamic factors will drive the modeling

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Mode-of-Action

• Issues
• Determine extrapolation based on MOA?
• Incorporation of susceptible lifestage(s) or
  population(s)
• Development of biologically-based models, or
  RfD/RfCs
• Consideration of population variability,
  background additivity
• Others
• Application of well-established MOA from one
  chemical to another for which data are limited
• Development of MOA categories aiming at category
  specific model development
• Incorporation into uncertainty analyses

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NCEAHuman Health Risk Assessment LTG2

• Providing risk assessment research, methods,
  guidelines, training materials, and technical and
  regulatory support to EPAs Program Offices and
  Regional Offices and the public
• Uncertainty analysis
• Identification of possible modes of action
• Physiologically-Based Pharmacokinetics (PBPK)
  Modeling
• Approaches to quantification
• Approaches for Assessing Risk of Environmental
  Exposures to Age-Susceptible Populations
  (children, elderly)
• Less than Lifetime Assessments
• Approaches for cumulative risk assessment (Fall
  2007)

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HHRA Methods, Models Guidance Example
Products of LTG2

• Cancer Guidelines and Childrens Supplemental
• Both documents are available at
  www.epa.gov/cancerguidelines
• An Inventory of Sources and Environmental
  Releases of Dioxin-Like Compounds in the United
  States for the Years 1987, 1995, and 2000 (Final
  Report)
• Summary of the NCEA Colloquium on Current Use and
  Future Needs of Genomics in Ecological and Human
  Health Risk Assessment (Final Report)
• Approaches for the Application of
  Physiologically-Based Pharmacokinetic (PBPK)
  Models and Supporting Data in Risk Assessment
  (Final Report)
• Updates of Bench Mark Dose (BMD) software
• Development of categorical regression (CatReg)
  models

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NCEA Methods, Models Example Products

• A Framework for Assessing Health Risk of
  Environmental Exposures to Children (Final
  Report)
• Child-Specific Exposure Factors Handbook 2006
  (External Review Draft)
• Aging and Toxic Response Issues Relevant to Risk
  Assessment (Final Report)
• Use of Physiologically Based Pharmacokinetic
  (PBPK) Models to Quantify the Impact of Human Age
  and Interindividual Differences in Physiology and
  Biochemistry Pertinent to Risk (Final Report)

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NCEA Methods, Models Example Products

• Approaches to Estimating the Waterborne Disease
  Outbreak Burden in the United States Uses and
  Limitations of the Waterborne Disease Outbreak
  Surveillance System (External Review Draft)
• Exposures and Internal Doses of Trihalomethanes
  in Humans Multi-Route Contributions from
  Drinking Water (Final Report)
• Toxicological Reviews of Cyanobacterial Toxins
  Anatoxin-a, Cylindrospermopsin and Microcystins
  (LR, RR, YR and LA) (External Review Draft)
• Concepts, methods, and data sources for health
  risk assessment of multiple chemicals, exposures,
  and effects.

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• LTG 3 Integrated Science Assessments
• (formerly called Air Quality Criteria Documents)

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New Integrated Science Assessments and NAAQS
Development Process
Integrated Science Assessment concise evaluation
and synthesis of most policy-relevant studies
Peer-reviewed scientific studies
Integrated Plan timeline and key
policy-relevant scientific questions
Workshop on science-policy issues
CASAC review and public comment
Draft ANPR policy assessment reflecting Agency
views on range of policy options and rationales
Risk/Exposure Assessment concise, quantitative
assessment focused on key results, observations
and uncertainties
Review by CASAC and the public
Agency decision making and draft proposal notice
Interagency review
Public comment period and CASAC review
EPA Advance Notice of Proposed Rulemaking
Interagency review
EPA final decision on standards
Public hearings and comments on proposal
Agency decision making and draft final notice
EPA proposed decision on standards
Interagency review
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Expert Advice and Consultation
2006 ORD contracted with The National Academies
National Research Council to convene two expert
panels on risk assessment.
Board on Environmental Studies and Toxicologys
(BEST) Committee on Improving Risk Analysis
Approaches Used by the US EPA
To develop scientific and technical
recommendations for improving the risk analysis
approaches. In making recommendations, the
committee will indicate practical improvements
that can be made in the near term (2-5 years) and
improvements that would be made over a longer
term (10-20 years).

• Clarify the current state of environmental human
  health risk assessment
• Envision and help prepare for the future of risk
  analysis

Questions for Consideration by the Committee

• What can we improve about risk assessment now?
• What methods are currently available that would
  allow us to make significant progress in
  improving current risk assessment practices?
• How can we best incorporate these new approaches
  and methods into our current practice?
• What will human health risk assessment be like in
  5 - 10 years and what should we be doing to get
  there?
• Are there alternative risk paradigms that can be
  useful?

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Board on Environmental Studies and Toxicologys
(BEST) Standing Committee on Risk Analysis Issues
and Reviews
The Standing Committee will plan and conduct a
series of public workshops that will serve as a
venue for discussion of issues critical to the
development and review of objective, realistic,
and scientifically based human health risk
analyses for selected environmental contaminants.
The Committee, in consultation with the sponsor,
will select the specific scientific issues and
contaminants that will be discussed at the
workshops.
? First workshop May 3 - 4, 2007 Implications
of Receptor-Mediated Events on Dose-Response ? Sec
ond workshop June 5, 2007 Quantitative
Approaches to Characterizing Uncertainty in Human
Cancer Risk Assessment Based on Bioassay
Results ? Third workshop November 8 - 9, 2007
Mouse Liver Tumors Benefits and Constraints on
Use in Human Health Risk Assessment, Qualitative
and Quantitative Aspects
For more information on these NRC
projects www.dels.nas.edu/best
56
The Next Five To Ten Years?

• What changes will occur that will have a
  significant impact on risk assessment?
• How should we prepare for them?
• Some example questions
• What new information will the omics
  advancements provide? How will it be useful in
  risk assessment?
• Will genomics change our focus to people rather
  than chemicals? For example, will genetic typing
  to understand individual susceptibilities become
  the rule?
• Will omics information on human impacts
  stimulate a search for various causal factors,
  rather than conducting risk assessment on a
  chemical by chemical basis?
• How will new computational capabilities and
  information technologies play a role in
  assessments?

57
The Next Five To Ten Years? (continued)

• More example questions
• Will BBDR models coupled with PBPK models take on
  a more central role?
• How will the new approaches for understanding
  individual and community exposures help us to
  refine our risk estimates?
• How can we begin to focus on stressors other than
  chemicals to understand risk? (attributable risk)
• How do we deal better with new technologies such
  as nanotechnology to understand risks before they
  are in widespread use?
• How much information and causal linkage will be
  necessary to assess precursor events in the
  absence of overt toxicity?

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Other Paradigm Cumulative Risk Assessment
Current Risk Assessment
Residential Location
Race/Ethnicity
Community Level Vulnerability
Environmental Hazards and Pollutants
Community Stressors
Neighborhood Resources
Structural Factors
Community stress
Exposure
Internal dose
Stress/Coping, Life Stage/Style
Individual Level Vulnerability
Biologically effective dose
Individual stressors
Health effects/ disparities
Modified from Gee Payne-Sturges, 2004