How EPA Is Incorporating 21st
Century Toxicology Into Its Work
John “Jack” R. Fowle III, Ph.D., D.A.B.T.
Deputy Director Health Effects Division,
Office of Pesticide Programs
US Environmental Protection Agency
1
Office of Chemical Safety and Pollution
Prevention at a Glance
• Safety evaluations required for human health and
ecological risks:
– Statutes: TSCA, FIFRA, FFDCA, FQPA, ESA
• Risk assessment and management decisions apply to:
– New and existing industrial chemicals.
– Antimicrobials, biochemical, and conventional active
ingredients, and food-use and non-food use inert ingredients.
• Available information:
– Varies across chemical programs with extensive requirements
for food use, conventional pesticide active ingredients to
minimal requirements for non-food use inert ingredients and
industrial chemicals.
2
Managing Chemical Risks• OCSPP is the Gateway to Market.
• Thousands of regulatory decisions annually.
• Must be timely (e.g., 90 days for new industrial chemicals, specific time frames for pesticides).
~9000 existing chemicals
~1500 Pre-manufacture Notices for new chemicals per year
~1,100 active ingredients &
19,000 products
Reevaluate existing pesticides on a regular schedule; evaluate new pesticides and new uses; evaluate inert ingredients
National Industrial
Chemical Program
National Pesticide
Program
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Managing Chemical Risks
• Large number of chemicals to review with many
possible adverse outcomes.
• Finite resources and time.
• Public expectation for sound science,
transparency, and timeliness for environmental
health protection.
• Science increasingly complex and changing.
Common Challenges:
Chemical by chemical testing
for all potential outcomes
Testing Battery
Different Testing Schemes
Integrated Testing & Assessment
Use Existing Knowledge of
Exposure & Effects
Examine a chemical or a group of
chemicals with shared properties•Physical Chemical Properties
•Structure-based extrapolation
•Biological activity-based extrapolation
•Other relevant information
Cance
r
ReproT
ox
DevT
ox
NeuroT
ox
Im
munoT
ox
Determine Information
needs and follow up
actions
Cance
r
ReproT
ox
DevT
ox
NeuroT
ox
Imm
unoTox
Heavy Reliance on
Extensive Animal Testing
Increasing Reliance on
in silico & in vitro Predictions
Generate information
For All possible Outcomes
Strategic Direction
Tailor In vivo Testing
(intelligent testing)
Empirical approach
Increasing Effectiveness, Reliability, and Rate of Assessments
Mechanism-Based Approach
Paradigm ShiftToday
NRC 2007 “Toxicity Testing in
the 21st Century: A Vision &
Strategy”• Transformative paradigm shift using in vitro &
computer systems.
– broader coverage of chemicals, end points, life stages.
– mechanistic & dose information for risk assessment.
– reduce cost & time of testing, increase
efficiency & flexibility.
– use fewer animals.
• Based on toxicity pathways.
A Vision for Future Risk Determination
Will know what to test, when to test, and how.
Most decisions informed by the inherent
properties of the chemical.
Require tests only when necessary.
Testing in animals will only be when absolutely
necessary and a rare event
This Will Take Time
Modified from NRC, 2007
Source
Fate/Transport
Exposure
Tissue Dose
Biologic Interaction
Perturbation
BiologicInputs
Normal
Biologic
Function
Morbidityand
Mortality
Cell
InjuryAdaptive Stress
Responses
Early Cellular
Changes
• Quantitative Dose-Response
• PK / PD
• Toxicity Pathway Identification
• in silico models
•Targeted Testing
Toxicity Pathways: Cellular
response pathways that,
when sufficiently
perturbed, are expected to
result in adverse health
effects.
Toxicity Testing in 21st Century: A Vision and a Strategy
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Animal Testing:
Reduce, Refine,
Replace
• 2005 OPPTS-ORD White Paper.
• 2007 NAS Report on Testing in the 21st Century.
• 2009 Agency’s Strategic Plan for Evaluating the
Toxicity of Chemicals.
Use of computational tools is not new to evaluate
& assign priorities for actions (e.g., industrial
chemical program, inert ingredients).
OCSPP Strategic DirectionTransition toward new integrative and
predictive 21st century techniques to
increase efficiency and effectiveness
of testing and assessment.
EPA’s Needs Expand the NAS Vision
• Include ecological as well as human effects
• Establish the process to bring new science
into regulatory practice
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Managing Chemical Risks
• Near Term (5 year) Goal:
– “Enhanced Tool Box” - Create means to
efficiently and credibly predict toxic potency
and exposure levels, and to focus information
needs.
– Examples: HPV/MPVs; pesticide inert
ingredients; certain antimicrobials pesticides;
metabolites and degradates of pesticide
active ingredients.
Challenge: Assessing Data-Limited Chemicals
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Evaluation for Relevant Effects
Risk Assessment
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In Vitro Profiling:
Molecular
interactions, Cellular
Responses
Existing Knowledge,
uses, exposure, toxicity
data, SAR, QSAR
Efficient Focused In
Vivo Testing
Research:
Learn & Refine
Non-Animal
Priority
Setting
Process
11
13
Managing Chemical Risks
Long Term (5-15 years)• Develop means to move in a credible and transparent
manner to hypothesis, mechanism-driven, and risk-
based approaches that focus on effects most relevant
to risk assessment and risk management:
– “Omics” technology in identifying toxicity pathways.
– Physiologically-based toxicodynamic and toxicokinetic
modeling.
– Improved exposure modeling.
– Improved diagnostic biomarkers and population surveillance
methods.
Challenge: Reducing Uncertainty
ER Binding ER TransctivationVTGmRNA
Vitellogenin InductionSex Steroids
AlteredReproduction/DevelopmentMolecular Cellular Organ Individual
Chemical 3-DStructure/Properties
Chemical 2-D StructureStructure
ER Binding ER TransctivationVTGmRNA
Vitellogenin InductionSex Steroids
AlteredReproduction/DevelopmentMolecular Cellular Organ Individual
Chemical 3-DStructure/Properties
Chemical 2-D StructureStructure
ER Binding ER TransctivationVTGmRNA
Vitellogenin InductionSex Steroids
AlteredReproduction/DevelopmentMolecular Cellular Organ Individual
Chemical 3-DStructure/Properties
Chemical 2-D StructureStructure
ER Binding ER TransctivationVTGmRNA
Vitellogenin InductionSex Steroids
AlteredReproduction/DevelopmentMolecular Cellular Organ Individual
Chemical 3-DStructure/Properties
Chemical 2-D StructureStructure
ER Binding ER TransctivationVTGmRNA
Vitellogenin InductionSex Steroids
AlteredReproduction/DevelopmentMolecular Cellular Organ Individual
Chemical 3-DStructure/Properties
Chemical 2-D StructureStructure
ER Binding ER TransctivationVTGmRNA
Vitellogenin InductionSex Steroids
AlteredReproduction/DevelopmentMolecular Cellular Organ Individual
Chemical 3-DStructure/Properties
Chemical 2-D StructureStructure
ER Binding ER TransctivationVTGmRNA
Vitellogenin InductionSex Steroids
AlteredReproduction/DevelopmentMolecular Cellular Organ Individual
Chemical 3-DStructure/Properties
Chemical 2-D StructureStructure
ER Binding ER TransctivationVTGmRNA
Vitellogenin InductionSex Steroids
AlteredReproduction/DevelopmentMolecular Cellular Organ Individual
Chemical 3-DStructure/Properties
Chemical 2-D StructureStructure
ER Binding ER TransctivationVTGmRNA
Vitellogenin InductionSex Steroids
AlteredReproduction/DevelopmentMolecular Cellular Organ Individual
Chemical 3-DStructure/Properties
Chemical 2-D StructureStructure
ER Binding ER TransctivationVTGmRNA
Vitellogenin InductionSex Steroids
AlteredReproduction/DevelopmentMolecular Cellular Organ Individual
Chemical 3-DStructure/Properties
Chemical 2-D StructureStructure
ER Binding ER TransctivationVTGmRNA
Vitellogenin InductionSex Steroids
AlteredReproduction/DevelopmentMolecular Cellular Organ Individual
Chemical 3-DStructure/Properties
Chemical 2-D StructureStructure
ER Binding ER TransctivationVTGmRNA
Vitellogenin InductionSex Steroids
AlteredReproduction/DevelopmentMolecular Cellular Organ Individual
Chemical 3-DStructure/Properties
Chemical 2-D StructureStructure
ER Binding ER TransctivationVTGmRNA
Vitellogenin InductionSex Steroids
AlteredReproduction/DevelopmentMolecular Cellular Organ Individual
Chemical 3-DStructure/Properties
Chemical 2-D StructureStructure
ER Binding ER TransctivationVTGmRNA
Vitellogenin InductionSex Steroids
AlteredReproduction/DevelopmentMolecular Cellular Organ Individual
Chemical 3-DStructure/Properties
Chemical 2-D StructureStructure
ER Binding ER TransctivationVTGmRNA
Vitellogenin InductionSex Steroids
AlteredReproduction/DevelopmentMolecular Cellular Organ Individual
Chemical 3-DStructure/Properties
Chemical 2-D StructureStructure
Receptor/Ligand
Interaction
•Gene
Activation
•Protein
Production
•Gonad
Development
•Altered Hormone
Levels
Impaired
Reproduction
Molecular Cellular Organ Individual
Chemical 3-
D
Structure/
Properties
Chemical
2-D
Structure
Structure
Mapping Toxicity Pathways to Adverse Outcomes
Establish Linkages & Dose Response Relationships 12
15
Smarter & Higher
Content Animal
Testing Designs:
Prioritization & Screening Tools
(effects & exposure) to efficiently
identify most likely risks
Alternatives to
Replace Animal
Testing
Diagnostic Biomarkers
(exposure, early effects,
susceptibility) for
surveillance of
populations
Sophisticated Risk
Assessment Methods
Effective Chemical Risk Management
Critical Pathways
Enhanced Integrated
Approaches to
Testing & Assessment
Data-Limited Chemicals
Today’s Tool Box
Enhanced Tool Box Using New Approaches
QSAR Models
Chemical grouping or
categories & read-across
In vitro
(mutagenicity)
ToxRefDb
ECOTOX
ACToR
MetaPath
Degradates
ToxCast
QSARs
DSSTox
TTCsInherent Properties of Chemicals
(chemical, biological & toxicity characteristics)
Existing information
Example: Future Priorization for the USEPA
Endocrine Screening Disruptor Program
• Federal Food, Drug, and Cosmetic Act (FFDCA)– Requires EPA to:
• Develop a screening program using validated assays to identify pesticides that may have an effect in humans similar to an effect produced by a naturally occurring estrogen
– Authorizes EPA to include:
• Other endocrine effects, as designated by the EPA Administrator
• Other non-pesticide chemicals that:
– Have “an effect cumulative to that of a pesticide,” and
– To which a substantial human population may be exposedSafe
• Drinking Water Act (SDWA) Amendments – Allow EPA to require testing of chemical substances found in
sources of drinking water, if a substantial human population may be exposed
EDSTAC Recommendations--
Basis of the EDSP
• Estrogen, androgen and thyroid
• Human and ecological effects
• Priority setting for a broad universe of chemicals
• 2-Tiered Approach
– Tier 1
• In vitro and in vivo screens
• Detect potential to interact with endocrine system
– Tier 2
• Multi-generation studies covering a broad range of taxa
• Provide data for hazard assessment
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Prioritizing Chemicals for Endocrine
Disruptor Tier 1 Screening: Effects
• EDSTAC (USEPA, 1998) recommended the use of measured or predicted receptor binding and/or transcriptional activation data derived through in vitro assays/High Throughput (HTP) Screening and (Q)SARs, respectively
• SAB/SAP (USEPA, 1999) concurred; however, concluded that HTP screening and (Q)SARs were not sufficiently developed at that time – encouraged continued research
• As part of USEPA’s computational toxicology and endocrine disruptor research programs, the Office of Research and Development (ORD), in collaboration with OPP and OSCP, has been developing in vitro assays, HTPs applications & (Q)SARs
Tool: (Q)SAR-Based System to Predict
Estrogen Receptor Binding Affinity
• ORD/OPP Collaborative Effort
• Application for use in a prioritization scheme
in the context of EDSTAC & SAB/SAP
recommendations
• Development focused on chemicals without
sufficient existing data to determine if Tier 2
testing required
• Model’s applicability domain – Structures
associated with pesticide inert ingredients &
antimicrobial pesticides
R 394
E 353 H 524
CC
T 347
HOOH
CH3 H
H H
H
AA BB
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HOOH
CH3 H
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AA BB
(Q)SAR-Based System to
Predict ER Binding Affinity
• External peer-review by USEPA SAP, August 2009– http://www.epa.gov/scipoly/sap/meetings/2009/08
2509meeting.html
• Development benefited from EDTA VMG-NA and two OECD peer consultations– May, 2008 Structural Alert Workshop
• http://www.olis.oecd.org/olis/2009doc.nsf/linkto/env-jm-mono(2009)4
– February, 2009 Expert Consultation to Evaluate an Estrogen Receptor Binding Affinity Model for Hazard Identification
• http://www.olis.oecd.org/olis/2009doc.nsf/linkto/env-jm-mono(2009)33
ToxPi: Prioritization Index for Endocrine Activity
ToxPi is calculated from a weighted combination of all data sources for each chemical.
The size of each slice indicates relative rank or score for each chemical; the distance from the origin
is proportional to the normalized value (e.g. assay potency or predicted permeability); the width
indicates the relative weight of that slice in the overall ToxPi calculation.
Prioritization Index = ToxPi = f(In vitro assays + Chemical properties + Pathways)
Bisphenol A Tebuthiuron
Ingenuity pathways
ER
AR
TROther
XME/ADME
KEGG pathways
LogP_TPSA
Predicted CaCO-2
Disease classes
Other NR
Example ToxPi Rankings from
ToxCast Phase I HPTE
ToxScore
Pyrimethanil
Tebuthiuron
Linuron
MethoxychlorRotenone BPA
309 C
hem
icals
sort
ed b
y T
oxP
i score
ToxPi
highestlowest
Ingenuity path
ER
AR
TROther XME/ADME
KEGG path
LogP_TPSA
CaCO-2
Disease classes
Other NR
DuPont’s Chemical Visualization Tool
Enhance Integrated Approaches to
Testing & Assessment (IATA)
Benefits:• Allow use of new methods in real-time and in
real situations within current risk assessment paradigm
• Provide an improved means to credibly predict risks and focus information needs and follow up actions
• Focus societal resources on chemicals of greatest concern
• Supports responsible use of animals
Chemical
RELEASE FATE / TRANSPORT CONCENTRATION ACTIVITY EXPOSURE
FRAMEWORK
Intermediates
Degradates
PR
OD
UC
T n
PR
OD
UC
T …
PR
OD
UC
T 8
PR
OD
UC
T 7
PR
OD
UC
T 6
PR
OD
UC
T 5
PR
OD
UC
T 4
PR
OD
UC
T 3
PR
OD
UC
T 2
PR
OD
UC
T 1
Release
Reaction
ProductUse
Disposal
LocationFrequencyTiming
PopulationMarket Share
Water
Outdoor
Air
Surface
Dust
Soil
Indoor
Air
Food
ChemicalManufacture
ChemicalTransportation
Production/Formulation
WorkplaceExposure
EnvironmentalRelease
EnvironmentalDisposal
Air
Water
Incineration
RecyclingSewage
Treatment
Food
Land
Transport
EnvironmentalRelease
Food
Water
Land
ProductDisposal
Air
Lifecycle Analysis
Consistent with NAS Science and Decisions and TSCA 2010
Application to Levels of
Organization Based on Source
to Outcome
Source
Environmental
Contaminant
Exposure
Cellular Effects
Individual
Population
Community
Mode of Action
Adverse Outcome Pathway
Source to Outcome Pathway
Toxicity Pathway
Molecular Initiating Event
Source-Exposure-Dose-Effects Continuum
TRANSPORT /
TRANSFORMATIONALTERED STRUCTURE /
FUNCTION
ENVIRONMENTAL
CHARACTERIZATION
SOURCE / STRESSOR
FORMATION
DOSE
EXPOSURE
EARLY KEY
BIOLOGICAL EVENTS
DISEASE
Toxicity Pathway
Chemical
Physical
Microbial
Magnitude
Duration
TimingDispersion
Kinetics
Themodynamics
Distributions
Meteorology
Air
Water
Diet
Soil & dust
Pathway
Route
Duration
Frequency
Magnitude
Statistical Profile
Reference Population
Susceptible Individual
Susceptible Subpopulations
Population Distributions
Absorbed
Target
Internal
Biologically
Effective
Molecular
Biochemical
Cellular
Organ
Organism
Edema
Arrhythmia
Necrosisetc.
Cancer
Asthma
Infertility
etc.
Community
Activity
Patterns
PBPKModels
Transport,Transformation &
Fate Models
Exposure
Models
BBDRModels
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Chemical Space
Quantitative Structure Activity Relationships
Quantitative Biological Activity Response
Adverse Outcome Space
Biological Activity Space
Cancer Developmental
Defects
Endocrine
Disruption
Respiratory
Disease
Neurologic
Effects
EPA has a lot of experience with Chemical databases – a few examples
Analog Identification Methodology (AIM
identifies close structural analogs that have measured data and points to
sources where those data can be found
Ecological Structure Activity Relationships (ECOSAR)
estimates the aquatic toxicity of industrial chemicals
ECOTOX
chemical toxicity data for aquatic life, terrestrial plants and wildlife
EPI Suite™
estimates physical / chemical properties and environmental fate
High Production Volume Information System (HPVIS)
health and environmental effects information
OncoLogicTM
evaluates the likelihood that a chemical may cause cancer
Use Cluster Scoring System (UCSS)
risk-screening system into which chemicals are grouped by common use
Moving beyond data warehouses to integrated knowledgebases
ACToR: Aggregated Computational Toxicology Resource
Aggregates data from over 500 public sources on over 500,000
environmental chemicals searchable by chemical name, structure, and other
identifiers.
Data includes chemical structure, physico-chemical values, in vitro assay
data and in vivo toxicology data.
Distributed Structure-Searchable Toxicity (DSSTox) Database Network
Structure-activity and predictive toxicology using structure searchable
standardized chemical structure files associated with toxicity data.
ToxRefDB: Toxicity Reference Database
Detailed chemical toxicity data in an accessible and searchable format.
Links to other public hazard, exposure and risk resources.
Systems Approaches to Modeling
Toxicity From Pathways to Virtual Tissues
chemicals pathways networks cell states tissue function
Quantitative
Dose-Response
Models
Future
Risk assessments
Moving beyond
empirical models, to
multi-scale computer
models of complex
biological systems.
Identify Key Targets and Pathways
33
Will require a sustained effort over many years
Establish data storage and management systems, elucidate toxicity pathways.
Develop & evaluate suite of high & medium through put assays.
Gain experience though testing in parallel with traditional assays.
Timeline
Achieving a
Paradigm Shift
Evolving Process - But milestones along the way
Design Intelligent Testing
Enhance Interpretation
Expand Tool Box
Temporally & spatially explicit models
Improved dosimetry, mode of action
Transition to
Alternatives
Evolution to a new paradigm will depend on success
of technological developments and acceptance.
Project Plans
More Efficient Animal
Studies
35
Research
Evaluation
Method
Development
Regulatory
Acceptance
Review
Decision for
Specific Application
Peer Review and
Stakeholder
Engagement
Establishment of
Reliability
Transferrable
Method
New Methods
for Applications
Computational
Tools, etc.
MAPPING THE PROCESS
Problem
Identification
Researchers
and
Regulators
Working
Closely
Together
Research Planning
Near-term Steps:
• Compile & integrate information for easy access
• Collaborate on research via national and international partnerships
• Develop risk assessment and management approaches via collaboration of regulatory programs and research community
• Engage external scientific peer review and all stakeholders early to ensure transparency and input with new approaches as they progress
A Paradigm Shift Based on
Incremental Steps
37
Stakeholder Engagement
• Pesticide Program Dialogue
Committee (PPDC):
– FACA Workgroup on 21st Century Toxicology/New
Integrated Testing Strategies Workgroup
• Purpose - advise on communication & transition:
– Improve understanding of the perspectives of all
stakeholders regarding new testing paradigm.
– Ensure input on key science and regulatory
developments.
– Develop common understanding for use of new tools.
International
Partnerships
• Information Sharing
• Common Application Tool Boxes
• Mutually Accepted Test Guidelines
• Harmonize Frameworks & Guidance
• Global Acceptance
Organization for Economic Cooperation & Development
North American Free Trade Agreement
International Program for Chemical Safety
European Food Safety Authority, etc.
http://www.epa.gov/pesticides/science/testing-assessment.html
In Summary
• In the near-term (present to 2-3 years):– Accelerated and enhanced priority
setting / screening to focus animal testing
– Enhance interpretation of current information
• In the long-term (~10 years):– Greater reliance on in silico, in vitro, and highly
targeted animal studies only as needed
– Mechanism-based assessments is the standard
Achievable with strong scientific & stakeholder
support through a transparent process