21st Century Screening
Assessment of Pesticides –
A Regulatory View
Vicki Dellarco, Ph.D.
Senior Science Advisor
Office of Pesticide Programs
US Environmental Protection Agency
Office of Pesticide Programs
Managing Chemical Risks
Gateway to Market
National Pesticide
Program
~1,100 active ingredients
& 19,000 products
• Reevaluate existing
pesticides on a
regular schedule
• Safety evaluations required
for human health & ecological
risks
– FIFRA, FFDCA, FQPA, ESA
• Risk management decisions
apply to
– Antimicrobials, biochemical &
conventional active ingredients
and food-use & non-food use
inert ingredients
• Available information
– Varies across chemical programs
with extensive requirements for
food use, conventional pesticide
actives to minimal requirements
for non-food use inert ingredients
Office of Pesticide Programs
1
Managing Chemical Risks
Common Challenges
• Large Number of Chemicals to Review with
Many Possible Adverse Outcomes
• Finite Resources & Time
• Science Increasingly Complex & Changing
• Public Expectation Sound Science,
Transparency & Timeliness for Environmental
Health Protection
Office of Pesticide Programs
2
Managing Chemical Risks
Strategic Direction
Transition toward new integrative &
predictive 21st century techniques, to
increase efficiency and effectiveness Animal Testing:
Reduce, Refine,
of testing & assessment
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
Office of Pesticide Programs
Use of computational tools is not new
to evaluate & assign priorities for
follow-up actions
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NRC 2007 “Toxicity Testing in the 21st Century: A
Vision and A Strategy
• Objective
– Foster transformative paradigm shift based largely on
increased use of in vitro & in silico systems that will:
• broader coverage of chemicals, end points, life stages
• reduce cost & time of testing, increase efficiency & flexibility
• use fewer animals
• more robust scientific basis by providing mode of action &
dosimetry information
Office of Pesticide Programs
Current Data Paradigm
in vivo testing
Cancer
Reproductive Toxicity
Developmental Toxicity
Neurotoxicity
KidneyToxicity
ImmunoTox
$Millions
Food Use, Conventional Pesticide Actives:
Generates in vivo animal data for all possible
outcomes to determine which of all possible
effects are relevant.
Office of Pesticide Programs
5
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Office of Pesticide Programs
Risk Assessment
Priority
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Process
Research:
Learn &
Refine
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Mapping Toxicity Pathways to Adverse Outcomes
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VTG mRNA
VTG mRNA
VTG mRNA
VTG mRNA
VTG mRNA
Sex Steroids
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Development
Cellular
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Libraries of Toxicological Pathways
Managing Chemical Risks
Challenge: Assessing Data-Limited Chemicals
• Near Term (≤5 years) Goal
–Integrated Approaches to Testing & Assessment
• “Enhance Tool Box” - Create means to efficiently & credibly
predict toxic potency & exposure levels and to focus
information needs
–Situations
• e.g., pesticide inerts, certain antimicrobials, metabolites &
degradates of pesticide actives
Office of Pesticide Programs
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Managing Chemical Risks
Challenge: Reducing Uncertainty
• Long Term (~15 years)
– Develop means to move, in a credible &
transparent manner to hypothesis & mechanismdriven, risk-based approaches that focus on
effects most relevant to risk assessment & risk
management
• “omics” technology in identifying toxicity pathways
• PDPK modeling
• Improved human exposure modeling
Office of Pesticide Programs
9
Integrated Approaches to Testing &
Assessment
Example Activities
Existing Knowledge,
exposure use, toxicity
data, SAR, QSAR
(Q)SAR-Based System to
Predict ER Binding Affinity
In Vitro Profiling:
Molecular interactions,
Cellular Responses
ToxCast HTP Research Program
Efficient Focused
In Vivo Testing
New F1 Extended Reproductive
Study
Office of Pesticide Programs
Partnerships
Agencies & International Organizations
• Collaborate on development & application of
predictive computational models
• Promote development of common databases
• Harmonize frameworks/guidance
• Build a common application tool box
–OECD QSAR Tool Box
Office of Pesticide Programs
International Partnerships
• Collaborate on development & application of
predictive computational models
– OECD Workshop (Dec 07, Wash DC) - Integrative
Approaches to Testing & Assessment
• Build a common application tool box
– OECD QSAR Tool Box
• Harmonize frameworks/guidance
Office of Pesticide Programs
Stakeholder Engagement
• Pesticide Program Dialogue
Committee (PPDC)
– Workgroup on 21st Century Toxicology/New
Integrated Testing Strategies
– Purpose is to advise on communication & transition
• Improve understanding of the perspectives of all
stakeholders regarding new testing paradigm
• Ensure input on key science & regulatory products
• Develop common understanding for use of new tools
Office of Pesticide Programs
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US EPA EDSP Implementation
Assay
Validation
Priority Setting
Procedures
Selecting chemicals
to be screened
Office of Pesticide Programs
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OECD Endocrine Testing &
Assessment Conceptual Framework
• Level 1 - Sorting & prioritizing with existing data
and/or (Q)SARs
• Level 2 - In vitro assays to provide mechanistic data
• Level 3 - In vivo assays providing data about single
endocrine mechanisms & effects
• Level 4 - In vivo assays providing data about multiple
endocrine mechanisms & effects
• Level 5 - In vivo assays providing data about
endocrine & other effects
Office of Pesticide Programs
(OECD, 2004)
USEPA Endocrine Disruptor
Screening & Assessment Program
• Sorting & Prioritizing Chemicals
• Tier 1 Screening
–Data to determine if a chemical has the potential to
interact with the estrogen, androgen or thyroid
systems
• Tier 2 Testing
–Data to determine if endocrine-mediated adverse
effects occur and quantify dose-response
• Hazard & Risk Assessment
Office of Pesticide Programs
(USEPA, 1998)
Sorting Chemicals for Endocrine
Disruptor Screening & Testing:
Four Categories
• Chemicals unlikely to interact with hormone systems
(e.g., certain polymers, strong mineral acids/bases)
• Chemicals without sufficient existing data to determine
if Tier 2 testing required
• Chemicals with sufficient existing data to determine if
Tier 2 testing required
• Chemicals with sufficient data to support a hazard
assessment
Office of Pesticide Programs
(USEPA, 1998)
Prioritizing Chemicals for Endocrine
Disruptor Screening & Testing
• Chemicals without sufficient existing data
–Considered by the EDSTAC (USEPA 1998) to have
the largest number of chemicals and the greatest
need for prioritization
–EDSTAC (USEPA, 1998) and the SAB/SAP
(USEPA, 1999) strongly recommended a
prioritization scheme that included an effects &
exposure component
Office of Pesticide Programs
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
Office of Pesticide Programs
(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
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Office of Pesticide Programs
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QSAR
focus
area
In vitro Assay
focus area
In vivo
Inerts;
Antimicrobial
Chemicals
MOLECULAR
Target
Receptor
Binding
ER
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CELLULAR
Response
Liver Cell
Protein
Expression
TISSUE/ORGAN
Liver
Altered
proteins(Vtg)
& hormones;
Vitellogenin
Gonad
(egg protein
transported to
ovary)
Ova-testis;
Complete
ovary in male
POPULATION
INDIVIDUAL
Sex
reversal;
Altered
behavior;
Skewed
Sex
Ratios;
Yr Class
Repro.
Toxicity Pathway
Adverse Outcome Pathway
Greater Toxicological Understanding
Greater Risk Relevance
(Q)SAR-Based System to
Predict ER Binding Affinity
• External peer-review by USEPA SAP, August 2009
– http://www.epa.gov/scipoly/sap/meetings/2009/082509meeting.
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
Office of Pesticide Programs
Future Prioritization for EDSP
Tier 1 Screening
• Inert ingredients & other chemicals
–develop in vitro & in silico tools that are integrated
with exposure-based metrics
• Pesticide active ingredients
–current plan is to use EPA’s schedule for reevaluating registered active ingredients in the
Registration Review program
(http://www.epa.gov/oppsrrd1/registration_review/)
• Consistent with EDSTAC & SAB/SAP
recommendations
Office of Pesticide Programs
Enhanced Integrated Testing &
Assessment
• Where we need to be in the near term
–Accelerated/enhanced priority setting/screening &
focused animal testing
• Where we would like to be in the long term
–Greater reliance on hypothesis & mechanism-based
assessments
• What needs to happen
–Collaborative research to develop scientific basis
–Partnerships, stakeholder input, peer review,
consensus building, staff training, development of
new polices, etc
Office of Pesticide Programs
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