21st century screening assessment of pesticides – a regulatory view
DESCRIPTION
21st Century Screening Assessment of Pesticides – A Regulatory View. Vicki Dellarco, Ph.D. Senior Science Advisor Office of Pesticide Programs US Environmental Protection Agency. Managing Chemical Risks. Safety evaluations required for human health & ecological risks FIFRA, FFDCA, FQPA, ESA - PowerPoint PPT PresentationTRANSCRIPT
Office of Pesticide Programs
21st Century Screening Assessment of Pesticides – A Regulatory View
Vicki Dellarco, Ph.D.Senior Science AdvisorOffice of Pesticide ProgramsUS Environmental Protection Agency
Office of Pesticide Programs 2
Managing Chemical Risks
Gateway to MarketNational 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
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Managing Chemical Risks
•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
Common Challenges
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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 follow-up actions
Managing Chemical Risks Strategic Direction
Transition toward new integrative & predictive 21st century techniques, to increase efficiency and effectiveness of testing & assessment
Office of Pesticide Programs
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
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Current Data Paradigm
Cancer
Reproductive Toxicity
Developmental Toxicity
Neurotoxicity
KidneyToxicity
ImmunoTox
in vivo testing
$Millions
Food Use, Conventional Pesticide Actives:Generates in vivo animal data for all possible outcomes to determine which of all possible effects are relevant.
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Evaluation for Relevant Effects
Risk Assessment
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In Vitro Profiling: Molecular
interactions, Cellular Responses
Existing Knowledge, exposure use, toxicity
data, SAR, QSAR
Efficient Focused In Vivo Testing
PrioritySettingProcess
Research: Learn & Refine
Libraries of Toxicological Pathways
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
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Managing Chemical Risks
•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
Challenge: Assessing Data-Limited Chemicals
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Managing Chemical Risks
• Long Term (~15 years)– Develop means to move, in a credible &
transparent manner to hypothesis & mechanism-driven, 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
Challenge: Reducing Uncertainty
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Integrated Approaches to Testing & Assessment
Existing Knowledge, exposure use, toxicity
data, SAR, QSAR
In Vitro Profiling: Molecular interactions,
Cellular Responses
Efficient Focused In Vivo Testing
(Q)SAR-Based System to Predict ER Binding Affinity
ToxCast HTP Research Program
New F1 Extended Reproductive Study
Example Activities
Office of Pesticide Programs
Partnerships
•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
Agencies & International Organizations
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
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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
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Priority SettingAssay Validation
Procedures
US EPA EDSP Implementation
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Selecting chemicals to be screened
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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
(OECD, 2004)
Office of Pesticide Programs
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
(USEPA, 1998)
Office of Pesticide Programs
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
(USEPA, 1998)
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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
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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
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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QSAR focus area
Inerts; Antimicrobial Chemicals
ReceptorBinding
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Liver CellProtein
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Vitellogenin (egg protein
transported to ovary)
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proteins(Vtg)& hormones;
GonadOva-testis;Complete
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Sex reversal;
Altered behavior;
Repro.
In vivo
MOLECULAR Target
CELLULARResponse
TISSUE/ORGAN INDIVIDUAL
Skewed Sex
Ratios;
Yr Class
POPULATION
In vitro Assayfocus area
Toxicity PathwayAdverse Outcome Pathway
Greater Toxicological Understanding Greater Risk Relevance
Office of Pesticide Programs
(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 re-evaluating registered active ingredients in the Registration Review program (http://www.epa.gov/oppsrrd1/registration_review/)
•Consistent with EDSTAC & SAB/SAP recommendations
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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