21st century screening assessment of pesticides – a regulatory view

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



•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


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


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


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.


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



•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



• 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


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


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


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


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


Priority SettingAssay Validation

Procedures

US EPA EDSP Implementation

15

Selecting chemicals to be screened


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)


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)


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)


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


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


(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

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In vitro Assayfocus area

Toxicity PathwayAdverse 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


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


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

21st century screening assessment of pesticides – a regulatory view

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