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## OPP’s Vision for an Integrated 

## Approach to Testing and Assessment FIFRA Scientific Advisory Panel Consultation on “Integrated Approaches to Testing and 

### Assessment Strategy: Use of New Computational and Molecular Tools”

May 24, 2011 John “Jack” R. Fowle III, Ph.D., D.A.B.T. Deputy Director, Health Effects Division USEPA Office of Pesticide Programs

# Purpose Seek guidance about OPP’s vision, initial efforts, and plans to enhance our use of IATA

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# Program Objectives

• Maximize use of existing data • Target in vivo toxicity testing • Build on an established foundation using a variety of tools in a tiered testing and assessment framework 

## • Systematically add new tools, methodologies • Advance understanding of key events in 

## toxicity pathways. 34



## Outline for Presentation

• Introduce Members of the Team • Overview of OPP • Why and How We are Enhancing our Use of IATA • Our Vision • Our Goals • For IATA • For this consultation • Plan to Achieve the Vision • Partnerships • Summary

# National Pesticide Program

• Mission: 

### • Best Possible Regulatory Decisions to Protect Public Health and the Environment • Rely on All Available and Relevant Scientifically Sound Information

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# National Pesticide Program
• At a Glance: • Over 5,000 regulatory decisions annually • Approximately 1,100 active ingredients & 

### 19,000 products • Re - evaluation of existing pesticides on a regular schedule to ensure safety 

### standards continue to be met

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## • Safety evaluations required for both human health & ecological risks • „Conventional,‟ biochemical, antimicrobial 

### active ingredients • Food - use & non -food use inert ingredients 

## • Data required for registration • Vary across types of pesticide chemicals • Extensive for food use, conventional active ingredients to minimal for non -food use inert ingredients 7 

# National Pesticide Program

## National Pesticide Program Challenges
• Large number of chemicals to review 

## with many possible adverse outcomes • Finite resources and time 

## • Public expectations for scientific soundness, transparency, and timeliness • Science increasingly complex & changing • New risk assessment & management challenges always arise 8

# Observations & Needs
• Current testing paradigm time tested strong 

## basis for risk management decisions • Time consuming and resource intensive • Dollars and animal usage 

## • Not easily adaptable when new issues arise • EDCs, cumulative risk 

## • Need agile approach • Broad coverage 

### • Readily augmented as knowledge changes 9

### Goal: Require Sufficient, Targeted Credible



### Information to Inform Decisions



## • Long Term Solution Not Generating More Information Faster

• Identify what specific data, for which chemicals, which exposures and which populations are essential to assess risk

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# OPP’s Objectives
• Evaluate pesticides more efficiently 

## • With greater accuracy • Enhance our abilities to target effects of 

## concern • Focus on the information most relevant 

## to the assessment

11Heavy reliance on animal studies Generate information for all possible outcomes Based on traditional toxicity tests Less reliance on animal studies Tailor data generation Based on understanding of toxicity pathways 

### Program Priority Work toward transitioning new 21st century technologies, to enhance the efficiency & effectiveness of chemical risk management 

## OPP Vision for a New Toxicology Testing & Assessment Paradigm

FUTURE CURRENT

## • INTEGRATE existing information • Use information from new technologies with combined estimates of exposure in a 

### manner that leads to better predictions of risk for regulatory endpoints 

## • FORMULATE plausible & testable hypotheses • TARGET in vivo testing on chemicals & 

## endpoints of concern 13 

## Integrated Approaches to Testing & 

## Assessment (IATA)

## • Originated from OECD • Dec 2007 workshop hosted by EPA 

## • Consistent with: • 2007 NRC Report • EPA‟s Strategic Plan for Evaluating the 

### Toxicity of Chemicals

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## Integrated Approaches to Testing &



## Assessment (IATA)

## Integrated Approaches to Testing &



## Assessment (IATA) • Not new • Long history with chemicals lack data • Industrial Chemical Program, pesticide inert ingredients – QSAR, Read across • OPP and Other Programs – MOA


## • Incorporates various tools and types of information


## • Evolves with science 1516



### Transforming Chemical 

### Safety Assessments

2005 2009

2007 2011

## 2007 NRC - Toxicity Testing in the 21st



## Century: A Vision & Strategy • Sponsored by EPA • Use cell - based (high throughput) assays to understand how chemicals perturb normal cellular functions (i.e., toxicity pathway) • Establish relationships of perturbations with “adverse outcomes” • Develop in vitro to in vivo extrapolation methods • Integrate results to predict hazard/risk

17 Broader coverage of chemicals & endpoints

Reduce cost & time of testing Use fewer animalsBiologic inputs “Normal” Biological Function

Adverse

Outcomes (e.g., mortality, Reproductive Impairment) Cell inury, Inability to regulate Adaptive Responses Early cellular

changes Exposure Uptake- Delivery to Target Tissues

Perturbation Cellular response pathway

Molecular initiating event Perturbed cellular

response pathway Adverse outcome relevant to risk assessment Toxicity Pathway Adverse Outcome Pathway NAS Model : Outcome Pathways – Definition and Example

## Adverse Outcome Pathway



# Concept • Key to achieving IATA 

## • Framework that portrays existing knowledge concerning the linkage between a direct 

## molecular initiating event and an adverse outcome at a level of biological organization relevant to risk assessment 

## • Basis for • Utilizing lower tier tests & non - animal models • Read across methods • Development of Expert Systems 

## • Consistent with MOA 19

### Adverse Outcome Pathway and the Data



### Streams that Inform the Pathway

Chemicals Molecular Target Cellular

Response Tissue/

Organ Individual Population Pharmaco kinetics In vitro studies Biomonitoring data Structure Activity Relationships
Toxicity Pathways Adverse Outcome Pathways In vivo studiesReceptor/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 Validity through Linkages & Dose Response Relationships 12

# More Effective Animal Usage

• Integrate approaches to evaluate 

### reproductive & other life stage effects • Full usage of animals in each study • Focus on effects of concern • Promote flexibility to use existing knowledge 

### • Reduce/refine animal usage

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Mortality • Systemic Toxicity •Disease • Cancer Reproductive

Fitness •Viable Offspring •Fertility Developmental

Impairment • Terato •Prenatal Deficits 

### Generates animal data for all possible outcomes to determine which possible effects are relevant

BATTERY of Animal Testing (Part 158 regulations) 

# Current Testing Paradigm( Q)SAR, in vitro screens Prioritize for further testing Targeted in vivo testing

Risk Assessment & Risk Management Exposure information Existing information Hazard Information Chemical groupings & read across Make toxicity predictions by combining different types of existing information on a similar chemical or group of similar compounds 24

Goal: Enhance integrated testing & assessment with new technologies & toxicity pathway knowledge

24Mortality

• Systemic Toxicity •Disease • Cancer Reproductive

Fitness •Viable Offspring •Fertility Developmental

Impairment • Terato •Prenatal Deficits Molecular Interactions Biochemical Responses Cellular Responses Tissue/Organ Function Chemical Inventories

C2Cl3 Cl Cl C

C2Cl3 Cl Cl C
C2Cl3 Cl Cl C Cl Cl Cl Cl Cl Cl Cl C l Cl Cl C l

Cl Cl Cl Cl Cl Cl Cl C l Cl Cl C l Cl Cl OH OH

OH Existing data; in silico and in vitro prioritization; screening Adverse Outcomes Efficient, focused in vivo animal testing 

## New Integrated Paradigm

25 Testing for relevant effects

## 2007 NAS Report Transforming



# Toxicology

Bioinformatics/ Machine Learning Analysis Cancer ReproTox DevTox NeuroTox PulmonaryTox ImmunoTox HTS

-omics in vitro Testing
$Thousands Targeted Animal Testing Combine in vitro testing & computational models to make predictions for In vivo outcomes & guide more

targeted animal testing

Research: Learn & Refine QSAR/SAR Priority Setting Screening

### Near Term Goal: 1 -5 years 

## Transition New Predictive Methods
• Strengthen priority-setting and screening for 

## data- poor compounds • Uses new predictive methods to fill data gaps • Guides targeted in vivo testing 

## • Maximize the value obtained from each in vivo study 

## • Incorporate new tools as they become available (e.g., QSAR, TTC) 

## • Transition away from chemical - by- chemical approaches by leveraging knowledge on groups of chemicals with shared properties 27

# Transition New Predictive Methods • Integrate into existing risk assessment 

## paradigm

• Use new methods in real time and real world situations 

## • Evaluate & refine through an iterative process 28 

## Risk = Hazard X Exposure

New TechnologiesInherent Properties of Chemicals

(chemical, biological & toxicity characteristics) 

## Integrate New Tools

29 Today’s Tool Box Improved Tool Box Using Newer Approaches Existing information + some use of: Expert Systems & Knowledge

- bases ToxRefDb ECOTOX ACToR ToxCast QSAR Models DSSTox .... And more Integrating these in a

way that makes sense ToxRefDb ECOTOX ACToR MetaPath ToxCast QSAR DSSTox .... And more30



# Managing Chemical Risks Long Term– Establish Validity (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 Uncertainty31 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

## Case Studies to Illustrate the



# Concepts • Propiconazole – Application of 

## Toxicogenomics to Identify Adverse Outcome Pathway 

## • Triclosan – Use of Adverse Outcome Pathway to Inform Risk Assessment

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## NOTE! CASE STUDIES ARE FOR ILLUSTRATIVE PURPOSES ONLY We Are Not Reassessing the Registration of These

Pesticides At this Time

## Propiconazole – Application of 

# Toxicogenomics to Identify AOP
• Developed MOA incorporating Apical, “Omic” and 

### Molecular endpoints • Future Challenge - Use Diagnostic Assays of Key Events of the MOA • Seek feedback about • Scientific soundness 

### • Other approaches to develop AOPs • General utility as an improvement over traditional risk assessment • Potential use for ecological risk assessment 33

## Triclosan – Use of AOP to Inform



# Risk Assessment
• Developed AOP to improve risk assessment 

### • Seek feedback about • Soundness of approach to understand interspecies differences • Factors most responsible for variability of toxico - kinetics and –dynamics affecting homeostasis especially in susceptible subpopulations • Current understanding of the magnitude of perturbation of thyroid hormones in humans that may be required to lead to adverse outcomes 3435

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 To Future Risk



## Determination Problem Identification Researchers and Regulators Working Closely Together Research Planning

# Partnerships & Collaborations

• Internal Partners 

### • EPA regulatory and research programs • External Partners • State, Federal & International Agencies • Stakeholders

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# International Partnerships
• Global acceptance 

## • Information sharing • Common application tool boxes 

## • Mutually accepted test guidelines • Harmonize frameworks & guidance

37 37 Organization for Economic Cooperation & Development North American Free Trade Agreement International Program for Chemical Safety European Food Safety Authority & others38



# 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.

# Stakeholder Input
• Kristie Sullivan, MPH will provide 

## stakeholder perspective on the approach • Scientific and Policy Advisor, Physicians Committee for Responsible Medicine • Member of the Pesticide Program Dialog 

### Committee Workgroup on 21st Century Toxicology/New Integrated Testing Strategies Workgroup 39

### PPDC Workgroup: 21st Century Toxicology/New Integrated Testing Strategies

• Objective • Focus on communication & transition issues 

### as EPA phases in new molecular and computational tools • Provide input on key activities needed for successful communication and transition

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# Our Goal For This SAP Consultation

41 • To what extent does our vision clearly articulate a sound scientific basis to make the risk assessment process more efficient and informative?
• What scientific principles should we apply to gauge the reliability and robustness of AOPs?
• What is the utility of the OECD principles for (Q)SAR expert systems, the IPCS Mode of Action Framework and other criteria EPA can use to reliably integrate predictive tools early in the process?

We Seek Your Feedback About:

## Our Goal For This Consultation



# cont’d

42 • How can we build on traditional approaches in concert with the new Tox 21 approaches to speed the development and discovery of AOPs and their subsequent acceptance?
• What is your initial thinking on the concepts, considerations and factors we should take into account in terms of developing and applying measures of success? “Consultation” Provides the Means For the Agency to Seek Input from the SAP Early in the Development and Implementation of Programs to Describe Our Thinking and to Seek Input that Can Be Incorporated at an Early Stage and Before Processes and Procedures are Fully Put in Place We Will Be Back As the Program Develops

# In Summary

Achievable with strong scientific & stakeholder support through a transparent process 

## Integrated Approaches to Testing & Assessment 

## using 21st Century Technologies

43 • We 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 • Initial focus on priority setting and capacity building • Long -term use for risk assessment/risk management

# Acknowledgements

• Kevin Crofton 

## • Elaine Francis • Nancy McCarroll • Jennifer McLain • Tim McMahon
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## • Stephen Nesnow 

## • Pat Schmieder • Tammy Stoker • Dan Villeneuve Many Others in ORD, OPP & Beyond 

## Steve Bradbury & Vicki Dellarco