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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. 

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4

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

5
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 

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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 

8 challenges always arise
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

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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

10
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

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Heavy 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

CURRENT FUTURE
• 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

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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

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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

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Broader coverage of chemicals & endpoints

Reduce cost & time of testing

Use fewer animals
Biologic

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 Pharmacokinetics

In vitro studies

Biomonitoring data

Structure Activity Relationships

Toxicity Pathways

Adverse Outcome Pathways

In vivo studies
ER Binding Transctivation ER 

VTGmRNA

VitellogeninInduction Sex Steroids Reproduction/ Altered Development

Molecular Cellular Organ Individual

Chemical 3 Structure/ -D

Properties

Chemical 2 Structure -D Structure

ER Binding Transctivation ER 

VTGmRNA

VitellogeninInduction Sex Steroids Reproduction/ Altered Development

Molecular Cellular Organ Individual

Chemical 3 Structure/ -D

Properties

Chemical 2 Structure -D Structure

ER Binding Transctivation ER 

VTGmRNA

VitellogeninInduction Sex Steroids Reproduction/ Altered Development

Molecular Cellular Organ Individual

Chemical 3 Structure/ -D

Properties

Chemical 2 Structure -D Structure

ER Binding Transctivation ER 

VTGmRNA

VitellogeninInduction Sex Steroids Reproduction/ Altered Development

Molecular Cellular Organ Individual

Chemical 3 Structure/ -D

Properties

Chemical 2 Structure -D Structure

ER Binding Transctivation ER 

VTGmRNA

VitellogeninInduction Sex Steroids Reproduction/ Altered Development

Molecular Cellular Organ Individual

Chemical 3 Structure/ -D

Properties

Chemical 2 Structure -D Structure

ER Binding Transctivation ER 

VTGmRNA

VitellogeninInduction Sex Steroids Reproduction/ Altered Development

Molecular Cellular Organ Individual

Chemical 3 Structure/ -D

Properties

Chemical 2 Structure -D Structure

ER Binding Transctivation ER 

VTGmRNA

VitellogeninInduction Sex Steroids Reproduction/ Altered Development

Molecular Cellular Organ Individual

Chemical 3 Structure/ -D

Properties

Chemical 2 Structure -D Structure

ER Binding Transctivation ER 

VTGmRNA

VitellogeninInduction Sex Steroids Reproduction/ Altered Development

Molecular Cellular Organ Individual

Chemical 3 Structure/ -D

Properties

Chemical 2 Structure -D Structure

ER Binding Transctivation ER 

VTGmRNA

VitellogeninInduction Sex Steroids Reproduction/ Altered Development

Molecular Cellular Organ Individual

Chemical 3 Structure/ -D

Properties

Chemical 2 Structure -D Structure

ER Binding Transctivation ER 

VTGmRNA

VitellogeninInduction Sex Steroids Reproduction/ Altered Development

Molecular Cellular Organ Individual

Chemical 3 Structure/ -D

Properties

Chemical 2 Structure -D Structure

ER Binding Transctivation ER 

VTGmRNA

VitellogeninInduction Sex Steroids Reproduction/ Altered Development

Molecular Cellular Organ Individual

Chemical 3 Structure/ -D

Properties

Chemical 2 Structure -D Structure

ER Binding Transctivation ER 

VTGmRNA

VitellogeninInduction Sex Steroids Reproduction/ Altered Development

Molecular Cellular Organ Individual

Chemical 3 Structure/ -D

Properties

Chemical 2 Structure -D Structure

ER Binding Transctivation ER 

VTGmRNA

VitellogeninInduction Sex Steroids Reproduction/ Altered Development

Molecular Cellular Organ Individual

Chemical 3 Structure/ -D

Properties

Chemical 2 Structure -D Structure

ER Binding Transctivation ER 

VTGmRNA

VitellogeninInduction Sex Steroids Reproduction/ Altered Development

Molecular Cellular Organ Individual

Chemical 3 Structure/ -D

Properties

Chemical 2 Structure -D Structure

ER Binding Transctivation ER 

VTGmRNA

VitellogeninInduction Sex Steroids Reproduction/ Altered Development

Molecular Cellular Organ Individual

Chemical 3 Structure/ -D

Properties

Chemical 2 Structure -D Structure

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 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

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Goal: Enhance integrated testing & 

assessment with new technologies & 

toxicity pathway knowledge

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Mortality 

•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

C Cl

C2Cl3

Cl

C Cl

C2Cl3

Cl

C Cl

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

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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

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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 

28 process 

Risk = Hazard X Exposure 

New Technologies
Inherent Properties of Chemicals

(chemical, biological & toxicity characteristics)

Integrate New Tools

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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 more
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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 Uncertainty 
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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

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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

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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

3737

Organization for Economic Cooperation & Development

North American Free Trade Agreement

International Program for Chemical Safety

European Food Safety Authority & others 
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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

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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

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• 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

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• 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

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• 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