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Fetal Origin of Adult Disease A Regulatory Perspective Dr. Steven Bradbury, Office Director Office of Pesticide Programs, USEPA

Evolving Science Developmental Origins of Adult Disease

Topics „ Current Regulatory Framework „

What do we do now to protect the fetus/children

„ Incorporating New Perspectives into the

Regulatory Approach „

What do we need to ask or know

„ 21st Century Science & Evolving the Testing

Paradigm „

Integrated testing strategies that rely on concept of toxicity pathways & targeted testing

National Pesticide Program: Regulatory Framework „ Federal Insecticide, Fungicide, & Rodenticide

Act (FIFRA) Pre-market approval (registration) of pesticide products „ Risk / benefit balancing standard „

„ Federal Food, Drug, & Cosmetic Act (FFDCA)

Tolerances for residues in food / feed „ Risk-only standard – “reasonable certainty of no harm” „

Regulatory Framework „ 1996 Food Quality Protection Act:

10X FQPA safety factor „ Aggregate food, drinking water and residential exposures „ Cumulative risks for common mechanism of action „ Endocrine screening & testing program „

Regulatory Framework „ Extensive data required to

demonstrate safety for registration application toxicology, chemistry, exposure, efficacy, environmental fate „

toxicology includes prenatal studies, reproductive, neurodevelopmental (triggered)

Development

„

Life stage exposure

Preconception Prenatal Postnatal Reproductive Age Adult

Assessing Risk „ Characterize Effects „ Developmental, endocrine, tumors, etc „ Critical susceptibility & exposure periods „ Mode of Action „ Metabolism & potential for bioaccumulation „ Epidemiological data

„ Characterize Exposure „ Timeframe (acute, short & intermediate, chronic) „ Route (oral, dermal, inhalation) „ Geographic & demographic considerations „ Human activity

Integrate

Protection of Fetus/Children: New Initiatives „ Endocrine Disruptor Screening Program „ Revised Risk Assessment Methods for

Workers, Children of Workers in Agricultural Fields, and Pesticides with No Food Uses „ Improved Animal Study Designs „

Extended One Generation Reproductive Study „

Evaluates developing reproductive, immunological, neurological and thyroid systems

„ 21st Century Computational Toxicology

Incorporating New Perspectives into the Regulatory Approach „ State-of-the-Science „ Research

phase or readiness for regulatory implementation?

Incorporating New Perspectives into the Regulatory Approach „ Evidence that fetal exposure to environmental

chemicals can lead to adult disease „ Evidence that your current test guidelines are not protective „

i.e., are missing effects? or are these “new” endpoints more sensitive than what we are already measuring?

„ Sufficient data about the disease process to

develop: early diagnostic indicators for screening „ reliable endpoints/tests „

Incorporating New Perspectives into the Regulatory Approach „ Validation & Acceptance of Methods „ Standardization

& optimization „ Availability of reference chemicals to assess relevance & reliability of methods „ How can new endpoints be integrated into current test guidelines to maximize the value obtained from each animal

MAPPING THE PROCESS PHASES

OUTCOMES

Research

Computational Tools Toxicity Pathway identification

Method Development

New Methods For Applications Transferable Method

Science & Technology

Evaluation Establishment of Reliability

Review Regulatory Acceptance

Peer Review Stakeholder Engagement Decision for Specific Application

Regulatory Implementation

Integrated Testing & Assessment Strategies „ 2007 NRC - Toxicity Testing in the 21st

Century: A Vision and Strategy „

Leverages recent advantages in molecular & predictive sciences „

„

In vitro HTP profiling, QSAR, etc

Focuses on concept of toxicity pathways & targeted/tiered testing

Evolving Paradigm „ Current Paradigm „ „ „ „

Heavy reliance on animal testing Resource & Time Intensive Generate information for all possible outcomes Empirical approach

„ New Paradigm „ „ „ „

Use existing knowledge, in silico, in vitro technologies Rely on knowledge of toxicity pathways Tiered & tailored to focus on effects of concern Reduce/refine animal usage

OPP Strategic Direction: Combine in vitro methods and computational models to predict in vivo outcomes and guide priority setting/screening and more targeted in vivo testing.

In Summary „ More complete understanding of disease

processes presents regulatory challenges „ Necessitates an evaluation of the current methods & assessment approaches to ensure they are protective „ Our office strategic direction - use of integrated approaches to efficiently & reliably assess risk „

Tiered & hypothesis based