Regulatory Approach. ▫ What do we need to ask or know. ▫ 21st Century
Science & Evolving the Testing. Paradigm. ▫ Integrated testing strategies that
rely on.
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