An Integrated Evaluation Strategy
for Making Regulatory Decisions:
Moving From Data Requirements to
Knowledge Requirements.
Douglas C. Wolf, D.V.M., Ph.D., Fellow IATP, ATS
Office of Research and Development
U. S. EPA
[email protected]
1
Overview of Presentation
Proposals that Stimulated the Change
Issues that have to be Addressed
Examples of Legislative Context
Problem Formulation for Regulatory Decisions
Approaches to Establish Necessary Knowledge and Supporting Activities
What the Future Will Look Like and How to Make It Happen
2
The Future of Toxicology
…the application of mathematical and computer models and molecular biological
approaches to improve…prioritization of data requirements and risk assessments.
To support the evolution of toxicology from a predominantly observational science at
the level of disease-specific models to a predominantly predictive science focused
upon a broad inclusion of target specific, mechanism-based, biological observations.
…a new toxicity-testing system that evaluates biologically significant perturbations
in key toxicity pathways by using new methods in computational biology and a
comprehensive array of in vitro tests based on human biology.
2003
2004
www.epa.gov/ncct
http://ntp.niehs.nih.gov
2007
3
http://dels.nas.edu/Report/Toxicity-Testing-Twenty-first/11970
NAS Vision for the Future
“Work towards transition to new integrative and
predictive molecular and computational techniques to
enhance efficiency and accuracy and to reduce reliance
on animal testing.”
Vision by the U. S. National Academy of Sciences
National Research Council 2007 report, Toxicity Testing
in 21st Century: A Vision and a Strategy
“The difficulty lies, not in the new ideas, but in escaping from the old ones”
John Maynard Keynes (1883–1946), British economist
4
Toxicity Testing in 21st Century: A Vision and a Strategy
5
Goal
Integrated evaluation strategy that provides
the necessary scientific knowledge to make a
regulatory determination of the potential for an
adverse impact, from the use of a chemical,
on public health and the environment with
speed, efficiency and accuracy.
6
Problem Statement
What is needed is a conceptual breakthrough which would
enable tailored risk assessments for a variety of risk
management contexts;
using in vitro, in silico and other new technology based
on an integrated evaluation strategy.
Allowing significantly more chemicals to be assessed without
increasing the amount of resources needed for testing or
evaluation;
Allowing new methods to be incorporated as they develop;
Improve relevance and accuracy while reducing the reliance on
whole animal testing;
Taking exposure and modes of action into consideration.
7
Why do we order a buffet when we
need a simple balanced meal?
8
9
I’LL HAVE A RAT AND MOUSE 2
YEAR STUDY, A MULTIGEN..... OH
AND AN IN VITRO ASSAY, I’VE GOT
TO WATCH MY ANIMAL USAGE!
10
We need something like this.
11
Toxic Substances Control Act of 1976
adequate data should be developed
information relating to chemical characteristics
test data to determine an unreasonable risk
periodic review of the standards for data development
methods for prioritization of data needs
SAR methods
predictive models
establish screening methods and the scientific basis for these methods
Safe Chemicals Act of 2010
develop minimum data set
information on chemical characteristics
information on use and exposure
develop alternative (non animal based) test methods
develop a strategic plan for implementing alternative test methods
use test methods that eliminate or reduce animal use
encourage submission of data using new methods
support the scientific basis for new method development
12
Safe Drinking Water Act (SDWA)
as amended 1996
SEC. 1442.
(A) improved methods
(i) to identify and measure the existence of contaminants in drinking water,
(ii) to identify the source of such contaminants;
(B) improved methods to identify and measure the health effects of
contaminants in drinking water;
Clean Water Act (CWA)
as amended 1987
SEC. 104.
(1) …conduct and promote the coordination and acceleration of, research,
investigations, experiments, training, demonstrations, surveys, and studies
relating to the causes, effects, extent, prevention, reduction, and elimination
of pollution;
13
Source-Exposure-Dose-Effects Continuum
SOURCE / STRESSOR
FORMATION
Chemical
Physical
Microbial
Magnitude
Duration
Timing
Transport,
Transformation &
Fate Models
BBDR
Models
TRANSPORT /
TRANSFORMATION
Dispersion
Kinetics
Themodynamics
Distributions
Meteorology
DISEASE
Exposure
Models
PBPK
Models
ENVIRONMENTAL
CHARACTERIZATION
Air
Water
Diet
Soil & dust
Toxicity Pathway
EARLY KEY
BIOLOGICAL EVENTS
DOSE
EXPOSURE
Activity
Patterns
ALTERED STRUCTURE /
FUNCTION
Pathway
Route
Duration
Frequency
Magnitude
Community
Cancer
Asthma
Infertility
etc.
Edema
Arrhythmia
Necrosis
etc.
Molecular
Biochemical
Cellular
Organ
Organism
Absorbed
Target
Internal
Biologically
Effective
Statistical Profile
Reference Population
Susceptible Individual
Susceptible Subpopulations
Population Distributions
14
Lifecycle Analysis
RELEASE
Chemical
Manufacture
CONCENTRATION
Workplace
Exposure
Water
Food
Environmental
Release
Land
Air
Production/
Formulation
Intermediates
Environmental
Disposal
EXPOSURE
En
vir
o
Ex nme
po
sur ntal
e
Sewage
Treatment
Indoor
Air
Product
Use
Release
Transport
Reaction
Market Share
Population
Location
Frequency
Timing
Outdoor
Air
Surface
Dust
Soil
Water
ES
TI
VI
TI
AC
En
vir
o
Ex nme
po
sur ntal
e
Food
Disposal
Water
Product
Disposal
Environmental
Release
Air
Land
ES
TI
VI
TI
AC
PRODUCT n
PRODUCT …
PRODUCT 8
PRODUCT
4 5
PRODUCT
PRODUCT PRODUCT
3
6
PRODUCT 7
PRODUCT 2
PRODUCT 1
Degradates
ACTIVITY
Incineration
Recycling
Chemical
ES
TI
VI
TI
AC
Chemical
Transportation
FATE / TRANSPORT
En
vir
o
Ex nme
po
sur ntal
e
Food
15
Consistant with NAS Science and Decisions and TSCA 2010
National Academy of Science
Exposure Project
Human and Environmental Exposure Science in the 21st Century
Develop a long-range vision for exposure science and a strategy with
goals and objectives for implementing the vision over the next twenty
years.
It will include development of a unifying conceptual framework for
advancement of exposure science to study and assess human and
ecological contact with chemical, biological, and physical stressors in
their environments.
http://dels.nas.edu/Study-In-Progress/Human-Environmental-Exposure-Science/DELS-BEST-09-02
16
Threshold of Toxicological Concern
Risk assessment tool based on the establishment of a
human exposure threshold value for chemicals, below
which there is a very low probability of adverse effects
to human health.
A safe level of exposure can be identified for many
chemicals based on their chemical structure and the
known toxicity of chemicals which share similar
structural characteristics.
Information on human exposure is crucial.
Use of the Threshold of Toxicological Concern (TTC) Approach for
the Safety Assessment of Chemical Substances
SCCP/1171/08, 19.11.08 European Commission 2008
17
Class I:
Simple chemical structure and efficient metabolism that would
suggest a low order of oral toxicity.
Class II:
Less knowledge of metabolism and toxicology, but there is no clear
indication of toxicity.
Most substances in this class have functional groups similar to Class I
but somewhat more reactive;
more complex structures than substances in Class I
Class III:
Chemical structure that permit no strong initial presumption of safety.
May suggest significant toxicity.
Structural information based on a "decision tree" algorithm and grouped into three structural
classes reflecting a presumed low, moderate and significant toxicity.
Cramer GM, Ford RA, Hall RA (1978). Estimation of toxic hazard – a decision tree approach.
Food Cosmet Toxicol, 16: 255-276.
18
International Life Sciences Institute
ilsi.org
ILSI North America
Refining TTC as tool for prioritization of food contaminants
ILSI Research Foundation
Extending TTC to support risk assessment of biocides
ILSI Health and Environmental Sciences Institute
TTC as a tool in mixtures risk assessment
ILSI Europe
TTC Task Force
19
Classification based on inherent properties
For a chemical: Inherency relates to those chemical-specific
properties associated with its impact on humans and the
environment. (EPA perspective)
The physico-chemical and material properties, atomic composition,
structure, size, surface area, solubility, surface charge, aspect ratio, etc.
The ability to interact with biological processes.
How it is made, used, degraded and disposed of.
20
Initial Screening will Require Relational
Integrated and Interactive Knowledgebases
Development and expansion of knowledgebases that
describe inherent properties of chemicals based on
their known molecular structure, and chemical and
biological interactions.
21
Ashby's poly-carcinogen
Represents a hypothetical
chemical made of many
of the known structural
alerts for mutagenicity.
Benigni et al, J Environ Sci Health C 25:53-97
Modified from
Ashby, J. (1985) Environ.Mutagen 7 , pp. 919-921.
22
Metabolism and Degradate Pathway Analysis
Systematic compilation of information on observed metabolites,
biotransformation reaction types, and relative biotransformation
rates into a structure-searchable database.
Structure-based identification of metabolites and transformations
Identification of differences in metabolism based on gender,
exposure dose, species, and methods
Identification of similar metabolites arising from different parent
chemicals.
Identification of metabolites as residues in the food web.
Develop a metabolism simulator.
23
Clustering Using Inherent Properties
Chemistry-based
Characteristics
429
27
350
Biological
Responses
6
100
21
356
Use and Exposure
Considerations
24
Design for the Environment
Clustering by inherent properties will enable
identification of negative chemical features such as
toxicity, persistence, and bioaccumulation.
Clustering by inherent properties will ALSO enable
identification of positive chemical features such as
minimal toxicity, no persistence, and lack of
bioaccumulation.
25
Tiered Testing
Most tiered testing discussions have been
focused on developing approaches that are
geared toward limiting or eliminating whole
animal testing.
Specifically decreasing or eliminating use of
mammalian experiments using primates,
canines, rodents, and related species.
26
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Risk Characterization, Evaluation, and Decision
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Chemical Inventories
Cl
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Existing Knowledge,
exposure, use,
toxicity data, SAR,
metabolism
prediction, degradate
analysis, QSAR
C
l
In Vitro Profiling:
Molecular
interactions, Cellular
Responses
QBAR
Efficient
Focused In
Vivo Testing
Evaluation for Relevant Effects
Screening
and
Prioritization
and
Evaluation of
knowledge
sufficiency
Research:
Learn & Refine
27
EPA has a lot of experience with Hazard prediction
and Chemical databases – a few examples
Analog Identification Methodology (AIM)
identifies close structural analogs that have measured data and points to
sources where those data can be found
Ecological Structure Activity Relationships (ECOSAR)
estimates the aquatic toxicity of industrial chemicals
ECOTOX
chemical toxicity data for aquatic life, terrestrial plants and wildlife
EPI Suite™
estimates physical / chemical properties and environmental fate
High Production Volume Information System (HPVIS)
health and environmental effects information
OncoLogicTM
evaluates the likelihood that a chemical may cause cancer
Use Cluster Scoring System (UCSS)
risk-screening system into which chemicals are grouped by common use
28
Moving beyond data warehouses to integrated knowledgebases
A knowledge-based system uses artificial intelligence techniques in problemsolving processes to support human decision-making, learning, and action.
ACToR: Aggregated Computational Toxicology Resource
Aggregates data from over 500 public sources on over 500,000 environmental
chemicals searchable by chemical name, structure, and other identifiers.
Data includes chemical structure, physico-chemical values, in vitro assay data and
in vivo toxicology data.
Distributed Structure-Searchable Toxicity (DSSTox) Database Network
Structure-activity and predictive toxicology using structure searchable standardized
chemical structure files associated with toxicity data.
ToxRefDB: Toxicity Reference Database
Detailed chemical toxicity data in an accessible and searchable format.
Links to other public hazard, exposure and risk resources.
29
Taking advantage of the development
of knowledgebases and moving
beyond just focusing on decreasing
animal use.
30
An Integrated Evaluation Strategy
An evaluation
strategy that results
in confidence that
regulatory decisions
are adequately
protective of public
health and the
environment.
Increasing levels of
certainty based on
the risk context of
the regulatory
decision.
Exposure, Dose and Route,
Mode of Action/Relevance,
in vitro assays, in vivo
assays, in silico
evaluation, level of
acceptance, integration of
information
Exposure, Dose and Route, Mode of
Action/Relevance, in vitro assays, in
vivo assays, in silico evaluation, level of
acceptance, integration of information
Exposure, Dose and
Route, Mode of
Action/Relevance, in vitro
assays, in vivo assays, in
silico evaluation, level of
acceptance, integration
of information
g
n
i
as nty
e
r ai
c
In ert
c
31
Toxicity Testing in 21st Century: A Vision and a Strategy
Source
Fate/Transport
Exposure
Tissue Dose
• Quantitative Dose-Response
• PK / PD
• Toxicity Pathway Identification
• in silico models
•Targeted Testing
Biologic Interaction
Perturbation
Normal
Biologic
Function
Biologic
Inputs
Toxicity Pathways: Cellular
response pathways that,
when sufficiently
perturbed, are expected
to result in adverse health
effects.
Early Cellular
Changes
Adaptive Stress
Responses
Modified from NRC, 2007
Cell
Injury
Morbidity
and
Mortality
32
Toxicity Pathway
Cellular response pathways that, when sufficiently
perturbed, are expected to result in adverse health
effects are termed toxicity pathways.
NRC (2007). Toxicity Testing in the Twenty-first Century: A Vision and a
Strategy. Washington, DC, National Academy of Sciences. 216 p.
33
Source
Application to Levels of
Organization Based on
Source to Outcome
Environmental
Contaminant
Exposure
Molecular Initiating Event
Cellular Effects
Individual
Population
Community
Toxicity Pathway
Mode of Action
Adverse Outcome Pathway
Source to Outcome Pathway
34
Molecular Initiating Event
The initial point of chemical-biological interaction within the
organism that starts the pathway is a molecular initiating event.
Mode of Action
Key events and processes, starting with the interaction of an agent with
the target cell, through functional and anatomical changes, resulting in
cancer or other adverse health effects.
Biological responses along the pathway that lead to, and are
experimentally or toxicologically associated with, the adverse outcome
are referred to as “key events”. All of these are empirically observable
precursor steps that are a necessary element of the mode-of-action or
are a biological marker for such an element.
USEPA (2005). Guidelines for Carcinogen Risk Assessment (Final). R. A. Forum, U.S.
Environmental Protection Agency. EPA/630/P-03/001F. p 166.
Boobis, A.R., et al. (2008). "IPCS framework for analyzing the relevance of a noncancer mode of
action for humans." Crit Rev Toxicol 38(2): 87-96.
35
Adverse Outcome Pathway
An adverse outcome pathway (AOP) represents existing knowledge
concerning the linkage between a direct molecular initiating event
and an adverse outcome relevant to risk assessment at the
individual or population levels thus spanning multiple levels of
biological organization.
Ankley, G.T., et al. (2010). "Adverse Outcome Pathways: A Conceptual Framework to Support
Ecotoxicology Research and Risk Assessment." Environmental Toxicology and Chemistry 29(3): 730-741.
Source to Outcome
The continuum or cascade of measurable events starting from
release into the environment and ending at an adverse outcome.
USEPA (2003). A Framework for a Computational Toxicology Research Program.
PA/600/R-03/065. p 5.
36
Application to Levels of
Organization Based on Source
to Outcome
Source
Community
Environmental
Contaminant
Population
Exposure
Individual
Molecular Initiating Event Cellular Effects
Toxicity Pathway
Mode of Action
Adverse Outcome Pathway
Source to Outcome Pathway
37
Toxicity Testing in 21st Century: A Vision and a Strategy
Source
Fate/Transport
Exposure
Tissue Dose
• Quantitative Dose-Response
• PK / PD
• Toxicity Pathway Identification
• in silico models
•Targeted Testing
Biologic Interaction
Perturbation
Normal
Biologic
Function
Biologic
Inputs
Toxicity Pathways: Cellular
response pathways that,
when sufficiently
perturbed, are expected
to result in adverse health
effects.
Early Cellular
Changes
Adaptive Stress
Responses
Modified from NRC, 2007
Cell
Injury
Morbidity
and
Mortality
38
Sustained Stress Environment
Cellular adaptation to its environment so that
it can survive and proliferate.
A basic tenet of evolutionary biology.
In the case of exposure to a chemical stressor,
the changes in a cell or tissue that allow the
tissue, organ, and organism to continue to
function and survive.
Karpinets and Foy: Journal of Theoretical Biology 227 (2004) 253–264
Karpinets and Foy: Carcinogenesis vol.26 no.8 pp.1323--1334, 2005
39
Toxicity Testing in 21st Century: A Vision and a Strategy
Source
Fate/Transport
Exposure
Tissue Dose
• Quantitative Dose-Response
• PK / PD
• Toxicity Pathway Identification
• in silico models
•Targeted Testing
Biologic Interaction
Perturbation
Normal
Biologic
Function
Biologic
Inputs
Toxicity Pathways: Cellular
response pathways that,
when sufficiently
perturbed, are expected
to result in adverse health
effects.
Early Cellular
Changes
Adaptive Stress
Responses
Modified from NRC, 2007
Cell
Injury
Potential
change in
susceptibility
New Normal
State of
Biological
Function
Morbidity
and
Mortality
40
ILSI Health and Environmental Sciences Institute
www.hesiglobal.org
Distinguishing Adverse from Adaptive, Non-functional and
Pharmacological Changes in Toxicity Studies Subcommittee
Develop an approach for evaluating the range from benign to adverse and use it for safety
assessment of chemicals/pharmaceuticals.
Develop criteria to facilitate the determination of adverse from other types of changes.
Develop an evaluation framework that integrates and prioritizes information that
characterizes changes biological systems.
Draft definitions:
Adverse Effect: A change in morphology, physiology, growth, development, reproduction,
or life span of a cell or organism, system, or (sub)population that results in an impairment of
functional capacity, an impairment of the capacity to compensate for additional stress, or an
increase in susceptibility to other influences.
Adaptive Effect: In the context of toxicology, adaptability is the process whereby a cell or
organism responds to a xenobiotic so that the cell or organism will survive in the new
environment that contains the xenobiotic without impairment of function.
41
Adverse Outcome Pathway
ER-Mediated Reproductive Impairment
Chemical effects across levels of biological organization
QSAR
focus
area
In vitro Assay
focus area
In vivo
Chemicals
MOLECULAR
Target
Receptor
Binding
ER
Binding
CELLULAR
Response
Liver Cell
Protein
Expression
POPULATION
TISSUE/ORGAN
INDIVIDUAL
Sex
reversal;
Liver
Altered
proteins(Vtg)
& hormones;
Vitellogenin
Gonad
(egg protein
transported to
ovary)
Ova-testis;
Complete
ovary in male
Altered
behavior;
Skewed
Sex
Ratios;
Yr Class
Repro.
Toxicity Pathway
Adverse Outcome Pathway
Greater Toxicological Understanding
42
Greater Risk Relevance
Associating Bioactivity in vitro with
Pathways and Diseases
43
Chemical Space
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Quantitative Structure Activity Relationships
Biological Activity Space
Quantitative Biological Activity Response
Adverse Outcome Space
Cancer
Developmental
Defects
Endocrine
Disruption
Respiratory
Disease
44
Neurologic
Effects
Clustering Using Inherent Properties for
Cumulative Risk Evaluation
Chemistry-based
Characteristics
429
27
350
Biological
Responses
6
100
21
356
Use and Exposure
Considerations
45
ILSI Health and Environmental Sciences Institute
www.hesiglobal.org
Emergence of Animal Alternative Needs in Environmental Risk
Assessment
Development of a sound technical basis for alternative tests as a means
to reduce, refine, or replace standard fish toxicity test procedures.
Risk Assessment for the 21st Century: a Vision and a Plan
(Risk21)
Bring applicable, accurate, and resource-appropriate approaches to the
evolving field of human health risk assessment.
Center for Alternatives to Animal Testing
Johns Hopkins Bloomberg School of Public Health
http://caat.jhsph.edu
Ongoing workshops in support of implementation of NAS vision.
46
We equate more extensive
evaluation with more
Exposure, Dose and Route,
animal testing.
Mode of Action/Relevance,
This is the current
model, the future will
be different.
in vitro assays, in vivo
assays, in silico evaluation,
level of acceptance,
integration of information
It may not necessarily
require more
animal testing
Exposure, Dose and Route,
Mode of Action/Relevance, in
vitro assays, in vivo assays, in
silico evaluation, level of
acceptance, integration of
information
Exposure, Dose and Route, Mode
of Action/Relevance, in vitro
assays, in vivo assays, in silico
evaluation, level of acceptance,
integration of information
g
in
s
y
ea int
r
c a
In e r t
c
It may mean more detailed in
vitro assays, enhanced exposure
assessment, greater specificity
of in silico models.
Greater certainty necessitates increased understanding,
47
quantitative data, and greater integration at each level.
Modeling Toxicity From Pathways to
Virtual Tissues
chemicals
pathways
networks
cell states
tissue function
Identify
Identify Key
Key Targets
Targets and
and Pathways
Pathways
Moving beyond
empirical models, to
multi-scale computer
models of complex
biological systems.
Quantitative
Quantitative
Dose-Response
Dose-Response
Models
Models
Future
Future
Risk
Risk assessments
assessments
48
Situational and Toxicity Pathway Based Assessments
Risk Context/Lifecycle Assessment/Exposure Context
Identify relevant adverse response in humans and wildlife
Describe Modes of Action
Identify Key Events
Develop and apply in vitro assays
Tissue and cellular dose
High-throughput screens
Additional targeted testing as needed based on results
Enhanced interpretation of data
Chemical Structure and Physical Chemical Properties/TTC
Assessment of Risk
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What Is Needed To Achieve The Goal Of An
Integrated Evaluation Strategy That Provides
The Necessary Knowledge For Chemical
Risk Assessment.
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Toxicity Testing in 21st Century: A Vision and a Strategy
In support of a paradigm shift from the use of experimental animals and
apical end points to more efficient in vitro and computational techniques.
Shift in orientation and perception
champions of new approach
Change in expertise and experience
training and staffing
Supportive policies and incentives
reward use of new technologies
use data in assessment processes
congressional implementation
support conducting new toxicity testing
use for regulation
re-examine testing programs and guidance's
Interpretation of adverse effects through perturbations of pathways
Communication
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http://www.epa.gov/pesticides/science/testing-assessment.html
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Council of Canadian Academies
The Council supports independent, science-based, expert assessments
(studies) that inform public policy development in Canada.
The Integrated Testing of Pesticides
The Minister of Health asked the Canadian Council of Academies to
assess the scientific status of integrated testing strategies in assessing
and regulating the risks of pesticides to both humans and
environments.
What is the scientific status of the use of integrated testing strategies
in the human and environmental regulatory risk assessment of
pesticides?
http://www.scienceadvice.ca/en/assessments/in-progress/pesticides.aspx
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General Concept to Move to Toxicity Pathway-Based
Assessment of Potential Risk
Identify relevant human disease or rodent adverse response
What are the human diseases that have a significant environmental component?
What are the primary rodent responses that drive our regulatory decisions?
Describe Modes of Action for these human diseases and rodent responses
Identify Key Events that describe the modes of action
Develop assays that predict or determine the activation or enhancement of key
event(s)
Establish toxicokinetics – tissue and cellular dose – that initiate key event
Develop high-throughput screens for identifying activation of key events and
their dose-response
Use high-throughput screens to determine the need for targeted testing
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NAS Activities
Toxicity Pathway-Based Risk Assessment: Preparing for
Paradigm Change: A Symposium Summary (2010)
Highlights from a May 2009 symposium, convened at the
request the U.S. Environmental Protection Agency to
stimulate discussion on the application of these approaches
and data in risk assessment.
Science and Decisions: Advancing Risk Assessment (2009)
The report concludes that EPA's overall concept of risk
assessment, which is based on the National Research
Council's 1983, Red Book, should be retained but that a
number of significant improvements are needed to advance
the use of risk assessment in decision making.
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The U.S. Environmental Protection Agency’s Strategic
Plan for Evaluating the Toxicity of Chemicals
www.epa.gov/spc/toxicitytesting
Process of moving from research to regulatory acceptance.
Institutional Transition
Operational transition –use new types of data and models for
toxicity testing and risk assessment
Organizational transition –implement new toxicity testing paradigm
hiring and training of scientists with needed scientific expertise
Outreach – educate stakeholders and improve risk communication.
EPA 100/K-09/001 March 2009
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“One of the greatest pains to human nature is the pain of a new idea.”
Walter Bagehot (1826–1877), British economist.
“To innovate is not to reform”
Edmund Burke (1729–1797), Irish philosopher, statesman.
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