Transcript Barone - Society of Toxicology

Human Health Risk Assessment:
EPA’s Current Challenges and the Future
Presentation for the
National Capital Area Chapter - Society of Toxicology
“Challenges and Opportunities in Putting High-Throughput Chemical Risk
Characterization Into Real-World Practice”
April 19, 2011
Washington, DC
Stan Barone Jr., PhD.,
National Center for Environmental Assessment
Office of Research and Development
United States Environmental Protection Agency
Human Health Risk Assessment
• Now and in the future, risk assessment remains
fundamental to U.S. EPA’s approach to analysis of
potential risk from exposure to environmental
contaminants
• Essential for U.S. EPA regulatory decision-making
• Evolving in the face of new understandings about
uncertainty, mode of action, metabolism,
susceptibility, etc.
• Addressing emerging science and new science
challenges
Office of Research and Development
National Center for Environmental Assessment
11
Current Approach
Table 4-31. Noncancer effects in animals repeatedly exposed to chemical x by the
oral route
Exposure
(mg/kgday)
NOAEL
0, 0.05, 0.2,
1, 5,
or 20
90 days in
DW
0.2
1
5
5
5
1
5
20
20
20
Degenerative nerve changes
Degenerative nerve changes
Hindlimb foot splay
Decreased body weight
Atrophy of testes & skeletal
muscle
Johnson et al., 1986
F344 rat, M&F
0, 0.01, 0.1,
0.5,
or 2.0
2 years in
DW
0.5
2
0.5
0.5
2
2
ND
2
2
ND
Degenerative nerve changes
(L
Hindlimb foot splay
Decreased body weight Early
mortality after 24 weeks
Other nonneoplastic lesions
Friedman et al., 1995
F344 rat, M&F
0, 0.1, 0.5, or
2.0 (M)
0, 1.0, or 3.0
(F)
2 years in
DW
0.5(M)
1.0(F)
2.0(M)
3.0(F)
2.0(M)
3.0(F)
ND
ND
degenerative nerve changes (L
Decreased body weight (8–
9%)
Early mortality after 60 weeks
Other nonneoplastic lesions
Reference/species
Burek et al., 1980
F344 rat, M&F
LOAEL
(mg/kg-day)
• Large number of animals
• Low throughput
• Expensive
• Time consuming
• Pathology endpoints
• Dose response extrapolations over a wide range
• Application of uncertainty factors
Effect
• Little focus on mode of action and biology
• Few epidemiology studies
5
2
Basic Principles of
Risk Assessment at EPA
• The starting point for risk assessment is a critical analysis of
available scientific information.
• Quantitative estimates of risk are, to the extent possible,
– Biologically-motivated,
– Data-driven.
• When there is insufficient data, default methods are used that
– Protect public health,
– Ensure scientific validity (i.e., scientifically plausible and
extensively peer reviewed), and
– Create an orderly, transparent and predictable process.
• Implementation of these principles involves extensive
independent peer review.
Office of Research and Development
National Center for Environmental Assessment
3
Human Health Risk Assessment
Transforming to address emerging science
and new science challenges
• There are tens of thousands of chemicals that are untested and lack
assessment of potential for human toxicity.
• Current toxicology testing methods are too expensive, too slow, and can cope
with too few chemicals.
• Toxicology approaches are evolving away from reliance on in vivo testing of
laboratory animals
• Current approaches to risk analysis need to be significantly modified to deal
with more chemicals; innovative approaches
– Screening
– Fingerprinting
– Toxicity pathways
– Focused high-throughput assessments
• Risk assessment approaches must be developed that can use the new
generation of data types and arrays; “omics”
• Thus, the environmental health community needs to develop next generation
of risk assessment tools, approaches, and practices…NexGen risk
assessment
Office of Research and Development
National Center for Environmental Assessment
4
Human Health Assessment Issues
Mechanistic Considerations in
Human Health Risk Assessment
• Increased need to characterize:
– A wider array of hazard traits
– More chemicals (no data on most chemicals in commerce)
• Human carcinogens increasingly emphasis on:
– Multiple toxicity pathways, mechanisms affected
– These mechanisms could inform new predictive approaches
In
vitro assays
Human biomarkers
• Dose-response curve:
– In an individual: can take multiple forms depending on genetic
background, target tissue, internal dose
– In a population: variability in susceptibility in response are key
determinants
Source: Guyton et al. Improving prediction of chemical
carcinogenicity by considering multiple mechanisms
and applying toxicogenomic approaches. Mutat Res.
681(2-3):230-40, 2009.
Office of Research and Development
National Center for Environmental Assessment
5
Environmental
Chemical Stressor
Biological
Background
Susceptibility:
Exposure:
Health and Disease
Endogenous
Status, Genetics,
& Xenobiotic
Age, Gender
Adverse endpoint
An individual’s dose response
What Can Be Learned from
Mechanistic Data and Analyses?
• Identify mechanism-based sources of
•
•
Probability of
Effect from
Environmental
Exposure
Environmental Chemical Dose
Heterogeneity in Background
Exposure and Susceptibility
•
human variability/ susceptibility (e.g.,
background diseases and processes,
genetic polymorphisms, age, coexposures)
Address mechanism-based likelihood
of other outcomes
Improve prediction of interactions
across environmental and endogenous
exposures
Identify mechanistic drivers of
response at low-doses
Population dose response
Source: National Academy of Sciences Report
“Science and Decisions: Advancing
Risk Assessment” Adapted from
Figure 5-3a (December 2008)
Fraction of
Population
Responding to
Environmental
Chemical
Environmental Chemical Dose
21
6
Focus on Mechanisms of
Human Disease
• Increases appreciation of individual and population heterogeneity of disease
mechanisms
• Improves prediction of interactions across environmental exposures
• Addresses mechanism-based likelihood of other outcomes
• Identifies mechanism-based sources of human variability/susceptibility (e.g.,
background diseases and processes, genetic polymorphisms, age, coexposures)
• Uses Systems biology level tools and data
• Advances high throughput methodologies (microarray, proteomics)
• The use of mechanistic data will play a key role in the future of risk
assessment to:
– Aid in identification of sources of human variability/susceptibility (e.g., background
diseases and processes, co-exposures, etc) and early stage disease biomarkers.
– Address likelihood of other outcomes
– Improve prediction of interactions across environmental and endogenous exposures
– Indentify mechanistic drivers of response at low doses.
Office of Research and Development
National Center for Environmental Assessment
7
High-Throughput Screening Assays
(EPA’s National Center for Computational Toxicology,
Office of Research and Development)
batch testing of chemicals for pharmacological/toxicological endpoints
using automated liquid handling, detectors, and data acquisition
LTS
MTS
HTS
uHTS
Gene-expression
1000s/day
10s-100s/yr
10s-100s/day
10,000s100,000s/day
Human Relevance/
Cost/Complexity
Office of Research and Development
National Center for Environmental Assessment
Throughput/
Simplicity
8
Future of Toxicity Testing
in vitro testing
in silico analysis
Cancer
ReproTox
DevTox
NeuroTox
PulmonaryTox
ImmunoTox
$Thousands
HTS
-omics
Office of Research and Development
National Center for Environmental Assessment
Bioinformatics/
Machine Learning
9
Toxicity Pathways
Chemical
Receptors / Enzymes / etc.
Direct Molecular Interaction
Pathway Regulation /
Genomics
Cellular Processes
Tissue / Organ / Organism Tox Endpoint
Office of Research and Development
National Center for Environmental Assessment
10
ToxCast in vitro HTS assays
Cellular Assays
•
Assays
(n = 467)
Cell lines
–
–
–
•
Primary cells
–
–
–
–
–
–
•
Chemicals
(n = 320)
Cytotoxicity
Reporter gene
Gene expression
Biomarker production
High-content imaging for cellular phenotype
Biochemical Assays
Protein families
–
–
–
–
–
–
–
–
•
http://www.epa.gov/ncct/toxcast/
Primary rat hepatocytes
Primary human hepatocytes
Assay formats
–
–
–
–
–
•
Judson et al EHP (2010)
Human endothelial cells
Human monocytes
Human keratinocytes
Human fibroblasts
Human proximal tubule kidney cells
Human small airway epithelial cells
Biotransformation competent cells
–
–
•
HepG2 human hepatoblastoma
A549 human lung carcinoma
HEK 293 human embryonic kidney
GPCR
NR
Kinase
Phosphatase
Protease
Other enzyme
Ion channel
Transporter
Assay formats
–
–
–
Radioligand binding
Enzyme activity
Co-activator recruitment
11
Signature Derivation for Rat Liver Carcinogens
12
Virtual Tissues, Organs and Systems:
Linking Exposure, Dosimetry and Response
Molecular
interactions
& fluxes
Intra/intercellular
signaling/
fluxes
Cell spatial
interactions
Lobular /
vascular
damage
Molecular
Network
Structure &
Dynamics
Cell Fate
Transitions
death
/division
Tissue
Morphology
changes
Liver
Injury
Office of Research and Development
National Center for Environmental Assessment
13
Challenges and Opportunities
Extrapolation from in vitro to in vivo
Recapitulation and modeling of complex cell-cell and
tissue interactions.
Development of virtual models to describe systems
biology
Recapitulation of complex behaviors
Office of Research and Development
National Center for Environmental Assessment
14
This strategy focuses on development of:
• A pilot implementation of a new approach for risk based decision-
making, including characterization of risk management needs,
policy relevant questions and implications for NexGen risk
assessments;
• An operational scale knowledge mining, creation and management
system to support risk assessment work and interface with gene
environment data bases.
• Develop approaches using HT/HC data for toxicity pathways to
predict/estimate points of departure for assessment purposes.
• Prototype examples of increasingly complex assessments
responsive to the risk context and refined through discussions with
scientists, risk managers, and stakeholders.
Office of Research and Development
National Center for Environmental Assessment
15
NexGen Types of Data
Tier 1
10,000s of chemicals
High
Throughput
Molecular Mechanisms
of Action
• In vitro only bioassay
batteries (~73-500
assays)
Network/disease
pattern recognition
Metabolism or
surrogates
QSAR
• Anchored to in vivo data
• Bioinformatic data
integration
Tier 2
1000s of chemicals
+High Content/Med
Throughput
Adds Tissue/Organism
Level Integration
• Short-term in vivo
exposures with in vitro
assays
Mammalian species
Alternative species
• Primary tissue culture
• In silico virtual tissues
• In vivo or anchored to in
vivo data
• Bioinformatic data &
knowledge integration
Tier 3
100s of chemicals
+High Content, Med/Low
Throughput
Adds Most Realistic
Scenarios
• Molecular epidemiology
& clinical Studies
• Molecular biology +
traditional animal
bioassay
• Environmental exposures
• Upstream & phenotypic
outcomes
• Mechanism of action for
multiple stressors
• Knowledge integration
Increasing Weight of Evidence
Screening/Ranking
Limited decision-making
Regulatory decision-making
Decision Framework for Incorporating High Throughput Data
Are there existing assessments
(hazard id & dose response), based
on in vivo data, that can be utilized?
Identify the
chemicals of
interest, exposure
sources and
pathways.
Conduct literature search to
determine if new data will
significantly alter existing
assessment; update if needed.
YES
NO
Are there in vivo data to
inform qualitative hazard?
YES
Use (Q)SAR and readacross to predict
estimates of risk based
on surrogate(s)
NO
Are there non-in vivo data
to inform qualitative hazard?
Overall WOE for hazard
NO
YES
What tissues/cell types/toxicity
pathways are affected by the
chemical in question?
Assemble WOE by:
• Proximity to in vivo condition:
tissue explants>cells in culture >
cell-free assays>in silico
• Traditional WOE criteria e.g.
multiple studies/laboratories,
multiple dose-response.
Is data sufficient to determine
relative potencies or dose-response?
NO
Assess dose-response:
• Conduct high throughput
testing with a battery of
assays
• Conduct alternative species
&/or targeted in vivo testing
(optional)
YES
how
how
and/or
Conduct high
throughput
testing with a
battery of
assays,
alternative
species
Use existing
assessments
to anchor in
vitro /in
silico
analyses, if
appropriate.
• ToxCast/ToxPi and
reverse dosimetry
• Predictive Phenotyping
• Traditional DR modeling
(w optional test data)
Relative potencies
and/or dose-response
• ToxCast/ToxPi and
reverse dosimetry
• Predictive Phenotyping
• Traditional DR modeling
(w optional test data)
Goals
1. Rank/ group chemicals
2. Assessment of high
priority chemicals
Incorporating CSS/Next Generation of Risk Assessment (3-5 yrs)
Three Assessment Tiers—
Informed by Molecular & System Biology - Responsive to Risk Context
Superfund tech center
& PPRTV’s
PPRTV’s & IRIS
IRIS, ISA’s & MultiPollutant Assessments
Tier 1 Assessments
• Screening &
prioritization
• Unknown hazard
but exposures
• Thousands of
chemicals
• High-throughput &
QSAR-driven
• Minimize false
negatives
Tier 2 Assessments
• Narrow scope decisionmaking
• Limited hazard &/or
exposures
• Many chemicals
(hundreds of chemicals)
• High-and medium
throughput assays & some
systems level integration
• Science-based defaults &
upper confidence limit risk
estimates
Tier 3 Assessments
• Broad scope, major
regulatory decisionmaking
• Highest national
hazard & exposures
• Few chemicals
(dozens)
• All feasible, policyrelevant emerging &
traditional data
• Best estimates of risk &
uncertainty analyses
Flagged
for
Additional
Analysis
Research by NCCT,
ORD labs, & partners
Testing
NTP, REACH, TSCA,
etc.
Predictiv
e
Systems
Models
Input to Decision-making
Testing, Research, Assessment Loop
Decision-making
15
The Path to 21st Century Toxicology
70
Toxicity Pathways in
Prioritization
60
50
Screening/Prioritization
40
Toxicity Pathways in Risk
Assessment
Institutional Transition
30
20
10
0
2010
2015
2020
2025
Toxicity Pathways in
Risk Assessment
Institutional Transition
Office of Research and Development
National Center for Environmental Assessment
19
The Future of Risk Assessment
Summary
• The landscape of risk assessment is changing to an extent that
•
•
•
•
•
significant modernization of risk assessment is necessary.
These changes are driven largely by advances in understanding the
gene environment; the important input and advice from expert
science panels; and volumes of new test data from Europe.
These events prompt us to look anew at risk assessment and
develop this strategy to thoughtfully position environmental health
scientists and assessors for the future and contribute to meaningful
change within the larger risk assessment/risk management
community.
The goal of this strategy is to map a course forward, focusing on
creating 1st approximation NexGen risk assessments, learning from
these efforts and, then, refining the next versions based on this new
knowledge.
It may take a decade before risk assessment can rely primarily on
new advances in science
It is necessary, however, to begin now to address needed changes.
24
Thank you
Figure by Jane Ades, Courtesy National Human Genome Research Institute