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US EPA CSS-HERA
Board of
Scientific
Counselors
Chemical Safety
Subcommittee
Meeting
US EPA CSS-HERA BOSC Meeting - February 2-5, 2021
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The work presented within represents US EPA Office of Research and Development research
activities. Material includes both peer reviewed, published results and work-in-progress
research. Please do not cite or quote slides.
-------
Table of Contents
CSS NAMs Research and Development Portfolio (Jeff Frithsen) 3
HERA Advancing the Science and Practice of Risk Assessment (Samantha Jones) 15
Moving from the StRAPs to Implementation by ORD Investigators (Jill Franzosa) 26
Evolution of NAMs in EPA: From Research to Application (Rusty Thomas) 37
The work presented within represents US EPA Office of Research and Development research activities. Material
includes both peer reviewed, published results and work-in-progress research. Please do not cite or quote slides.
-------
e
Research and
Development
Chemical Safety for Sustainability (CSS)
National Research Program
Board of Scientific Counselors (BOSC)
Chemical Safety Subcommittee
Implementation Meeting
Jeffrey Frithsen National Program Director (NPD)
JoeTietge, Principal Associate NPD
Kathie Dionisio,Associate NPD
Heidi Bethel,Associate NPD
February 2,2021
-------
oEPA E=S= ^ Focus of this BOSC Meeting
CSS Focus:
Presentation of selected research demonstrating examples of
the development, testing and implementation of New Approach
Methods (NAMs);
Demonstration of selected tools.
HERA Focus:
Presentation of research related to applying NAMs in HERA
assessments;
Systematic review tools and approaches;
Dose-response analyses and models.
NAMs: Any technology, methodology, approach or combination
thereof that can be used to provide information on chemical hazard
and risk that avoids the use of intact animals.
2
-------
rnA Research and CSS Research Portfolio and NAMs S
#% Development \\ NgFi J
\ \ \ LL
Topic
Research Areas
Outputs
Products
Presentations
High-Throughput Toxicology (HTT)
8
36
Sessions 1A; 1C;
ID; 2
Chemical Evaluation
Rapid Exposure Modeling and Dosimetry
(REMD)
8
50
Session IB; 2; 3
Emerging Materials and Technologies
(EMT)
2
13
Adverse Outcome Pathways (AOP)
8
42
Session 2
Complex Systems
Virtual Tissue Modeling (VTM)
3
16
Session ID
Science
Ecotoxicological Assessment and Modeling
(ETAM)
10
34
Session 1C
Solutions-Based
Translation and
Knowledge Delivery
Chemical Safety Analytics (CSA)
4
24
Session 3
Informatics, Synthesis, and Integration
(ISI)
5
29
Sessions 2; 3
CSS Research Areas that support work on NAMs.
3
-------
x>EPA
Meeting Date
Primary
Topic
HTT
REMD
EMT
AOP
VTM
ETAM
CSA
ISI
February 2021
IMAMS
XXX
XXX
XX
X
X
X
X
Summer 2021
PFAS
XXX
XXX
XXX
XXX
X
X
Fall 2021
Complex
Systems
XXX
XXX
XXX
X
Knowledge
Delivery
X
X
X
XX
XXX
BOSC Review of Other Parts
Research and
Development
4
-------
oEPA
Research and
Development
Planning
National Programs Lead
Strategic Focus
Resources allocated at
Research Area level
StRAP to Implementation to Delivery
RACTs
Implementation
Research Area
Implementation Plans
Center Lead
Tactical focus
Resources allocated for
specific products
Delivery
sot aai
Sequence Alignment to Predict Across Species
Susceptibility (SeqAPASS): A Web-Based Tool
Addressing the Challenges of Cross-Species
Extrapolation of Chemical Toxicity
Includes data, models,
methods, EPA and journal
publications
Joint activity of National
Programs and Centers
Chemical Safety
for Sustinablility
STRATEGIC RESEARCH ACTION PLAN
2019-2022
-------
oEPA
Research and
Development
Why NAMs?
Strong focus of the CSS Program for over a decade.
Critical component of the CSS Program's long-term vision:
Provide the information needed to inform Agency decisions
about chemicals;
Accelerate the pace of chemical assessment and decision-
making;
Replace, Reduce and Refine vertebrate animal testing;
Provide scientific innovation and leadership to transform
chemical screening and assessment.
Supports Agency objectives, regulatory drivers, and the
needs of multiple partners and stakeholders.
T- ^
1
r i
4
Establish
scientific
confidence and
demonstrate
application
k-
Develop NAMs
that fill critical
information
gaps
L. .U
New Approach
Methods Work Plan
Reducing we of animate In chemical testing
U5 Envuoanei«Ut Yrotsction Agency
Otbcv ot Rnw h anil EVvelopmnit
Otlicv ttf ClMB» alSli'
-------
Research and
Development
New or
Existing NAM
Identify,
Develop, &
Integrate
TSCA Strategic Plan for NAMs
Training and
Education
Implement
l!\S
Integrate
NAM
Additional
Data or Case
Studies to
Address
Uncertainties
Fit-for-Purpose: Developing and Using NAMs for TSCA Decisions
ib
with
Stakeholders
(Public,
Private and
Government)
Meet TSCA
Section 4(h) to
Reduce, Refine,
or Replace
Vertebrate
Animal Testing
-------
oEPA
Research and
Development
CSS Partners for NAMs
External to ORD Partners
Internal to ORD Partners \
-------
oEPA V CSS Session I
* Presentations focus on examples of the development of
NAMs to address specific research needs and topics.
* Presentations align with CSS Charge Question I:
Please provide specific sugg
improve approaches to adv
of NAMs conducted under
* Four concurrent sessions, each having three focused
presentations by ORD scientists.
-------
SERA V CSS Session 2
* Highlights research aimed at facilitating the application of
NAMs in decision-making.
* Presentations align with CSS Charge Question 2:
Please comment on the ex
research activities have the appropriate approach, structure,
and components to increase
use of NAMs in Agency de
* Four presentations will be made.
-------
rOA Research and
V/uM Development
* Provides demonstrations of three selected CSS tools.
* Tools utilize the results of NAM research. However, these
tools have a broader focus.
* Presentations align with CSS Charge Question 3:
Please provide suggestions
how these CSS products can be improved and best
implemented to serve EPA
stakeholders?
CSS Session 3
-------
*>EPA
Research and
Development
Final Comments:
* Presentations contain peer^reviewed published results,
works in press, and results from works in progress.
* ORD investigators welcome this opportunity to engage with
the BOSC and talk about our science.
* Have fun!
-------
Health and Environmental Risk Assessment (HERA)
National Research Program
Board of Scientific Counselors (BOSC)
CSS-HERA Subcommittee Implementation Meeting
Samantha Jones, National Program Director (NPD)
Beth Owens, Principal Associate NPD
February 2,2021
-------
Research and
Development
Implementation of HERA
Research - Advancing the Science
and Practice of Risk Assessment
-------
oEPA
Research and
Development
ORD Implementation of Planned Research
Measure pollutant(s) in
the environment
(air, water,
land)
CEMM
Center for
Environmental
Measurement and
Modeling
Generate data/models
inform pollutant(s)
assessment
Center for
Environmental
Solutions &
Emergency Response
CESER
Center for Public
Health &
Environmental
Assessment
Develop
treatment
technologies to
remove pollutant(s)
CPHEA
J
Assess health
and ecological
effects of pollutant(s)
exposure
Organizational structure is designed to enhance
our scientific leadership, better integrate scientific
approaches to problems, support mission and
partner focused solutions, create communities of
practice, and align the size and structure to
optimize the use of our workforce.
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k Assess mem
¦^t^SCTS.
3
-------
rOA Research and
V/uM Development
Addressing Agency Priorities and Mandates
Clea
FAWT^FAl
rivii
H
E
R
A
Toxic Substances C
omprehensive Environmental Response, Compensation, and Liability
Act (CERCLA
ents a
niw
Federal Insecticide, Fungicide, and Rodenticide Act (FIFRA)
Broad Input to Support
Agency and ORD Strategic Goals
Children's Health
Environmental Justice
-------
rOA Research and
V/uM Development
HERA Vision and Structure
To innovate and advance the
science and practice of
assessments
By developing a portfolio of fit-for-purpose
human health and environmental assessment
products and assessment research that meet
the needs and priorities of EPA programs and
regions, states, tribes, and external
stakeholders.
Topic
Research Area
Science
Assessments &
Translation
1. Science Assessment Development
2. Science Assessment Translation
Advancing the
Science and
Practice of Risk
Assessment
3. Emerging and Innovative Assessment
Methodologies
4. Essential Assessment and Infrastructure
Tools
5
-------
oEPA
Research and
Development
Delivering Assessment Products and Scientific
Advancements Research
Assessment products such as:
Integrated Science Assessments (ISAs) for the health criteria for particulate
matter and ozone, and the ecological criteria for oxides of nitrogen, oxides of
sulfur, and particulate matter.
Integrated Risk Information System (IRIS) assessment materials for inorganic
mercury salts, methylmercury, and 5 PFAS.
Provisional Peer-Reviewed Toxicity value (PPRTV) assessments for 2-ethylhexanol,
2-nitropropane, p-a,a,a-tetrachlorotoluene.
Models, databases, and software products such as:
Advancements to Health and Environmental Research Online (HERO) and
Health Assessment Workplace Collaborative (HAWC) databases.
Benchmark dose software (BMDS) and All Ages Lead model (AALM).
Integrated Science Assessment
for Oxides of Nitrogen. Oxides
of Sulfur and Particulate Matter-
Ecological Criteria
HAW#
HEALTH ASSESSMENT
WORKSPACE COLLABORATIVE
Dose (mg/kg-day HEP)
-------
rOA Research and
Development
Delivering Assessment Products and Scientific
Advancements Research
Arzuaga, X. et al. (2019). Use of the Adverse Outcome Pathway (AOP) framework to evaluate species
concordance and human relevance of Dibutyl Phthalate (DBP)-induced male reproductive toxicity.
Reproductive Toxicology.
Alman, B. et al. (2019). Associations between PM2.5 and risk of preterm birth among liveborn infants.Annals of
Epidemiology.
Kirrane, E. et al. (2019). A Systematic Review of Cardiovascular Responses Associated with Ambient Black
Carbon and Fine Particulate Matter. Environment International.
Radke-Farabaugh, E. et al. (2019). Development of outcome-specific criteria for study evaluation in systematic
reviews of epidemiology studies, Environment International.
Lizarraga, L.,J. Dean, J. Kaiser, S.WesselkamperJ. Lambert, and J. Zhao. (2019). A Case Study on the Application of An
Expert-driven Read-Across Approach in Support of Quantitative Risk Assessment of p,p'-
Dichlorodiphenyldichloroethane. Regulatory Toxicology and Pharmacology.
Reyes, J., and P. Price. (2018). Temporal Trends in Exposures to Six Phthalates from Biomonitoring Data
Implications for Cumulative Risk. Environmental Science & Technology.
7
-------
oEPA
Research and
Development
Topic 2 - Advancing the Science and Practice of Risk
Assessment
Participant selection -
\sure measurement
\e ascertainment
Confounding -
Analysis
Snsitivity
NormaW *ss'
lUmP«°n
V V.
0ose level
Advancing the Science and Practice of Risk Assessment
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8
-------
Implementation of Research under HERA RAs 3 and 4
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Emerging and Innovative Assessment Methodologies
Focus on evaluating and optimizing the integration of
existing, new, and emerging data streams, techniques,
models, tools, or other methodologies for practical
implementation in assessing human and environmental
health.
Essential Assessment and Infrastructure Tools
Delivering state-of-the-science assessment products
requires the use of software and database tools to
provide the necessary infrastructure.
Enables the maintenance and development of new or
existing tools and databases used in the assessment
process and provides training on these resources and
applications.
9
Anchored in assessment development.
Improve the accuracy, efficiency, flexibility, and
utility of applications across the large landscape of
assessment activities served by the HERA
program.
-------
Research under Review
Advance, translate, and build confidence in the application of new approach methods (NAMs) and
data: As NAMs' science advances, risk assessors still encounter many chemicals with little-to-no
data that require assessment. Research is required to translate and build confidence in the application
of these NAMs in HERA science assessment contexts.
Advance methods for systematic review: Incorporating the principles of systematic review into the HERA
portfolio of assessment products has been a goal of the HERA program for the last several years. In order to
achieve this goal, the HERA program intends to advance the field of systematic review more broadly.
Advance methods in dose-response modeling and tools: Dose-response modeling is a critical step in
human health assessment. Existing methods have improved upon older methodologies; however, unresolved
issues, uncertainties, and complications remain that require targeted research. HERA has planned research
products that will result in dose-response methods that are more precise, robust, and meet varied needs.
-------
THANKYOU!
https://www.epa.gov/research/health-and-environmental-risk-
assessment-strategic-research-action-plan-2019-2022
-------
*»EPA
United States
Environmental Protection
Agency
Moving from the StRAPs to
Implementation byORD Investigators
Jill Franzosa, PhD
Office of Research and Development
Center for Computational Toxicology and Exposure
Disclaimer: The views expressed in this presentation are those of the author
and do not necessarily reflect the views or policies of the US EPA.
February 2, £021
-------
A EPA
United States
Environmental Protection
2019 - 2022 Strategic Research Action Plans
StRAPs finalized and published on EPA
internet
Focused on defining national program
structure and identifying specific outputs
to meet the needs of partners
Informed design and planning of research
activities to fulfill the outputs
Chemical Safety
for Sustinablility
STRATEGIC RESEARCH ACTION PLAN
2019-2022
Health and Environmental
Risk Assessment
STRATEGIC RESEARCH ACTION PLAN
2019-2022
https://www.epa.gov/research/strategic-research-action-plans-2019-2022
-------
oE
United States
Environmental Protection
Agency
StRAP Implementation
Output is a body of work that addresses partner needs through delivery of one or more products
Products can be peer-reviewed journal articles, models, databases, software, methods, reports or assessments
Agency Research Needs
StRAP
Implementation
Program, Region, or
State Need
Research Area
Program, Region, or State Need
Program, Region, or
State Need
T
Product
Product
Product
Product
Output
Product Product
NPD led
Center led
-------
SERA
United States
Environmental Protection
Agency
Research Area Coordination Team (RACT)
WMt-
Objective
Expand involvement of partners
Improve understanding what is needed
Ensure proposed products are what is
needed by partners
Who
Program Office representative(s)
Regional Representative(s)
State Representative
NPD Representative
ORD Scientists
Outcome
Products responsive to outputs
By-in from partners
Collaboration with partners
Purpose: Define the products that ORD will develop to meet the objectives of the outputs
-------
SERA
United States
Environmental Protection
Agency
The Process for RACTs
Meet weekly/biweekly basis
from April - September
Balanced product proposals
with ORDs capacity to ensure
partner needs met
Developed ideas for products
to meet the outputs
Delivered Research Area
Descriptions for products
-------
AEPA
United States
Environmental Protection | g ^ I m a
Delivery of Research Area Descriptions
Program/Regional/State Needs:
How this research will be applied to meet the needs of EPA programs/regions, states, tribes,
and/or other partners
Key statutes and/or regulatory issues that the research will support
Output:
Output Description:
What information is needed by the program, region, state, or tribal partner(s)
How the products build on each other to form the Output
Description of how the partner will use the Output
EPA Program/Regional or State/Tribal Partner(s)
Product:
Brief Description and Research Use:
Description of research and how it will be used by the partner to address their identified
regulatory, policy, and/or other need(s).
EPA Program/Regional or State/Tribal Partner(s)
-------
SERA
United States
Environmental Protection
Agency
RACT Output Leads and Product Leads
Output Leads
Nominated by Center management
Provide scientific leadership
Coordinate and communicate with Product Leads
Include representation from across ORD Centers
Product Leads
Develop research products and components to fulfill
objectives of the output
Lead and coordinate product research teams
Include representation from across ORD Centers
-------
oE
United States
Environmental Protection
Agency
CSS Example: Translating Partner Needs to Outputs
PARTNER NEED
RESEARCH
AREAS
OUTPUTS WITH DNT PRODUCTS
HTT
Develop, evaluate, apply, and interpret a
developmental neurotoxicity (DNT) battery of assays
to reduce uncertainties in chemical safety
evaluations
Developmental neurotoxicity (DNT): DNT is an
important risk assessment endpoint for chemical
assessments. However, currently available in vivo
methods are costly and do not fully represent
important mechanisms and pathways. Therefore,
there is a need for alternative approaches for
evaluating DNT, including valid in vitro methods and
modeling approaches. (OCSPP; OLEM; OCHP)
AOP
Develop and conduct strategic in vitro and in vivo
studies for high-priority AOPs to help establish
validity of NAMs approaches, support predictive
model development, and reduce vertebrate animal
testing through in vivo testing refinements for
decision-relevant endpoints
VTM
Integrate and evaluate phenotypic responses in
human cell based in vitro and virtual tissue model
systems to predict chemical hazard during growth
and development
*
O
*
VTM
Develop and apply in silico agent-based and
computational models to evaluate the effects of
chemicals on biological pathways critical for lifestage
endpoints
>V
= ~3^
U U"
*
JUL
-------
oE
United States
Environmental Protection
Agency
CSS Example: Developing products to fulfill the Output
OUTPUT
-------
AEPA
United States
Environmental Protection
What We Developed
Topic
Research Areas
Outputs
Products
High-Throughput Toxicology (HTT)
8
36
Chemical Evaluation
Rapid Exposure Modeling and Dosimetry
(REMD)
8
50
Emerging Materials and Technologies
(EMT)
2
13
Adverse Outcome Pathways (AOP)
8
42
Complex Systems
Virtual Tissue Modeling (VTM)
3
16
Science
Ecotoxicological Assessment and
Modeling (ETAM)
10
34
Solutions-Based
Translation and
Knowledge Delivery
Chemical Safety Analytics (CSA)
4
24
Informatics, Synthesis, and Integration
(ISI)
5
29
-------
Thank you!
Comments/Questions.
Hi $ iif . t iii/ ti'L j >i
Hlliinli -:U W
(il l II iu
-------
Evolution of NAMs in EPA: From
Research to Application
CSS HERA Board of Scientific Counselors Meeting
February 2, 2020
Rusty Thomas
Director
Center for Computational Toxicology and Exposure
The views expressed in this presentation are those of the presenter and do not necessarily reflect the
views or policies of the U.S. EPA
-------
svEPA EPA Faces Multiple Challenges in Evaluating the
United States
Environmental Protection I ¦ 1 w ¦ 4 a ¦% a a m a m a
Human and Environmental Risks of Chemicals
Number of Substances
Amount of Data
Reliability/Relevance
60,000
40,000
20,000
Canadian DSL EU REACH EU REACH Pre- USEPATSCA
Registered Registered Non-Confidential
USEPATSCA
Non-Confidential
Active
% of Non-Confidential, Active TSCA
Inventory with Repeat Dose
Toxicity Studies
Yes
26%
*Data from ToxValDB
(Dec 2019)
Time
Chemical Assessment
for
Chemical X
Regulatory Organization Y
January 2020
Center for Computational
Toxicology & Exposure
$10,000,000
$1,000,000
$100,000
o
$10,000
Economics
$1,000
..¦III
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^ ^ cf
cf ~4*
\0
Broad Range of Decision Contexts
Prioritization
Emergency
Response
Screening Level
Assessments
Provisional
Assessments
Exposure
Assessments
Risk
Assessments
Toxicity
Assessments
Endangered
Species
Protection
-------
oEPA
United States
Environmental Protection
Agency
1980
1979
NHERL-Duluth
releases first
QSAR for BCF
111
To Address These Challenges ORD has a History in
Research on New Approach Methods (NAMs)
2000
T
2003
Strategic Plan for
CompTox Research
Program
2010
T
2012
ORD StRAP I
2020
2008
Tox21 MOU
Signed
2016
ORD StRAP II
I
2018
TSCA Alternatives
Strategic Plan
2020
EPA NAM
Workplan
Released
2019
ORD StRAP
Center for Computational
Toxicology & Exposure
-------
oEPA
United States
Environmental Protection
Agency
What is a New Approach Method?
Coined in ~2014, but the definition of a
New Approach Method (NAM) has evolved
over time
Currently, it is broadly descriptive reference
to any non-animal technology,
methodology, approach, or combination
thereof that can be used to provide
information on chemical hazard and risk
assessment
Functionally equivalent to "alternatives", but
can include exposure NAMs, eco NAMs,
toxicokinetic NAMs, etc.
A Strategic Roadmap for Establishing
New Approaches to Evaluate the Safety
of Chemicals arid Medical Products
in the United States
frupraffirrui update GfcAFT
Center for Computational
Toxicology & Exposure
-------
oEPA Despite this History, NAM Development and
United States
Environmental Protection jk mm 4 m m a m m m m m a bb j ¦ % *
Application is Still in its Formative Years...
i
limk
t
We are here
Center for Computational
Toxicology & Exposure
-------
s>EPA
United States
Environmental Protection
Agency
Directing NAM Research Through Formative Years
Involves an Integrated Strategy
Long Term
Research
Strategies
Four Year
Research Plans
wEPA
Research
Products
SOT Sag.
The Next Generation Blueprint ot Computational
Toxicology at the U.S. Environmental Protection Agency
T
Chemical Safety
for Sustainability
STRATEGIC RESEARCH ACTION PLAN
2019-2022
f Health and Environmental
Risk Assessment
STRATEGIC RESEARCH ACTION PLAN
2019-2022
1
1
Center for Computational
Toxicology & Exposure
-------
s>EPA
United States
Environmental Protection
Agency
There is a Significant Overlap Between Elements of
the EPA NAM Research Strategies...
TSCA Alternatives Strategic Plan
Identify,
Develop, &
Integrate
H Evaluate H
Scientific
v ^
Reliability
and
/?¦ Relevance »
Pk A 1
DECISION
Ready for
Evaluation?
DECISION
Ready for
TSCA Decision
Context?
Training and
Education
Implement
Fit-for-Purpose: Developing and Using NAMs for TSCA Decisions
EPA CompTox Blueprint
Outreach &
Training
Meet TSCA
1
' c!
Section 4(h) to
Reduce, Refine,
&
and Replace
Vertebrate
-------
oEPA
United States
Environmental Protection
Agency
Highlights of the Research You Will Hearing About
Today
Establishing
Confidence
Outreach &
Training
Estimate toxicokinetic parameters for
hundreds of chemicals
Put in vitro testing concentrations in a dose
context
Broadly evaluate potential impacts of
chemicals across biological space and
species
Systematically address limitations in in vitro
test systems
Identify likely tissue, organ and organism
effects and susceptible populations
Throughput
r
Uncertainty
& Variability
Software &
Decision
Support Tools
Estimate chemical exposures with uncertainty
for thousands of chemicals
Put hazard in a risk context
Identify potential exposure pathways for
unknown chemicals
Establish consistency and confidence in non-
targeted methods
Center for Computational
Toxicology & Exposure
-------
s>EPA
United States
Environmental Protection
Agency
Highlights of the Research You Will Hearing About
Tomorrow and Thursday
Case studies and proof-of-concept
applications with State, Region, and Program
Partners
Incorporating metabolite similarity into read
across
Outreach &
Training
Establishing
Confidence
Throughput
r
Software &
Decision
Support Tools
Application of AOPs for evaluating mixtures
Uncertainty
& Variability
Data extraction and curation for model training
and evaluation
Data integration, data visualization, and
decision support tools
Center for Computational
Toxicology & Exposure
-------
<>EPA But, There are LOTS of Activities You Won't Hear
About This Time
United States
Environmental Protection
Agency
Center for Computational
Toxicology & Exposure
-------
s>EPA
United States
Environmental Protection
Agency
Working with Federal, State, and International
Collaborators to Develop, Evaluate, and Apply NAMs
APCRA Inter-Governmental
Consortium
Chemical
Research in
Toxicology
Accelerating the Pace of Chemical Risk Assessment
'Office ofReararch and Development,
:Haldiy Environment. and Coiumne;
*OI}iu!ufRe«anii amlDevdopment, U
nation Ural, European Chemical. Agttxy, 00
th Tnangle PaitNoMh Caobm 27711, United Slate.
APCRA
inimal le.Ung apptoaihe.. have lhown ptomttf to provide *e* at t "
arge amount dau lo HI infarmiilon gap. to bolh h.«ani % * "if
ind tTo»n, In onto lo <»« spenence with the ne« . .'35* . J* .1 .(V."
lata and lo advance the application. nf NANf data to evaluate * *
:be lafctt at data-poof cheinkaU demon* raUm kale .tudle.
laMStudki can be wed lo explore the domain. |