vvEPA
United States
Environmental Protection
Agency
Role of Semantics, Ontologies, and Adverse Outcome Pathways as a Point of Integration in Chemical Assessments
Michelle Angrish1, George Woodall1, Sean Watford2-3'4'5, and Paul Whaley6
1NCEA, US EPA, RTP, Durham. NC, 27711,2NCCT, US EPA, RTP, Durham, NC, 27711,3ORAU, Oak Ridge, TN, 37830 , "Environmental Science and Engineering, GSGPH UNC-Chapel Hill, Chapel Hill, NC, 27599, Currently Booz
Allen Hamilton, Washington D C., 6Evidence Based Toxicology Collaboration, JHUBSPH, MD and Lancaster Environment Centre, Lancaster, UK.
Abstract
The quality and utility of literature based chemical assessments has been improved by leveraging
the power of systematic review (SR) and systematic mapping (SM, also referred to as evidence
mapping) approaches to aggregating and evaluating evidence of health risks posed by exposure
to environmental chemicals. Taking maximal advantage of SRs and SMs is currently impeded by
linguistic inconsistencies resulting from different communities using different vocabularies to
describe common study characteristics, requiring the systematic reviewer to anticipate all the
concepts, relationships, and words related to a science question when developing a search string
sensitive enough to locate all potentially relevant studies. The state-of-the-art approach, to use
dictionaries and thesauruses are useful for ensuring all semantically related terms are included in
a search, but they do not offer the context necessary to capture relationships between concepts,
e.g. according to biological organization such as gene expression. We are therefore exploring the
use of ontologies and semantic mapping as a part of evidence integration in literature based
chemical assessments. An ontology is a controlled vocabulary of precisely-defined terms and the
specified relationships between them, interpretable by both humans and machines. Here we give
an example of how literature prioritized for thyroid and neurological health outcome data
extracted from human and animal literature studies can be matched to ontology concepts that
serve as a point of integration in a semantic framework bounded by a structured Adverse
Outcome Pathway (AOP) framework. When implemented, this ontological approach may solve
the problem of a researcher needing perfect a priori knowledge of all relevant terms and
relationships in order to query a database for comprehensive information about mechanisms of
thyroid toxicity: this information is already provided in the database ontology.
Background
Systematic Review (SR, Figure I ~) is a formal
method used in literature based assessments meant
to insure rigor and transparency.
Systematic Mapping (SM, also referred to as
evidence mapping) is a technique borrowing from
SR principles and can be applied during the
scoping, planning and problem formulation phase
of a chemical assessment to summarize the
characteristics of the evidence base. In chemical
assessments, these characteristics are usually broad
data categories such as evidence type, chemical,
type of animal model or human population,
outcome, etc. which are important to know before
making decisions on how to approach the
assessment, staffing needs, and to identify key data
gaps.
Semantics is the study of linguistics, their meaning, relationship, and structure.
Ontologies are "A kind of controlled vocabulary of well-defined terms with specified
relationships between those terms, capable of interpretation by both humans and computers"
(whetzel et. Al, 2011).
Adverse Outcome Pathways (AOPs, Figure 2 below) are meant to describe how perturbation
of a biological system leads to a particular adverse health outcome using components called
molecular initiating events (MIEs, green bar below), Key Events (KEs, yellow and orange bars
below), Key Event Relationships (KERs, arrows below), and Adverse Outcomes (AOs, red bar
below) that are supported by scientific information.
Increasing biological organization
Exposure
to
chemical
X
I
Michelle Angrish I angrish.michelle@epa.gov I 919-541-5381
Approach: Evidence Mapping and literature-based information integration into an Adverse Outcome Pathway
Bound the literature search by
well characterized molecular
targets in the thyroid pathway
linked to adverse outcomes.
>=>
Problem
Formulation,
Scoping & Planning
r\
•rate
Iterate
'
Broad Literature
Search
Aim to find all potentially
relevant citations
<=>
Title and Abstract screen results
for potentially relevant studies
and tag for evidence stream and
health outcome.
"=>
Title/Abstract Screen
Irrelevant studies are excluded based on PECO Statement
(Population, Exposure, Comparator and Outcomes)

111!!
i "i
Bound literature search by:
•	NA+/I" (Sodium/Iodide) Symporter
(NIS)
•	Neurological Health Outcomes
Tag for evidence stream:
•	Animal
•	Human
•	In vitro
Tag for health outcome
•	Hepatic
•	Cardiovascular
•	Neurological
•	Etc.
Subset studies tagged for
Neurological health outcomes,
screen for relevant studies, and
tag for.

Full Text Screen
Exclude irrelevant studies
(Population, Exposure, Comparator and Outcomes)

1 ฎ i
Create an evidence inventory from
well characterized studies that
includes information on well
characterized thyroid pathway
components.

Evidence Inventory
ฆ4
i
I
Subset studies tagged for Neurological
health outcomes, full text screen for
relevance and tag for lA'/l"
(Sodium/Iodide) Symporter (NIS).
Inventory reported evidence
Evidence Inventory
z
T
Annotate evidence inventory with ontologies amenable to AOP framework
J
Level of biological
organization
Molecular
Cellular
Tissue
Organ
Individual
Population
Ontology semantic mappings
National Cancer Institute (NCI): thyroxine (T4)
+drug, food, chemical or biomedical material
++physiology/regulatory factor
+++hormone
++++thyroid hormone
+++++thyroxine
synonym: thyroxin
Protein Ontology (PO): Sodium Iodide Symporter (NIS)
+molecular entity
+++organic amino entity
++++amino acid chain
+++++protein
++++++sodium/iodide cotransporter
synonym: NIS



Kev Event
- Level of biological organization
Process

ComDonent(s)
ซซ Process
PO
e.g. Sodium Iodide Symporter
(NIS) mRNA

> Object
/y Context

* * ' / x
Key Event
NCI
Decreased thyroxine (T4)
-D
Feed annotated
information into AOP
AOP
U.S. Environmental Protection Agency
Office of Research and Development
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The views expressed are those of the authors and do not necessarily reflect the views or policies of the U.S. Environmental Protection Agency.

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