The document discusses systematic review workflows and methodologies utilized by the U.S. EPA to evaluate biological information and assess chemical toxicity. It outlines processes for literature review, data tagging, and the integration of expert knowledge, as well as how these methods enhance understanding of biological mechanisms. Additionally, the assessment includes findings from studies investigating the developmental toxicity of perfluorohexane sulfonate (PFHxS) in conjunction with various endocrine-disrupting chemicals.

1. Chemical Assessment Division
U.S. EPA
Systematic Review Workflows and Semantic Solutions
for Integrating Biological Information
8/9/2020 EBTC pre-GRADE 2020 1
The views expressed here are mine alone and do not necessarily reflect the views or policies of the U.S.
Environmental Protection Agency. Mention of trade names or commercial products does not constitute
endorsement or recommendation for use.

2. How do I consistently describe biological information? Systematic review methods can be applied to
transparently and objectively answer questions from the available literature while also consistently
documenting those decisions computationally allowing smarter use of expert time.
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A question is
asked and the
literature are
reviewed.
During review references are
tagged for:
• Evidence stream
• Study design
• Exposure
• Species
• Health Outcome
• Supplemental Information
Each of these tags are domains
containing deeper metadata.
Prioritization NormalizationExploration
Entities, Groups,
Relations, and
Ontology mapping
The extracted terms are normalized
using controlled vocabularies and
ontologies.
• Terms are preprocessed
• Match terms to ontologies
• Expert review of mapped terms
• Store terms in structured
formats that can be easily
imported and exported.
• Term tags for provenance
documented at each step
SMEs inventory
literature
• During literature inventory
domain metadata are extracted
into structured formats using
systematic review tools.
• The supplemental information
tag includes the mechanistic
domain. References containing
mechanistic data are
summarized using sub-tags (i.e.
for MOA) within this domain.

3. How do
systematic
review
methods and
tools support
biological
understanding?
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Explain the concept of systematic review methods
and workflows
Information retrieval, screening, documentation, and
summary
Data accessibility, extraction, and visualization
Semantic solutions for biological plausibility
frameworks
Automation and AI

4. 8/9/2020 EBTC pre-GRADE 2020 5
Systematic Review Methods in a Literature Based Assessment
How can they help? I want to know about mechanism.
Biological mechanism can be
documented transparently using
systematic review tools by domain
experts:
• Develop search terms and
screening criteria;
• Search and review literature for
information relevant to a
knowledge domain;
• Tag domain relevant references
for subtopics.
• Extract data and select
appropriate terminology and
measurement methods
SMEs crowd
source systematic
review
• Literature search
• Manual review or assisted with
machine learning algorithm
• Title/Abstract
• Full text
• Data Extraction

5. 8/9/2020 EBTC pre-GRADE 2020 6
Literature search, screen, and tag
Screening decisions
can be tracked
transparently and
objectively while
also documenting
those decisions
computationally
allowing smarter
use of expert time.

6. Structured formats for summarizing literature
Extract summary level information
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Study design and exposureSpecies
Exposure
Health outcomes

7. • Health Assessment Workplace
Collaborative
• Digital assessment tool
• Key modules for:
• Literature screening documentation
• Risk of bias/study evaluation
• Animal bioassay data extraction
• Epidemiology data extraction
• Interactive summary visualizations
• Coming soon
• In vitro data extraction
Structured formats for empirical data
EBTC pre-GRADE 2020 88/9/2020

8. Evidence Maps for Domain Exploration
An example
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Drill down
Topic clusters
Domain

9. Evidence Maps for Domain Exploration
Drill down for hypothesized cancer MOA
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SMEs inventory
pertinent
observations
• Genotoxic
• Alters DNA repair or causes
genomic instability
• Cell proliferation, cell death,
cell nutrition
• Oxidative stress
• Receptor-mediated effects
• Immunomodulation/immunosu
ppression
• Epigenetic alterations
• Immortalization
• Induces chronic inflammation
• uncertain
Possible key
events are
identified
The experimental details are
extracted and tagged to each
possible key event.
• Define each possible key event
• Measurement methods for key
events are clearly defined
• The ‘site’ or biological
organization for each key event
is clearly defined.
• The sequence of key events is
clearly defined.
Analytic construct is deployed for
evaluating support for
hypothesized mode of carcinogenic
action.
• Consistency
• Strength
• Specificity
• Dose-response concordance
• Temporality
• Biological plausibility
• Coherence
• Analogy
Evaluate
experimental
support for
hypothesized
MOA

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Mapping Evidence to an Adverse Outcome Pathway Ontology Model
Adapted from Ives, et al. December 2017
AOP Categories
addressed in SR
AOP Categories addressed
in Ontology Mapping

11. AOP
Categories
Human Reviewers
Context

12. Health Term Review
Term Mapping
The developmental toxicity of perfluorohexane sulfonate (PFHxS) is largely unknown despite widespread environmental contamination and presence in human serum,
tissues and milk.To thoroughly investigate PFHxS toxicity in developing rats and to mimic a realistic human exposure situation, we examined a low dose close to human
relevant PFHxS exposure, and combined the dose-response studies of PFHxS with a fixed dose of twelve environmentally relevant endocrine disrupting chemicals
(EDmix).Two reproductive toxicity studies in time-mated Wistar rats exposed throughout gestation and lactation were performed. Study 1 included control, two doses
of PFHxS and two doses of PFHxS+EDmix (n = 5-7). Study 2 included control, 0.05, 5 or 25 mg/kg body weight/day PFHxS, EDmix-only, 0.05, 5 or 25 mg PFHxS/kg plus
EDmix (n = 13-20).PFHxS caused no overt toxicity in dams and offspring but decreased male pup birth weight and slightly increased liver weights at high doses and in
combination with the EDmix. A marked effect on T4 levels was seen in both dams and offspring, with significant reductions from 5 mg/kg/day. The EDmix caused anti-
androgenic effects in male offspring, manifested as slight decreases in anogenital distance, increased nipple retention and reductions of the weight of epididymides,
ventral prostrate and vesicular seminalis.PFHxS can induce developmental toxicity and in addition results of the co-exposure studies indicated that PFHxS and the
EDmix potentiate the effect of each other on various endpoints, despite their different modes of action. Hence, risk assessment may underestimate toxicity when
mixture toxicity and background exposures are not taken into account.
Extract terms
from text
UMLS
Mapping
AOP
Categories
SR Reviewer
selects terms
Store selected terms and
reviewer concordance
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13. • Katia Tsaioun
• Sebastian Hoffman
• Paul Whaley
• Rob de Vries
EBTC Zebrafish Working Group
Key Personnel and Acknowledgements
• Meisha Mandal
• Virginia “Ginnie” Hench
• Steve Edwards
ORD
• Andy Shapiro
• Michele Taylor
• Kris Thayer
• George Woodall
Program Offices
• Kristan Markey
• Kellie Fay
EBTC pre-GRADE 2020 14
• Tom Filer
• Samuel Kovach
• Kristen Magnuson
• Jessica Wignall
• Arun Vargese
8/9/2020
• Daniele Wykoff