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Hristo Aladjov1, Amy Clippinger2 and Gilman Veith3 1Institute of Biophysics and Biomedical Engineering, Bulgarian Academy of Sciences, Sofia BG 2People for the Ethical Treatment of Animals, Norfolk VA USA 3International QSAR Foundation, Two Harbors MN USA

Abstract

The 21st-Century shift to more prospective hazard identification and

hypothesis generation requires greater strategic application of systems

biology, QSAR and archived toxicological data in the form of adverse

outcome pathways (AOPs). AOPs describe the causal linkages among

biological responses to chemicals over time. The complexity of integrating

science can be a barrier to progress in terms of the toxicity pathways and

networks involved as well as the need to organize knowledge from many

disciplines.

Effectopedia is an open-knowledge aggregation and collaboration tool for

delineating AOPs in an encyclopedic and predictive manner. It includes

discrete cause-effect studies and critical reviews that are relevant to

toxicology. To achieve human and machine interpretability, Effectopedia

uses an ontology-enhanced, natural language interface that offers

clarifying questions and special tags to define the semantic knowledge

while preserving the natural language description of the AOP’s elements.

The use of ontologies also allows Effectopedia contributors to publish

their contributions as nanopublications.

Effectopedia serves as a graphical editor to delineate causal linkages at

any level of biological organization and test species. It creates a common

organizational space that (1) helps experts identify gaps in knowledge of

causal linkages of biological responses and (2) acts as a web-based

conference room for dialogue and synthesis by experts with interest in

specific AOPs. Effectopedia’s live documents are instantly open for

focused discussions and feedback, whilst giving credit to original authors

and reviewers. New contributions are immediately distributed to interested

parties, keeping all information current and documented. Uncoupling the

contribution and review processes also permits organizations to define

their own seals of approval and associate them with special interest

pathways without slowing down the Wiki-inspired stream of contributions.

Effectopedia: collaborative assembling of quantitative adverse outcome pathways

Sourc

e

Envir

onm

enta

l

Conta

inm

ent

Exposure

Mole

cula

r

Initia

ting

Event

Org

anelle

and

Mol. A

ssem

blie

s

Effects

Cellu

lar

Effects

Tis

sue

Effects

Org

an

Effects

Org

an

Syste

ms

Effects

Indiv

idual

Effects

Popula

tion

Effects

Com

munity

Effects

Toxicity Pathway

Mode of Action

Adverse Outcome Pathway

Source to Outcome Pathway

Adverse Outcome Pathways

Cause

Link

Effect

LBO

Gender

molecular organelle

-

mix

ed

male

AOP as Diagram and Chart

• Pathway space defines the biological context in which effects can be explained/described by specialists.

• Pathway space is multidimensional and requires the knowledge of disciplines that do not normally collaborate

• Life stage

• Taxonomy

• Gender

• Time to effect

• Level of biological organization

• User defined

• Effect definitions are provided just once and shared across all pathways that include them.

• Shared effects become common nodes in the network of connected pathways stored in Effectopedia.

Pathway Space

• Quantitative linkages include

• Thresholds for effects

• Dose-Response relationships

• Response-Response relationships

• Qualitative linkages

• Provide explanation of plausible underlying molecular mechanisms

Metabolic

activation

Binding to the

receptor

Chemical interaction

Tested Chemical

Active Metabolite

Molecular Initiating

Events

Biological Effects

Adverse Outcome

Assessment Endpoint

Chemical Adverse

Outcome

MIE 1

MIE 2

MIE n

Effect 1

Effect 2

Effect m

Effect 1

Effect 2

Effect k1

Effect 1

Effect 2

Effect k2

Effect 1

Effect 2

Effect kn

…

What other downstream

effects?

Effect x

Downstream Effect 2

Downstream Effect 3

What other causes can lead to this

effect?

Effect x

Upstream Cause 1

Upstream Cause 2

Knowledge

Database

Social

Architecture

Architecture of

Participation

Application

Architecture

Users

Scientific Community,

Government, Industry,

NGO, General Public

Social dimension that

enables users to

interact and create

focused discussions

involving all

stakeholders

Encourage every user to add

value directly to the system

with:

• voluntary or sponsored,

• implicit or explicit,

• spontaneous or organized

contributions.

Adapted from Dion Hinchcliffe (Transforming Software Architecture for the 21st Century (September 2009))

Structural Alert

Adding Knowledge by Asking Simple Questions

Start Building a Pathway from both Ends

Adverse Effects are observable loss or deterioration of normal function

Downstream Effect

Pathway Elements

Availability and Examples

Technological Benefits

•Organize the existing distributed knowledge, facilitate networking and interdisciplinary collaboration

• Effectopedia defines internal organizational space which helps scientists with different backgrounds to determine where their knowledge belongs, and aids them in identifying both the larger context of their research and the individual experts who might be actively interested in it.

•Effective publishing

• Effectopedia enables AOPs to be “live” scientific documents in which authoring and reviewing is an iterative process open for the entire scientific community, allowing young, established and retired researchers to contribute with desired level of effort. The platform also allows entering quantitative and semantic information which makes it directly suitable for modeling and other forms of processing and analysis.

•Reducing costs – share the costs for common needs and invest only in custom needs.

• Form alliances for supporting the development of a platform that will benefit all stakeholders and provide a standard set of features to build on. Building it open source means that all stakeholders are free to chose their own developer for the custom modules.

• Reduce the cost of research and benefit from a larger pool of expertise available across the Effectopedia community.

• Create and fund data gap challenges.

• Reduce cost for a new substance registration and make the electronic submission easier. For example, only quantitative information about the triggered MIES might be required when established pathways for these MIES already exist – eliminating the need for acquiring the most expensive information needed for chemical evaluation.

•Increase efficiency

• Use Effectopedia in large organizations for internal team collaboration connecting different experts working on the same problem.

• Build and maintain the knowledge in one place and allow evaluation on multiple legislative / organizational quality and approval criteria. This, for example, allows the evaluation of the same pathway by harmonized AOP quality criteria accepted by OECD and different ones defined by WHO, IQF and governmental agencies like EPA.

•Visibility, accessibility and public presence

• Companies and regulatory agencies can actively interact with nonprofits and the general public, providing transparent science-based justification for their decisions.

• Increase business visibility by publishing all data that are not considered competitive advantage.

• Requires sufficient funding for

• Building critical mass of knowledge

• Building the user interface and introduce features that facilitate the user interaction with the system

• Find the balance

• Simple enough to make it manageable, but complex enough to be useful

• Accessibility and advertisement

• Effectopedia is free and open to the public

• Scientific community support

Example1. Estrogen Binding Mediated Population Reduction

•As shown above, pathway originating at n-octylphenol causes different ER-mediated effects in males and females at the cellular level but lead to the same adverse outcome at higher levels.

•Besides the gender specific ER pathway, n-amylaniline also causes oxidation of hemoglobin which initiates a possible mortality pathway. The blend of observed effects is Log P and dose related for alkyl anilines.

Availability: GNU General Public License version 3.0 Source repository Effectopedia website www.effectopedia.org

To load the example in Effectopedia use the following steps:

1.Download Effectopedia application from sourceforge.net or effectopedia.org.

2.Select: “Review the current status of existing adverse outcome pathways”.

3.In the search field type “Example1”.

4.Press search button.

5.From the results click on the title of the pathway to load it in the pathway viewer

6.Use example1 - example7 or other keywords like “inhibition” to load different examples

• Instant notification

• When user contribution is discussed

• When user contribution is linked

• Create and fund/inspire data gap challenges

• Advanced pathway visualization / analysis tools

• Human and machine interpretability

• Effectopedia will employ ontology encased natural language interface that allows semantic encoding of the information. This will enable computational use of the encoded data, automated multi-language translations, nano-publishing, and more.

Important Features

Establishing Effectopedia

Acknowledgments • Effectopedia appreciates the generous support provided by

• International QSAR Foundation

• People for the Ethical Treatment of Animals

• IBPhBME, Bulgarian Academy of Sciences

• OECD, Paris

• National Science Foundation ДТК02/58, Bulgaria

• REACH Monitor, Barcelona, Spain

Effectopedia has modular architecture which allows different usage patterns.

• Gray shaded boxes represent modules that can be executed on local machine as part of standalone application.

• Orange shaded modules provide the core Effectopedia functionality. They have mixed usage: as server side and / or as application embedded modules.

• Blue shaded modules provide access to database (local or remote) functionality.

• Purple shaded modules provide web interface to the Effectopedia core functionalities.

Applications in Toxicology •Collate the descriptive mechanistic information and quantitative potency data for well-studied chemical case studies which have been spread across the many disciplines by our growing specializations. •When assembled in the AOP format, categories of chemicals can be grouped in a transparent mechanistic manner and read-across estimates within these categories can select defensible scaling of potency. •QSAR models describe possible molecular interactions which can be linked to all known molecular initiating events and AOPs that lead to the adverse outcomes being assessed. •Integrating QSAR models to AOPs permits large lists of untested chemicals to be screened and prioritized for their potential to cause specific hazards and generate hypotheses for chemical specific testing requirements. •By screening chemicals for thousands of possible molecular interactions and hundreds of in vitro and in vivo assays, the timeline for development of safer new products can be improved. •Exposure results in hundreds of molecular effects for a given chemical and modeling the selectivity for the chemical for off-target adverse effects quickly will reduce R&D time for new product development. •Integration of QSAR models and AOPs for Predictive Hazard Assessment and Priority Setting

• Predicting the most important molecular interactions for a chemical in a given bioassay cannot be determined using Structural Alerts and simple models. Effectopedia enables an array of possible interactions to be evaluated by the downstream biological linkages as well as chemistry.

•Shape a new vision for experimental design

• Identify tests that are required but rarely used in decision making and risk assessment processes.

• Identify tests that are frequently used and part of multiple pathways and look for low cost non animal alternatives.

• Precisely define the context in which observations are made to allow the unique behaviors of thousands of chemicals to be interpreted for many species and test conditions.

Effects at each level of observation (LOE) are linked to “causes” at lower LOEs

Architecture

Effectoped aInternational QSARFoundation

The Online Encyclopedia of Adverse Effect Pathways

Search Engine

Data Indexing

Edit HistoryTracking

COREGraphic

User

Interface Data

Abstraction Layer

User authorisation

management

Third Party Modules �

and Services

Open Web �

API

Web

Interface

Local Memory

Local Files

Database

User Security Files

Third Party �

Applications

Web Server

Database �Server(s)

Third Party �

Web Interfaces �

and Services

Effectoped aInternational QSAR Foundation

Effectoped aInternational QSAR Foundation