GENERAL CONCEPTS IN QSAR FOR USING THE
QSAR APPLICATION TOOLBOX
PART IIIFORMING CHEMICAL CATEGORIES
WHAT DO WE MEAN BY A CHEMICAL CATEGORY?
A chemical category is a group of chemicals with attributes in common:
Structure e.g., common substructure or electronic properties
Property e.g., similar physicochemical, topological, geometrical, or
surface properties
Behavior e.g., toxicological response underpinned by common toxicity
mechanisms
Function e.g., preservatives, solvents, detergents, fragrances,
lubricants , heat transfer, etc.
ANNEX IX OF REACH
Substances whose physicochemical, toxicological and ecotoxicological
properties are likely to be similar or follow a regular pattern as a result of
structural similarity may be considered as a group, or “category” of
substances.
Application of the group concept requires that physicochemical
properties, human health effects and environmental effects or
environmental fate may be predicted from data for a reference
substance within the group by interpolation to other substances in the
group (read-across approach). This avoids the need to test every
substance for every endpoint.
Source: OECD Manual for Investigation of High ProductionVolume (HPV) Chemicals. OECD Paris.
OECD DEFINITION OF CATEGORY
A chemical category is a group of chemicals whose physicochemical
and toxicological properties are likely to be similar or follow a regular
pattern as a result of structural similarity
These structural similarities may create a predictable pattern in any or all
of the following parameters: physicochemical properties, environmental
fate and environmental effects, and human health effects
FORMING CHEMICAL CATEGORIES
Chemical categories are being grouped based on attributes important to
toxicological behavior
Literature and other data sources are used to organize available data for
common assessment endpoints
Read-across and trend analysis are used to extrapolate the data from
tested chemicals to untested chemicals
In many cases, the analysis of trends (our examples in this lecture) is
used to designate the boundaries for similarity in each of the categories
GENERAL CONCEPTS IN QSAR FOR USING THE
QSAR APPLICATION TOOLBOX
PART IVQSAR AND THE OECD TOOLBOX
Integrating Methods for Convenience, Consistency and Documentation
WHY DO WE NEED THE QSAR TOOLBOX?
Defining category boundaries requires the calculation of complex
attributes of chemicals to determine which attributes best explain
available data
In many cases, metabolic simulators are needed to provide metabolic
maps and active metabolites
To do trend analysis, hundreds of available data must be compiled and
flexibly analyzed for trends
QSAR APPLICATION TOOLBOX
Filling data gaps using available test data
and principles of predictive toxicology
Developed for OECD and ECHA by the Laboratory of
Mathematical Chemistry, Bourgas, Bulgaria
Professor Ovanes Mekenyan, Head
-ENV/JM(2006)47
General Objectives:
QSAR APPLICATION TOOLBOX
Improve accessibility of (Q)SAR methods and databases
Facilitate selection of chemical analogues and categories
Integrate metabolism/mechanisms with categories and QSAR
Assist in the estimation of missing values for chemicals
TYPICAL QUERIES WITH THE QSAR APPLICATION TOOLBOX
Is the chemical included in regulatory inventories or existing chemical
categories?
Has the chemical already been assessed by other
agencies/organizations?
Would you like to search for available data on assessment endpoints for
each chemical?
TYPICAL QUERIES WITH THE QSAR APPLICATION TOOLBOX
Explore a chemical list for possible analogues using
predefined, mechanistic, empiric and custom-built categorization
schemes?
Group chemicals based on common chemical/toxic mechanism and/or
metabolism?
Design a data matrix of a chemical category?
QSAR TOOLBOX WORKFLOW
The first version of the QSAR Toolbox is designed to
facilitate the work of hazard assessors in filling data gaps
for untested chemicals through the use of chemical categories
Chemical
Input
Chemical
Profiling
Category
Definition
Filling
Data
Gaps
ReportHazard
Endpoints
LOGICAL SEQUENCE OF USING TOOLBOX COMPONENTS
User Alternatives for Chemical ID:A. Single target chemical• Name• CAS# • SMILES/InChi• Draw Chemical Structure• Select from User List/Inventory
B. Group of chemicals• User List• Inventory• Specialized Databases
Chemical
Input
Chemical
Profiling
Category
Definition
Filling
Data
Gaps
ReportHazard
Endpoints
LOGICAL SEQUENCE OF USING TOOLBOX COMPONENTS
General characterization schemes:• Substance information• Predefined• Mechanistic• Empirical• Custom• Metabolism
Chemical
Input
Chemical
Profiling
Category
Definition
Filling
Data
Gaps
ReportHazard
Endpoints
LOGICAL SEQUENCE OF USING TOOLBOX COMPONENTS
Compiling Endpoint Data (SIDS plus)• Aquatic Toxicity (complete AQUIRE)• Ecotoxicology (complete ECOTOX)• Bioaccumulation• Mutagenicity• Skin Sensitization• Carcinogenicity• Rodent Repeat Dose • Documented QSAR Estimates
Chemical
Input
Chemical
Profiling
Category
Definition
Filling
Data
Gaps
ReportHazard
Endpoints
LOGICAL SEQUENCE OF USING TOOLBOX COMPONENTS
Forming and Pruning Categories:• Predefined• Mechanistic• Empirical• Custom• Metabolism
Chemical
Input
Chemical
Profiling
Category
Definition
Filling
Data
Gaps
ReportHazard
Endpoints
Forming and Pruning Categories:
• Predefined• OECD categorization• US EPA categorization• Inventory affiliation• Database affiliation• Substance type
Chemical
Input
Chemical
Profiling
Category
Definition
Filling
Data
Gaps
ReportHazard
Endpoints
LOGICAL SEQUENCE OF USING TOOLBOX COMPONENTS
Accepted Approaches• Read-across• Trend analysis• QSAR models
Chemical
Input
Chemical
Profiling
Category
Definition
Filling
Data
Gaps
ReportHazard
Endpoints
LOGICAL SEQUENCE OF USING TOOLBOX COMPONENTS
Report the results:• Estimate Reporting Formats (QMRF)• IUCLID 5 Harmonized Templates• SIDS Data Dossiers• Complete Session History • User-Defined Reports
Chemical
Input
Chemical
Profiling
Category
Definition
Filling
Data
Gaps
ReportHazard
Endpoints
LOGICAL SEQUENCE OF USING TOOLBOX COMPONENTS
SUMMARY
Explore a chemical list for possible analogues using predefined,
mechanistic, empiric and custom-built categorization schemes?
Group chemicals based on common chemical/toxic mechanism and/or
metabolism?
Design a data matrix of a chemical category?