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?