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Although great care has been taken to provide accurate and current information,
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tion, shall be liable for any loss, damage, or liability directly or indirectly caused or
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demarks and are used only for identification and explanation without intent to
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ISBN: 0-8247-2397-X

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 Contents

Contributors . . . . ix

1. A Brief Introduction to Predictive

Toxicology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1
Christoph Helma
What Is Predictive Toxicology? . . . . 1
Ingredients of a Predictive Toxicology System . . . . 3
Concluding Remarks . . . . 7
2. Description and Representation
of Chemicals . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11
Wolfgang Guba
Introduction . . . . 11
Fragment-Based and Whole Molecule Descriptor
Schemes . . . . 13
Fragment Descriptors . . . . 14
Topological Descriptors 19
3D Molecular Interaction Fields . . . . 23
Other Approaches . . . . 27

iii
iv Contents

3. Computational Biology
and Toxicogenomics . . . . . . . . . . . . . . . . . . . . . 37
Kathleen Marchal, Frank De Smet, Kristof Engelen, and
Bart De Moor
Introduction . . . . 37
Microarrays . . . . 41
Analysis of Microarray Experiments . . . . 46
Conclusions and Perspectives . . . . 74
4. Toxicological Information for Use
in Predictive Modeling: Quality,
Sources, and Databases . . . . . . . . . . . . . . . . . . . 93
Mark T. D. Cronin
Introduction . . . . 93
Requirements for Toxicological Data for Predictive
Toxicity . . . . 98
High Quality Data Sources for Predictive
Modeling . . . . 104
Databases Providing General Sources of
Toxicological Information . . . . 104
Databases Providing Sources of Toxicological Information
for Specific Endpoints . . . . 110
Sources of Chemical Structures . . . . 119
Sources of Further Toxicity Data . . . . 121
Conclusions . . . . 123
5. The Use of Expert Systems for Toxicology Risk
Prediction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 135
Simon Parsons and Peter McBurney
Introduction 136
Expert Systems . . . . 137
Expert Systems for Risk Prediction . . . . 147
Systems of Argumentation . . . . 153
Summary . . . . 167

6. Regression- and Projection-Based Approaches

in Predictive Toxicology . . . . . . . . . . . . . . . . . . 177
Lennart Eriksson, Erik Johansson, and
Torbjörn Lundstedt
Introduction . . . . 178
Contents v

Characterization and Selection of Compounds:

Statistical Molecular Design . . . . 179
Data Analytical Techniques . . . . 182
Results for the First Example—Modeling and Predicting
In Vitro Toxicity of Small Haloalkanes . . . . 190
Results for the Second Example—Lead Finding and
QSAR-Directed Virtual Screening of
Hexapeptides . . . . 203
Discussion . . . . 211

7. Machine Learning and Data Mining . . . . . . . . 223

Stefan Kramer and Christoph Helma
Introduction . . . . 223
Descriptive DM . . . . 231
Predictive DM . . . . 239
Literature and Tools=Implementations . . . . 246
Summary . . . . 249

8. Neural Networks and Kernel Machines for Vector

and Structured Data . . . . . . . . . . . . . . . . . . . . . 255
Paolo Frasconi
Introduction . . . . 255
Supervised Learning . . . . 258
The Multilayered Perceptron . . . . 268
Support Vector Machines . . . . 279
Learning in Structured Domains . . . . 288
Conclusion . . . . 299

9. Applications of Substructure-Based SAR in

Toxicology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 309
Herbert S. Rosenkranz and Bhavani P. Thampatty
Introduction . . . . 309
The Role of Human Expertise . . . . 311
Model Validation: Characterization and
Interpretation . . . . 316
Congeneric vs. Non-congeneric Data Sets . . . . 335
Complexity of Toxicological Phenomena and Limitations
of the SAR Approach . . . . 342
Mechanistic Insight from SAR Models . . . . 345
vi Contents

Application of SAR to a Dietary Supplement . . . . 348

SAR in the Generation of Mechanistic
Hypotheses . . . . 354
Mechanisms: Data Mining Approach . . . . 355
An SAR-Based Data Mining Approach to Toxicological
Discovery . . . . 357
Conclusion . . . . 361

10. OncoLogic: A Mechanism-Based Expert System for

Predicting the Carcinogenic Potential of
Chemicals . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 385
Yin-Tak Woo and David Y. Lai
Introduction . . . . 385
Mechanism-Based Structure–Activity Relationships
Analysis . . . . 387
The OncoLogic Expert System . . . . 390

11. META: An Expert System for the Prediction of

Metabolic Transformations . . . . . . . . . . . . . . . 415
Gilles Klopman and Aleksandr Sedykh
Overview of Metabolism Expert Systems . . . . 415
The META Expert System . . . . 416
META Dictionary Structure . . . . 417
META Methodology . . . . 418
META_TREE . . . . 419

12. MC4PC—An Artificial Intelligence Approach to the

Discovery of Quantitative Structure–Toxic Activity
Relationships . . . . . . . . . . . . . . . . . . . . . . . . . . . 423
Gilles Klopman, Julian Ivanov, Roustem Saiakhov,
and Suman Chakravarti
Introduction . . . . 423
The MCASE Methodology . . . . 427
Recent Developments: The MC4PC Program . . . . 433
BAIA Plus . . . . 438
Development of Expert System Predictors Based on
MCASE Results . . . . 443
Conclusion . . . . 451
Contents vii

13. PASS: Prediction of Biological Activity Spectra for

Substances . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 459
Vladimir Poroikov and Dmitri Filimonov
Introduction . . . . 459
Brief Description of the Method for Predicting Biological
Activity Spectra . . . . 461
Application of Predicted Biological Activity Spectra
in Pharmaceutical Research and
Development . . . . 471
Future Trends in Biological Activity Spectra
Prediction . . . . 474

14. lazar: Lazy Structure–Activity Relationships for

Toxicity Prediction . . . . . . . . . . . . . . . . . . . . . . 479
Christoph Helma
Introduction . . . . 479
Problem Definition . . . . 482
The Basic lazar Concept . . . . 484
Detailed Description . . . . 485
Results . . . . 491
Learning from Mistakes . . . . 493
Conclusion . . . . 495

Index . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 501
 Contributors

Suman Chakravarthi Case Western Reserve University,

Cleveland, Ohio, U.S.A.
Mark T. D. Cronin School of Pharmacy and Chemistry,
John Moores University, Liverpool, U.K.
Bart De Moor ESAT-SCD, K.U. Leuven, Leuven, Belgium
Frank De Smet ESAT-SCD, K.U. Leuven, Leuven, Belgium
Kristof Engelen ESAT-SCD, K.U. Leuven, Leuven, Belgium
Lennart Eriksson Umetrics AB, Umeå, Sweden
Dmitri Filimonov Institute of Biomedical Chemistry of Russian
Academy of Medical Sciences, Moscow, Russia
Paolo Frasconi Dipartimento di Sistemi e Informatica,
Università degli Studi di Firenze, Firenze, Italy
Wolfgang Guba F. Hoffmann-La Roche Ltd, Pharmaceuticals
Division, Basel, Switzerland
Christoph Helma Institute for Computer Science, Universität
Freiburg, Georges Köhler Allee, Freiburg, Germany
ix
x Contributors

Julian Ivanov MULTICASE Inc., Beachwood, Ohio, U.S.A.

Erik Johansson Umetrics AB, Umeå, Sweden

Gilles Klopman MULTICASE Inc., Beachwood, Ohio, and
Department of Chemistry, Case Western Reserve University,
Cleveland, Ohio, U.S.A.
Stefan Kramer Institut für Informatik, Technische Universität
München, Garching, München, Germany

David Y. Lai Risk Assessment Division, Office of Pollution

Prevention and Toxics, U.S. Environmental Protection Agency,
Washington, D.C., U.S.A.

Torbjörn Lundstedt Acurepharma AB and BMC, Uppsala,

Sweden
Peter McBurney Department of Computer Science,
University of Liverpool, Liverpool, U.K.

Kathleen Marchal ESAT-SCD, K.U. BMC, Leuven, Leuven,

Belgium

Simon Parsons Department of Computer and Information

Science, Brooklyn College, City University of New York, Brooklyn,
New York, U.S.A.
Vladimir Poroikov Institute of Biomedical Chemistry of
Russian Academy of Medical Sciences, Moscow, Russia
Herbert S. Rosenkranz Department of Biomedical Sciences,
Florida Atlantic University, Boca Raton, Florida, U.S.A.

Roustem Saiakhov MULTICASE Inc., Beachwood, Ohio, U.S.A.

Aleksandr Sedykh Department of Chemistry, Case Western
Reserve University, Cleveland, Ohio, U.S.A.

Bhavavni P. Thampatty Department of Environmental and

Occupational Health, Graduate School of Public Health, University
of Pittsburgh, Pittsburgh, Pennsylvania, U.S.A.

Yin-Tak Woo Risk Assessment Division, Office of Pollution

Prevention and Toxics, U.S. Environmental Protection Agency,
Washington, D.C., U.S.A.
1
A Brief Introduction to
Predictive Toxicology

CHRISTOPH HELMA
Institute for Computer Science, Universität
Freiburg, Georges Köhler Allee, Freiburg, Germany

1. WHAT IS PREDICTIVE TOXICOLOGY?

The public demand for the protection of human and environ-

mental health has led to the establishment of toxicology as
the science of the action of chemicals on biological systems.
Toxicological research is focused presently very much on the
elucidation of the cellular and molecular mechanisms of toxi-
city and the application of this knowledge in safety evalua-
tion and risk assessment. This is essentially a predictive
strategy (Fig. 1): Toxicologists study the action of chemicals
in simplified biological systems (e.g., cell cultures, laboratory
animals) and try to use these results to predict the potential
impact on human or environmental health.
1
2 Helma

Figure 1 Abstraction of the predictive toxicology process.

Predictive toxicology, as we understand it in this

book, does something very similar (Fig. 1): In predictive
toxicology, we try to develop procedures (algorithms in
computer science terms) that are capable to predict toxic
effects (the output) from chemical and biological information
(the input).
Figure 1 summarizes also the key ingredients of
a predictive toxicology system. First, we need a description
of chemicals and biological systems as input for predi-
ctions. This information is processed by the prediction
algorithm, to generate a toxicity estimation as output. We
can also distinguish between data (input and output) and
algorithms.
A Brief Introduction to Predictive Toxicology 3

2. INGREDIENTS OF A PREDICTIVE
TOXICOLOGY SYSTEM
2.1. Chemical, Biological, and
Toxicological Data
Most of the research in predictive toxicology has been devoted
to the development of algorithms, but for a good performance,
the data aspect is at least equally important. It is in principle
possible to use many different types of information to describe
chemical and biological systems. The key problem in predic-
tive toxicology is to identify the parameters that are relevant
for a particular toxic effect. The situation is relatively easy, if
the underlying biochemical mechanisms are well known. In
this case, we can determine a rather limited set of para-
meters, that might be relevant for our purpose. In practice,
however, biochemical mechanisms are frequently unknown
and=or too complex, to determine a suitable set
of parameters a priori. Methods for parameter selection
are therefore an important research topic in predictive
toxicology.
Toxicity data are needed for two purposes: First of all, we
need to validate prediction methods, and this can be done by
comparing the predictions with realworld measurements. But
we can use toxicity data also as input to one of the data driven
approaches that are capable of generating prediction models
automatically from empirical data (Fig. 2). In this case, the
quality of the prediction model is largely determined by the
quality of the input data.
Despite many possibilities, practical applications
have focused on a relatively small set of chemical and
biological features. The most popular chemical features are
closely related to the chemical structure (e.g., presence=
absence of certain substructures) or to properties, that
can be calculated from the chemical structure (e.g., physico-
chemical properties). As no experimental work is needed to
obtain this type of data, the rationale for their choice is
obvious, but other substance-related information (e.g.,
biological activities in screening assays, IR-spectra) can be
used as well.
4 Helma

Figure 2 Abstraction of a data driven approach in predictive

toxicology.

Up to now information about biological systems has been

rarely considered in predictive toxicology. Biological systems
have been treated as ensembles of uniform members (e.g.,
equal individuals), without any biological variance. The expli-
cit consideration of the biological part of the equation will be
an interesting research topic of the next years.a
Chemical, biological and toxicological data and their repre-
sentation are the topics of the first section of this book. It
contains the chapters Description and Representation of
Chemicals by Guba (1), Computational Biology and
Toxicogenomics by Marchal et al. (2), and Toxicological Informa-
tion for Use in Predictive Modeling: Quality, Sources, and Data-
bases by Cronin (3).

a
The chapter from Marchal et al. (2) provides some examples how to use
biological information for predictive purposes.
A Brief Introduction to Predictive Toxicology 5

2.2. Prediction Algorithms

For the prediction algorithm, we have the choice between two
strategies. We can try to mimic a human expert by building
an expert system, or we can try to deduce a prediction model
from empirical data by a data-driven approach as in Fig. 2.
The basics of expert systems and some exemplary appli-
cations are the topic of Parson and McBurney’s chapter, The
Use of Expert Systems for Toxicology Risk Prediction (4).
Two of the programs [META (5) and OncoLogic (6)] discussed
in the section Implementations of Predictive Toxicology Sys-
tems are also expert systems.
If we intend to generate a prediction model from experimen-
tally determined toxicity data as in Fig. 2, we have the choice
between many different methods. Statistical methods, for exam-
ple, have been successfully applied in quantitative structureac-
tivity relationships (QSAR) for decades. Eriksson et al.(7)
describe statistical techniques in the chapter entitled Regres-
sion- and Projection-Based Approaches in Predictive Toxicology.
More recently, techniques originating from artificial
intelligence research have been used in predictive toxicology.
These computer-science oriented developments are summar-
ized in two chapters: Machine Learning and Data Mining
by Kramer and Helma (8) and Neural Networks and Kernel
Machines for Vector and Structured Data by Frasconi (9).
Three programs of the section Implementations of Predictive
Toxicology Systems [MC4PC (10), PASS (11), lazar (12)] use
such a data-driven approach.
I want to stress the point that similar predictions can be
obtained with a variety of methods. The choice of the method
for a particular purpose will depend largely on the scope
of the application, present research trends and the personal
preferences of the individual researcher.

2.3. Application Areas

The primary aim of predictive toxicology is, of course, the pre-
diction of toxic activities of untested compounds. This enables
chemical and pharmaceutical companies, for example, to eval-
uate potential side effects of candidate structures even without
6 Helma

synthesizing them. The same feature is also attractive for

governmental authorities that have to deal with compounds
with incomplete toxicity information. Present predictive toxi-
cology systems are efficient enough to process thousands if
not millions of compounds in a reasonable amount of time.
The prioritization of compounds for physical toxicity assays
is another important application of predictive toxicology.
Many predictive toxicology systems are capable to pro-
vide a rationale for their predictions. If the prediction is based
on chemical substructures and=or chemical properties, it is
straightforward to use this information for the design of less
dangerous, but equally efficient compounds (computer aided
drug design).
A frequently overlooked but, in my opinion, very important
feature of many predictive toxicology systems is their applicabil-
ity as a tool for the generation and verification of scientific
hypotheses. The chapter Applications of Substructure-Based
SAR in Toxicology by Rosenkranz and Thampatty (13) provides
some examples for the creative use of a predictive toxicology
system for scientific purposes as well as some mainstream
applications.

2.4. Implementations
We can use any statistics and=or data mining package (8)
[maybe in conjunction with a computational chemistry pack-
age for calculating chemical descriptors (1)] for the prediction
of toxic properties, but it is also possible to use a program that
has been developed specifically for an application in predic-
tive toxicology.
In the section Implementations of Predictive Toxicology
Systems, we describe two expert systems: OncoLogic: A
Mechanism-Based Expert System for Predicting the Carcino-
genic Potential of Chemicals by Woo and Lai (6) and META:
An Expert System for the Prediction of Metabolic Transforma-
tions by Klopman and Sedykh (5), as well as three data driven
systems: MC4PC—An Artificial Intelligence Approach to the
Discovery of Quantitative Structure Toxic Activity Relation-
ships (QSTAR) by Klopman et al. (10), PASS: Prediction of
A Brief Introduction to Predictive Toxicology 7

Biological Activity for Substances by Poroikov and Filimonov

(10), and lazar: Lazy Structure–Activity Relationships for
Toxicity Prediction by Helma (12). Two further expert
systems (DEREK and StAR) have been presented already in
The Use of Expert Systems for Toxicology Risk Prediction (4).

3. CONCLUDING REMARKS

Predictive toxicology is clearly an interdisciplinary science

with contributions from chemistry, biology, and medicine as
well as statistics and computer science. As a deep knowledge
of all of these areas is probably beyond the scope of an indivi-
dual scientist, interdisciplinary collaboration is crucial for the
development of a successful predictive toxicology system. This
requires, however, that the involved persons have at least a
basic understanding of the involved disciplines to allow a suc-
cessful communication.
This book is an attempt to provide an introduction to the
most important techniques and disciplines that are currently
involved in predictive toxicology. Although it was written
with an interdisciplinary audience in mind, some readers
might have trouble understanding some chapters where the
author comes from a completely different professional
background. For this reason, we have added a Glossary
and one or two references to Introductory Literature as addi-
tional material to each chapter. The Glossary provides a defi-
nition of the most important terms in the respective chapterb,
and the introductory literature provides suggestions for the
scientific background that is needed to understand the
corresponding chapter.
It is obvious that a printed book can contain only a lim-
ited amount of information and will miss the latest develop-
ments after some time. For this reason, we will provide
additional material, that is related to the content of this book,
on the website www.predictive-toxicology.org. You can con-

b
Please note that the specfic meaning or usage of the terms may vary from
chapter to chapter.
Other documents randomly have
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XVII I 26

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