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Published on 01 March 2017 on http://pubs.rsc.org | doi:10.1039/9781782623731-FP001
Computational Systems Pharmacology and Toxicology

View Online
Issues in Toxicology
Series editors:
Diana Anderson, University of Bradford, UK
Michael D. Waters, Michael Waters Consulting, USA
Timothy C. Marrs, Edentox Associates, UK
Editorial advisor:
Alok Dhawan, CSIR-Indian Institute of Toxicology Research, Lucknow, India
Titles in the Series:

1: Hair in Toxicology: An Important Bio-Monitor
2: Male-mediated Developmental Toxicity
3: C ytochrome P450: Role in the Metabolism and Toxicity of Drugs and
other Xenobiotics
4: Bile Acids: Toxicology and Bioactivity
5: The Comet Assay in Toxicology
6: Silver in Healthcare
7: In Silico Toxicology: Principles and Applications
8: Environmental Cardiology
9: B iomarkers and Human Biomonitoring, Volume 1: Ongoing Programs
and Exposures
10: Biomarkers and Human Biomonitoring, Volume 2: Selected Biomarkers
of Current Interest
11: Hormone-Disruptive Chemical Contaminants in Food
12: Mammalian Toxicology of Insecticides
13: The Cellular Response to the Genotoxic Insult: The Question of Thresh-
old for Genotoxic Carcinogens
14: Toxicological Effects of Veterinary Medicinal Products in Humans: Vol-
ume 1
15: Toxicological Effects of Veterinary Medicinal Products in Humans: Vol-
ume 2
16: Aging and Vulnerability to Environmental Chemicals: Age-related Disor-
ders and their Origins in Environmental Exposures
17: Chemical Toxicity Prediction: Category Formation and Read-Across
18: The Carcinogenicity of Metals: Human Risk Through Occupational and
Environmental Exposure
19: Reducing, Refining and Replacing the Use of Animals in Toxicity Testing
20: Advances in Dermatological Sciences
21: Metabolic Profiling: Disease and Xenobiotics
22: Manganese in Health and Disease
23: Toxicology, Survival and Health Hazards of Combustion Products
24: Masked Mycotoxins in Food: Formation, Occurrence and Toxicological
Relevance
25: Aerobiology: The Toxicology of Airborne Pathogens and Toxins
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26: Chemical Warfare Toxicology, Volume 1: Fundamental Aspects

27: Chemical Warfare Toxicology, Volume 2: Management of Poisoning
28: Toxicogenomics in Predictive Carcinogenicity
29: Human Stem Cell Toxicology
30: The Comet Assay in Toxicology, 2nd edition
31: Computational Systems Pharmacology and Toxicology
How to obtain future titles on publication:

A standing order plan is available for this series. A standing order will bring
delivery of each new volume immediately on publication.
For further information please contact:

Book Sales Department, Royal Society of Chemistry, Thomas Graham House,
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Computational Systems
Pharmacology and Toxicology
Edited by
Dale E. Johnson
University of Michigan, USA
Rudy J. Richardson
University of Michigan, USA
Published on 01 March 2017 on http://pubs.rsc.org | doi:10.1039/9781782623731-FP001 View Online
Issues in Toxicology No. 31
Print ISBN: 978-1-78262-332-8

PDF eISBN: 978-1-78262-373-1
EPUB eISBN: 978-1-78801-120-4
ISSN: 1757-7179
A catalogue record for this book is available from the British Library
© The Royal Society of Chemistry 2017
All rights reserved
Apart from fair dealing for the purposes of research for non-commercial purposes or for
private study, criticism or review, as permitted under the Copyright, Designs and Patents
Act 1988 and the Copyright and Related Rights Regulations 2003, this publication may
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Preface
Our motivation for bringing about a book on systems computational

pharmacology and toxicology was a natural development from teaching
courses on these subjects, first at the University of California in Berkeley
and later at the University of Michigan in Ann Arbor. Our courses and this
book address a critical need to modernize pharmacology and toxicology—to
transform these fields from descriptive disciplines to predictive sciences.
This transformation is necessary, because classic descriptive approaches
are far too inefficient and expensive to assess the medical efficacy or toxicity
of the many thousands of synthetic chemicals or natural products to which
humans and other species are or will be exposed.
Not long ago, the approaches set forth in this book were either not possible
or performed by specialists using such tools as quantum mechanics and
mainframe computers. Now, because of rapid advances in technology,
software, and theory, coupled with the public availability of large chemical
and biomedical data sets through the internet, it is possible for non-specialist
bench scientists to undertake sophisticated molecular modeling, bioinfor-
matics, cheminformatics, and systems biology procedures on desktop
computers as well as mobile devices, including to some extent electronic
tablets and smart phones. Thus, powerful computational tools have become
highly accessible, but knowing how and when to use the right tools in the
right way can be a daunting task. This book seeks to make the job easier to
understand and implement.
Recognizing that we now have the capability to understand pharmacological
and toxicological effects at multiple biological levels, our book highlights the
process of integrating the elements of complex phenomena into a systems
approach. Thus, whereas inverse docking and pharmacophore mapping can
identify molecular targets of candidate drugs or toxicants, intelligent
mining of databases can identify networks of genes and proteins involved

Edited by Dale E. Johnson and Rudy J. Richardson
Published by the Royal Society of Chemistry, www.rsc.org
vii
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viii Preface
in the system-wide biological responses to chemicals. A pharmacological or
toxicological effect may begin with atomic-level binding, but ultimately the
intact organism responds in a holistic manner. It is necessary to continually
readjust our focus by many orders of magnitude to encompass the spectrum
from molecular orbitals to human populations.
The tools and models discussed in the book hold tremendous promise
for advancing applied and basic science, streamlining drug efficacy and
safety testing, and increasing the efficiency and effectiveness of risk assess-
ment for environmental chemicals. The content of chapters is designed to
provide readers with an understanding of the basic principles and current
methods of computational pharmacology and toxicology. These principles
and approaches are discussed in several chapters in order to show how to
connect chemicals with diseases and associated genes, and how to create
pharmacology/toxicology connectivity maps or networks.
Vital to these expositions of principles and methods are illustrations of
modeling and/or predicting potential pharmacological or toxicological
effects from multiple properties. These characteristics include chemical
structure, inference from similar compounds, in silico target identification,
exposure, bioaccumulation, environmental persistence, biomarkers, and
networks of biological pathways affected by a chemical.
Systems toxicology approaches used in the safer design of chemicals and
identification of safer alternatives, which are major parts of global green
chemistry initiatives, are also discussed, along with the concept of the
adverse outcome pathway and modeling approaches for hazard identification
and risk assessments for large numbers of environmental chemicals for
which supporting data are sparse.
The book also expands the conventional boundaries of research and
development of pharmaceutical agents. Thus, traditional Chinese medicines
that include recipes containing several pharmacologically active phytochem-
icals are becoming role models of polypharmacy research.
The final chapter describes an inquiry-based computational toxicology
course. Students work in small cooperative groups and are given tools, data,
and basic concepts to solve toxicity-related environmental, public health,
and/or disease-oriented problems in novel ways. Several case studies serve
both to educate the reader and to provide material for teaching.
As co-editors, we are each involved in research and education on the topics
covered in the book. We have authored or co-authored several of the chapters
ourselves, and the other chapters have been written by experts recruited
from around the world.
Dale E. Johnson and Rudy J. Richardson
Contents
Chapter 1 Systems Biology Approaches in Pharmacology and

Toxicology 1
Dale E. Johnson
1.1 I ntroduction 1
1.2 Systems Toxicology 2
1.3 Chemical Toxicities 3
1.3.1 Single-Target Toxicity Concepts 3
1.3.2 Toxicological Profiling for Potential Adverse
Reactions 5
1.3.3 Toxicological Concepts for Safer Chemical
Design 6
1.3.4 Biomarkers 8
1.4 Environmental Toxicology 9
1.4.1 Adverse Outcome Pathway 9
1.4.2 Expanding Exposure Concepts 10
1.4.3 Exposome 11
1.5 Systems and Network Pharmacology 12
1.5.1 Secondary Pharmacology and Off-Target
Effects 13
1.5.2 Prediction of Potential Adverse
Effects 14
1.6 Conclusions 14
References 14

ix
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x Contents
Chapter 2 Databases Facilitating Systems Biology Approaches in
Toxicology 19
Dale E. Johnson and Ann M. H. Heslin
2.1 I ntroduction 19
2.2 Categorized Lists of Databases for Systems Toxicology 21

2.2.1 TOXNET Databases (Including Those with
Direct Links from TOXNET) 21
2.2.2 US EPA Chemical Toxicity Databases 24
2.2.3 National Toxicology Program Databases 24
2.2.4 Additional Toxicity Databases 25
2.2.5 Chemical–Gene–Protein Databases 26
2.2.6 Pathway-Network Databases 27
2.2.7 Chemistry, Structural Alert, and QSAR
Databases and Tools 28
2.2.8 Drug and Drug Target Databases 30
2.3 Websites with Extensive Links to Databases and
Tools 31
2.4 Conclusions 31
References 32
Chapter 3 Tools for Green Molecular Design to Reduce

Toxicological Risk 36
David Faulkner, Leah K. Rubin Shen, Vanessa Y. De La Rosa,
Dale E. Johnson, Rachel Hemingway, Richard V. Williams,
Philip N. Judson, John Arnold and Chris D. Vulpe
3.2 Physiochemical, Genotoxicity, and Blood–Brain
Barrier Passage Properties of Chemicals 38
3.3 Tools for Green Molecular Design 39
3.3.1 Expert Systems 39
3.3.2 Decision Trees 44
3.3.3 QSAR Tools 44
3.3.4 Representative Tools 45
3.4 Case Study 50
3.5 The Design of Ideal Tools for Chemists 51
3.6 Conclusions 54
References 54
Chapter 4 Linking Environmental Exposure to Toxicity 60

Noffisat Oki, Jeremy Leonard, Mark Nelms, Shannon Bell,
Yu-Mei Tan, Lyle Burgoon and Stephen Edwards
4.2 The AOP Framework: An Organizing Principle for
Toxicological Data 64
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Contents xi
4.2.1 AOP Knowledge Management 67
4.2.2 Phases of AOP Development 68
4.2.3 Data Resources for AOP Development 70
4.3 Environmental Exposure and Pharmacokinetic
Considerations for Adverse Outcome Development 73
4.4 The AEP Framework: An Organizing Principle for

Exposure Data 75
4.4.1 Data resources for AEP development 79
4.5 AEP–AOP Integration for Linking Toxicity to Exposure:
Applications of the AOP and AEP Frameworks for Risk
Assessments and Chemical Management Decision
Making 80
4.6 Conclusions and Future Directions 82
References 83
Chapter 5 Linking Drug or Phytochemical Exposure to Toxicity 89

C. A. Rodríguez, N. S. Teuscher and J. A. Uchizono
5.2 Pharmacokinetic and Toxicokinetic Models 91
5.2.1 Structural Models 91
5.2.2 Variance Models 98
5.3 PK/PD Relationships 102
5.3.1 Mathematical Description of
Pharmacodynamic Effects 104
5.3.2 Combined PK/PD and TK/TD Modeling 109
5.3.3 Modeling Pharmacodynamics in the Absence
of Pharmacokinetic Data: K-PD Models 110
5.4 Modeling Drug Interactions with Phytochemicals 111
5.4.1 Inhibition of Metabolism 112
5.4.2 Induction of Metabolism 113
5.4.3 Enhancement of Absorption 114
5.4.4 Inhibition of Absorption 115
5.4.5 Modeling of Pharmacodynamic Interactions 115
5.5 Conclusions 116
References 116
Chapter 6 Chemical Similarity, Shape Matching and QSAR 120

E. V. Radchenko, G. F. Makhaeva, V. A. Palyulin
and N. S. Zefirov

6.2 Molecular Similarity, Chemical Spaces and Activity
Landscapes 121
6.2.1 Molecular Similarity: Concept and Definitions 121
6.2.2 Chemical Spaces and Activity Landscapes 131
6.2.3 Applications of Molecular Similarity Analysis 138
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xii Contents
6.3 Q uantitative Structure–Activity/Property
Relationships (QSAR/QSPR) 142
6.3.1 Congeneric Series and Consistent
Mechanisms 143
6.3.2 Diverse Series and Big Data 148
6.4 Conclusion 153

Acknowledgements 154
References 154
Chapter 7 In silico Chemical–Protein Docking and Molecular

Dynamics 174
Sanjeeva J. Wijeyesakere and Rudy J. Richardson

7.2 Molecular Docking: Overview and Applications 175
7.2.1 Genetic Algorithms 177
7.2.2 Monte Carlo Procedure 177
7.2.3 Matching Algorithms 177
7.3 Scoring Ligand Poses 178
7.4 Inverse Docking 179
7.5 Case Study: Using In silico Docking to Investigate
Interactions of 1,3-Dinitrobenzene with Adenosine
Deaminase 179
7.6 Case Study: Using In silico Docking to Assess
Binding of Bisphenol-A to Estrogen-Related
Receptor-γ 180
7.7 Molecular Dynamics 182
7.7.1 Running MD Simulations 182
7.7.2 Analysis of MD Trajectories 183
7.7.3 Case Study: Gaining Insights into the
Conformational Dynamics of Human
Neuropathy Target Esterase via MD
Simulations of its Catalytic Domain
Homologue Patatin-17 in Complex with
Organophosphorous Compounds 185
References 187
Chapter 8 Computational Tools for Chemical Toxicity Testing

and Risk Assessment Under the Framework of Adverse
Outcome Pathways 191
M. Mumtaz, P. Ruiz and Q. Zhang

8.2 The AOP Concept 193
8.3 Quantitative Methods in Traditional Apical
Endpoints Testing 194
8.4 PBPK Modeling and In vitro to In vivo Extrapolation 196
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Contents xiii
8.5 S AR Modeling 197
8.6 Computational Modeling of Toxicity Pathways 198
8.6.1 Concept of Toxicity Pathways 198
8.6.2 Purpose of Modeling Toxicity Pathways 199
8.6.3 How to Model Toxicity Pathways 200
8.6.4 Case Studies 203

8.6.5 Education on Computational Toxicology 205
8.6.6 Pathway Modeling Software Tools 205
References 206
Chapter 9 In silico Toxicology: An Overview of Toxicity Databases,

Prediction Methodologies, and Expert Review 209
D. Bower, K. P. Cross, S. Escher, G. J. Myatt
and D. P. Quigley

9.2 Toxicity Databases 215
9.2.1 Overview 215
9.2.2 Database Organization 216
9.2.3 Genetic Toxicity and Carcinogenicity 217
9.2.4 Reproductive and Developmental Toxicity 219
9.2.5 Acute and Repeated Dose Toxicity 220
9.3 In silico Methodologies 221
9.3.1 Overview 221
9.3.2 Expert Alerts 221
9.3.3 QSARs 223
9.3.4 Read-Across 226
9.4 Expert Reviews 227
9.4.1 Assessing Experimental Data 227
9.4.2 Drawing Conclusions from Multiple Systems 228
9.4.3 Reviews Accepting or Refuting An In silico
Result 230
9.4.4 Documenting In silico Results 233
9.5 Conclusions 233
References 236
Chapter 10 Data Sources for Herbal and Traditional Medicines 243

Hsueh-Fen Juan

10.2 TCM Databases 244
10.2.1 Chem-TCM (Chemical Database of
Traditional Chinese Medicine) 244
10.2.2 HIT (Linking Herbal Active Ingredients to
Targets) 244
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xiv Contents
10.2.3 T CMSP (Traditional Chinese Medicine
Systems Pharmacology Database and
Analysis Platform) 246
10.2.4 TCMGeneDIT (A Database for Associated
TCM, Gene and Disease Information Using
Text Mining) 248

10.2.5 TCMID (Traditional Chinese Medicine
Integrative Database for Herb Molecular
Mechanism Analysis) 249
10.2.6 TTD (Therapeutic Target Database) 251
10.3 Omics Data in TCM 253
10.3.1 Genomics in TCM 253
10.3.2 Transcriptomics in TCM 254
10.3.3 Proteomics in TCM 256
10.3.4 Metabonomics in TCM 256
10.4 Summary 257
References 257
Chapter 11 Network Pharmacology Research Approaches for

Chinese Herbal Medicines 261
Dale E. Johnson

11.1.1 Modernization of TCM 263
11.1.2 Concept of Network Pharmacology 263
11.2 Network Pharmacology in TCM Research 265
11.3 Network Pharmacology in the Understanding of
Herb–Drug Interactions 268
11.4 Pharmacogenomics in TCM 269
11.5 TCMs in Clinical Trials 271
11.6 The Future of Network Pharmacology in Traditional
Medicine 273
11.7 Conclusion 274
References 274
Chapter 12 Chemical–Disease Category Linkage (CDCL):

Computational Methods Linking Traditional Chinese
Medicines and Western Therapeutics 279
Dale E. Johnson and Kit Wun Kathy Cheung

12.1.1 Databases for CDCL Information and Study 281
12.1.2 TCM Classifications 283
12.1.3 Active Ingredients in Herbs 286
12.2 Open Access Tools for CDCL Informatics 287
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Contents xv
12.3 C omputational CDCL Studies with Commercial
Tools 289
12.4 Herb–Drug Interactions 292
12.4.1 Pharmacokinetic Interactions 292
12.4.2 Pharmacogenomic-Related Interactions 294
12.5 Combination Therapies and Future Directions 294

12.6 Conclusions 295
References 296
Chapter 13 Educational Programs for Computational Toxicology

and Pharmacology 300
Dale E. Johnson and Rudy J. Richardson

13.2 Historical Context: Computational Toxicology 301
13.2.1 Background 301
13.2.2 Programs at University of California
Berkeley and University of Michigan 302
13.3 Inquiry-Based Science Courses 303
13.4 Current Computational Toxicology Courses 304
13.4.1 Toxicology Tutorials 305
13.4.2 Course Concepts 305
13.4.3 Case Studies 306
13.5 Course Projects 310
13.5.1 Starting Projects 310
13.5.2 Typical Project Categories 310
13.5.3 Therapeutics vs. Environmental Chemicals 311
13.5.4 Challenges in Computational Toxicology 311
13.6 Sample Project: The Chemical of Concern Question 312
13.6.1 Health Effects Inquiry 313
13.6.2 Endpoints for Breast Cancer 313
13.6.3 Project Question 314
13.7 Course Projects Presented and Published 314
13.7.1 Projects Presented at National Scientific
Meetings 314
13.7.2 Projects from the Courses Published in
Journals 316
13.8 Computational Pharmacology as Part of the
Principles of Drug Action 316
13.9 Conclusion 318
References 319
Subject Index 324

Published on 01 March 2017 on http://pubs.rsc.org | doi:10.1039/9781782623731-00001
Chapter 1
Systems Biology Approaches in

Pharmacology and Toxicology
Dale E. Johnson*a,b
a
University of Michigan, School of Public Health, Department of
Environmental Health Sciences, Ann Arbor, MI 48109-2029, USA;
b
University of California, Berkeley, Department of Nutritional Sciences
and Toxicology, Morgan Hall, Berkeley, CA 94720-3104, USA
*E-mail: [email protected]
1.1 Introduction
The science and practical field of toxicology has been changing dramatically
over the last 15–20 years, transitioning into a more systems biology and net-
work-based approach.1–4 Several factors have been involved, including the
developing genomics era where the understanding of genetic changes has
enhanced the ability to understand diseases and chemically-induced toxic-
ities at the molecular level. The genomics era has also ushered in “omics”
technologies and approaches such as transcriptomics, metabolomics,
proteomics, and epigenomics, which have changed the way we view mech-
anisms of toxicity and the perturbation of biological systems that lead to
adverse outcomes.5 These advances have been coupled with the public avail-
ability of large datasets of information and new modeling approaches that
have enhanced the ability to understand toxicological events and effects at
multiple biological levels.6 Since our scientific approaches, inquiries, and
visions aimed at understanding toxicological events and outcomes have

1
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2 Chapter 1
been broadened tremendously, this reinforces our need for new and better
ways to assess toxicity and risk. The large numbers of uncharacterized chem-
icals already present in the environment and new chemicals that continue
to enter it has required hazard and risk assessments to be made with very
few data. These factors have had a major influence on the need to accelerate
new approaches and move away from an overdependence on in vivo animal

testing and make better use of computational, molecular, and in vitro tools.6,7
The identification of the majority of toxic events in in vivo animal toxicology
studies rely on high-dose exposure to the animals and default linear extrap-
olation procedures,8 with the incorporation of newer technologies absent in
the vast majority of animal studies. This has been considered a shortcom-
ing in risk assessment and several weaknesses in this process include the
comparative shape of the dose–response relationship after relevant levels of
human exposure, whether biological and/or toxicological thresholds do in
fact exist and for what toxicological endpoints, and potential population
variability in response.5
1.2 Systems Toxicology

Accordingly, research in toxicology has moved into a new systems-ori-
ented phase called systems toxicology, which involves the study of complex
molecular response networks initiated by exposure (both intentional and
unintentional) to chemical substances. At the heart of systems toxicology
approaches are the development and usage of quantitative mechanistic mod-
els that create a predictive toxicology aspect relevant to all toxicology fields,
including drug research and development and environmental research.
The overall approach involves the integration of classical toxicology with
the quantitative analysis of large networks of chemically-induced molecu-
lar and functional changes, which occur across multiple levels of biological
organization.5 Examples of key influential events in this transition since the
year 2000 include the release of human genome sequencing data including
specific signal transduction domains, the development and issuance of the
report Toxicity Testing in the Twenty-first Century by the National Research
Council (NRC),9 which has influenced all sectors of the toxicology field, and
the development and publication of the adverse outcome pathway (AOP)
approach,6,10,11 which has highlighted the realities that exist as the science
moves away from an overdependence on in vivo testing and makes greater
use of computational, molecular, and focused in vitro tools. Additional driv-
ers of change include the European Union (EU) report from the Scientific
Committee on Health and Environmental Risks, the EU’s Registration, Eval-
uation, Authorisation and Restriction of Chemical Substances (REACH) pro-
gram, and the International Programme on Chemical Safety (IPCS).7,12 The
paradigm shift can also be seen in the drug research and development sector,
but rather than focusing on drugs during late stages of development or on
marketed drugs, the systems-related efforts are positioned at the front end
of research, both on safer chemical design and extensive target research.
View Online
Systems Biology Approaches in Pharmacology and Toxicology 3

While the drug industry is required to conduct animal toxicology studies by
regulatory agencies and international guidelines, the major effort underway
is to determine chemical liabilities early in the drug discovery pipeline, both
to reduce the time and cost of failures later in the process, but also to avoid
costly failures once a drug reaches the market.5 Currently, there is an Inter-
national Consortium for Innovation and Quality in Pharmaceutical Develop-

ment (IQ), where several pharmaceutical and biotechnology companies have
created a Nonclinical to Clinical Translational Database (WG1) to allow anal-
ysis of the reliability and potential limitations of nonclinical data in predict-
ing clinical outcomes, including the evaluation of conventional biomarkers
of toxicity.13 Current screening approaches applied to the front end of drug
research are described below.
1.3 Chemical Toxicities

1.3.1 Single-Target Toxicity Concepts
The science and practice of toxicology over the past several decades have
consistently used classic toxicological approaches, such as in vivo and in
vitro toxicology studies, combined with predictive toxicological method-
ologies. The desired endpoints of the in vivo animal research efforts have
been the determination of a toxic dose where a chemical could be shown
to induce pathologic effects after a specified duration of treatment or expo-
sure. Where appropriate, these studies have included the estimate of the
lowest observed adverse effect level, the no observed adverse effect level,
and the maximally tolerated dose (MTD).5,14 These adverse effect level
estimates are traditionally used in drug research and development to pre-
dict the first dose in humans and to predict margins of safety estimates
based on delivered dose and/or internal exposure from pharmacokinetic/
pharmacodynamic (PK/PD) modeling with extrapolations into clinical
trial subjects. By regulatory requirements, all potential drugs undergoing
research and development will undergo both in vitro and in vivo studies,
and, if the compound reaches the clinical trial stage successfully, data
from human exposure to judge the adequacy of nonclinical data in pre-
dicting clinical outcomes. Uncertainties in these estimates include the
definition of adverse, which is specific for each organ system in each
study and typically determined by the study pathologist; the accuracy of
cross-species extrapolations (particularly rodent-to-human); and the true
definition of risk–benefit for each individual drug. However, the genera-
tion of classical toxicology data does not assure the accurate prediction of
potential human toxicity. Sundqvist and colleagues15 have reported on a
human dose prediction process, supplemented by case studies, to integrate
uncertainties into simplified plots for quantification. Drug safety is recog-
nized as one of the primary causes of attrition during the clinical phases
of development; however, in numerous instances the actual determination
of serious adverse effects only occurs after the drug reaches the market.
View Online
4 Chapter 1
In the United States, ∼2 million patients are affected with drug-mediated
adverse effects per year, of which ∼5% are fatal.16 This places drug toxicity
as one of the top five causes of death in the United States, and the costs to
the health care system worldwide are estimated at US$40–50 billion per
year.16 In drug development there are always risk–benefit considerations,
which will weigh any potential toxicity against the benefit expected to be
gained by a patient taking the drug. An example of the uncertainty of these
estimates can be seen in the methods used for carcinogenicity testing and
evaluation for drug approval. The design of these studies rely on high-dose
exposure to animals and default linear extrapolation procedures, while
little consideration is given to many of the new advances in the toxicological
sciences.17 Carcinogenicity studies are typically 2-year studies in rodents
conducted with three dosage groups (low, mid, and high dose) and one or
two concurrent control groups. Dose levels are established from previous
studies, such as 13-week toxicity studies, where a MTD has been estimated.
Each group in the carcinogenicity study has 60–70 animals of each sex, and
the analysis of whether there is a potential carcinogenicity concern is based
on an analysis of each tumor in each tissue or organ system individually
by gender; certain tumors are combined via standardized procedures for
statistical analysis. The analysis uses the historical database from the labo-
ratory where the studies are conducted to determine whether each tumor is
considered common or rare, using the background incidence of 1% as the
standard. Common tumors are those with a background incidence of 1%
or over and rare tumors are those with a background incidence below 1%.
In the statistical analysis, p-values for rare and common tumors are evalu-
ated for pair-wise significance at 0.05 (for rare) and 0.01 (for common). The
rare vs. common tumor classification is an arbitrary tumor threshold and
adjustments to the specific classifications by individual tumor, which can
occur from laboratory to laboratory and via analyses of different control
groups, can have consequences in the overall tumor evaluation outcome.8
Applying a “weight of evidence” approach into the evaluation procedures,
particularly during regulatory review, attempts to alleviate some of the
uncertainties; however, after more than 50 years of on-going experience,
these studies still fail to bring the 21st century mindset to carcinogenic-
ity testing. The classic toxicological process for drug development assumes
that a chemical interacts with a higher affinity to a single macromolecule
(the toxicological target), and therefore a single biological pathway may
be perturbed at the initial target modulation. This would be followed by
downstream activation of secondary and possibly tertiary pathways that
result in the tissue or organ effect as indicated by key biomarkers.2 In this
concept, the magnitude of toxicological effects are related to the concen-
tration of altered molecular targets (at the site of interest), which in turn is
related to the concentration of the active form of the chemical (parent com-
pound or metabolite) at the site where the molecular targets are located.
Also included in this concept is the unique susceptibility of the organism
exposed to the compound.
View Online
1.3.2 Toxicological Profiling for Potential Adverse Reactions

Predictive toxicology efforts in drug research and development involve the
use of multiple sources of legacy data including data generated by chemical
and pharmaceutical companies and data submitted to regulatory agencies.
These efforts have led to the “data warehouse” model which includes data
generated through high throughput and targeted screening, and in vitro and
in vivo toxicology studies on thousands of compounds and structural ana-
logues. In a majority of cases these data also include findings from clinical
trials where an experimental drug was tested on humans.
The information is applied in a “backward” fashion to predict potential
findings where data do not yet exist or where decisions are being made
on new potential drug candidates. Bowes and colleagues18 have described
a pharmacological profiling effort by four large pharmaceutical compa-
nies: AstraZeneca, GlaxoSmithKline, Novartis, and Pfizer. The companies
suggest that ∼75% of adverse drug reactions can be predicted by studying
pharmacological profiles of candidate drugs. The pharmacological screen-
ing identifies primary effects related to the intended action of the candi-
date drug, whereas identification of secondary effects due to interactions
with targets other than the primary (intended) target could be related to
off-target adverse events. The groups have identified 44 screening targets
including 24 G-protein coupled receptors, eight ion channels, six intracel-
lular enzymes, three neurotransmitter transporters, two nuclear receptors,
and one kinase. These types of screening data are used in the data ware-
house model, typically configured in a proprietary fashion within each
company. Other collaborative efforts have been developed and data from
these sources would also be incorporated.
Blomme and Will19 have reviewed the current and past efforts by the phar-
maceutical industry to optimize safety into molecules at the earliest stage
of drug research. They conclude that new and emerging technologies in the
past two decades have had limited impact on nonclinical attrition rates asso-
ciated with safety issues. In addition, they point out that front-loading series
of toxicology assays to “kill early, kill often” have been challenged due to high
false-positive rates and an overall low positive predictive value. The primary
issue cited is the lack of information on an efficacious exposures (PK/PD)
and the fact that the assays are more likely to represent hazard identifica-
tion and not risk assessment. Therefore, it is suggested that these data be
used as alerts rather than discontinuance criteria. In a more systems toxi-
cology approach, a large effort is now being directed towards understanding
the extent of pharmacological modulation of both precedented and unprec-
edented targets in relation to potential safety liabilities and developing tech-
nologies to determine achievable therapeutic windows. Blomme and Will19
discuss efforts at AbbVie and Pfizer where target safety assessments are
explored. The assessments include the biology of the target, tissue expres-
sion maps, messenger RNA and proteins, human genetic data, phenotypes
from genetically engineered animal models, historical data from on-going
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6 Chapter 1
and past clinical trials targeting similar targets and associated pathways,
extensive datamining via biomedical databases, and in silico simulation of
the various consequences of target modulation. The majority of systems
research in drug safety use specific toxicities as the starting point. Ivanov
and colleagues20 discuss the use of specific methods to counteract ventricu-
lar tachyarrhythmia (VT). While the in vitro HERG potassium channel assay
is used universally as a predictor of VT, this is only one mechanism of action
and other targets must also be identified and explored. These researchers
have used the following approach: (1) creation of VT positive and negative
compound libraries; (2) in silico prediction of extensive drug–target interac-
tion profiles of chemical libraries identifying potential VT-related targets;
(3) gene ontology and pathway enrichment on these potential VT targets to
elucidate potential biological processes; (4) creation of a cardiomyocyte reg-
ulatory network based on general and heart-specific signaling and regula-
tory pathways; and (5) simulation of the changes in the regulatory network
caused by the inhibition at each node in order to define potential VT-related
targets. These are the type of studies that lead to more refined in vitro and in
silico assessments of potential drug adverse effects at the early stage of drug
research.
Verbist and colleagues21 have outlined another type of systems toxicol-
ogy proposal at Janssen involving QSTAR (quantitative structure-transcrip-
tion-assay relationships) by integrating high-throughput gene expression
profiling data; chemical information, particularly detailed analogue analysis;
and bioassay data. Using several compounds from a single chemical scaffold
targeting PDE10A, a target of pharmacological interest at Janssen, changes
in tubulin gene expression were identified in a subset of compounds. There-
fore a screening process was developed involving multiple cell lines, gene
expression profiling, in vitro micronucleus assays, and high-content imaging
to show microtubule aggregates as compared to other phenotypes. Besides
the chemical series of interest, known positive and negative compounds
were included in the process. This study presents a valuable proof-of-
concept of how to link and potentially improve the risk assessment in early
drug discovery using several technologies in a drug research systems
toxicology approach.
1.3.3 Toxicological Concepts for Safer Chemical Design

Voutchkova and colleagues22 have outlined an extensive framework for safer
chemical design using multiple data and modeling resources. These types of
data generation and modeling approaches are the basis of the process for a
green chemistry model for specific series of chemicals used or proposed for
use as reagents, solvents, or chemical intermediates in chemical synthesis.
The simplified scheme involves a model building process, where chemical
structures of interest are evaluated for chemical motifs (structural alerts)
known to be associated with human health or environmental hazards, chemicals
are clustered into hazard categories and specific high- or higher-throughput
View Online

and targeted assays are identified for each hazard category. Analogue series
directly applicable to the chemistry under evaluation are prepared or
obtained and screened in the relevant assays. With homologous or structur-
ally similar series, local chemical-toxicity models can be developed, validated
and incorporated into the initial computational screening process. This
general method can be applied to any specific hazard, any series of chem-
icals, and any assay methodology. Examples of hazard categories include
carcinogenicity; reproductive and developmental; mutagenicity; neurotoxic-
ity; endocrine disruption; cardiovascular; dermatotoxicity; digestive system
toxicity; hematotoxicity; hepatotoxicity; immunotoxicity; muscular toxicity;
nephrotoxicity; ocular toxicity; ototoxicity; respiratory toxicity; persistence in
the environment; bioaccumulative in the environment; toxic to water organ-
isms; water contaminant; and air pollutant. Structural motif alert and expert
predictions can be achieved using OpenTox,23 an open access system used
to predict potential hazards from chemical structures and known chemical
motifs associated with human health and environmental endpoints, and
Derek from Lhasa,24 a rule-based expert system that de-convolutes a chemical
structure into sub-structural fragments and addresses potential toxicity con-
sistent with the above hazard categories. The software is also used to create
specific local expert predictions from screening data. Meteor (Lhasa) predicts
potential metabolites and the metabolite structures can be used in Derek
predictions. This type of inquiry is highly useful for establishing basic infor-
mation for rank-ordering compounds, as in early candidate selection, and in
the process of safer chemical synthesis. Multiple screening approaches have
been used for evaluation of chemical toxicity using high-throughput tech-
nology and multiple assays. These include the United States Environmental
Protection Agency (EPA) ToxCast program25 where over 2000 chemicals have
been evaluated in over 700 high-throughput assays. This is a section of the
Tox21 testing program, a collaboration among EPA, the National Institutes
of Health (NIH), including the National Center for Advancing Translational
Sciences at the National Toxicology Program at the National Institute of Envi-
ronmental Health Sciences, and the United States Food and Drug Admin-
istration. The Tox21 program involves high-throughput screening of more
than 10 000 environmental chemicals and approved drugs using more than
100 assays. All data are publicly available, as discussed later. Wink and col-
leagues26 discuss a quantitative high-content imaging in vitro process to elu-
cidate chemical interactions with cellular adaptive stress response pathways
to gain a better insight into chemical toxicities at a phenotypic cellular level.
The key to their reported technology is a panel of reporter cell lines to mon-
itor multiple key nodes of the adaptive stress response pathways. Examples
include cellular redox homeostasis, unfolded protein response, endoplas-
mic reticulum damage, inflammatory signaling, and DNA damage response.
These assays hold the potential to be incorporated into multiple large-scale
screens to evaluate health-related chemically-induced biological phenomena
in drug research as well as hazard identification.
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8 Chapter 1
1.3.4 Biomarkers
Biomarkers are typically used to define the onset, continuation, and
either positive or negative characteristics of the induced biological effects
of the drug (chemical) under research. Biomarkers have been classified
as biomarkers of exposure, susceptibility, and outcome. The definition of
biomarker as used in drug discovery and development is a characteristic

that is objectively measured and evaluated as an indicator of normal bio-
logical processes, pathogenic processes, or pharmacologic response(s) to
a therapeutic intervention.27 In pharmacological studies, where a relevant
therapeutic target is identified and pursued, biomarkers are developed that
correlate with the proof of concept for the drug candidate. Biomarkers are
developed to show (1) that a desired modulation of the target occurs as
anticipated by the chemical therapeutic; (2) that the chemical-induced tar-
get modulation produces a desired biological effect; (3) that the induced
biological effect alters the disease under study; and (4) that there may be
increased susceptibility to the therapeutic candidate by certain individu-
als, such as those based on pharmacogenetic predispositions. In toxicology
studies, biomarkers are objectively measured and evaluated as indicators
of (1) normal biological processes; (2) pathogenic processes; (3) pharmaco-
logic response(s) to a therapeutic intervention, which in some cases could
mean excessive or nonspecific pharmacologic activity; and (4) exposure–
response relationships. Pharmacogenetic markers are also studied from
a toxicological standpoint, particularly in relation to drug metabolism. In
environmental research and risk assessment, biomarkers are frequently
referred to as indicators of human or environmental hazards. Discover-
ing and implementing new biomarkers for toxicity caused by exposure
to a chemical from a therapeutic intervention or in some cases through
unintentional exposure continues to be pursued through the use of animal
models to predict potential human effects, from human studies (clinical or
epidemiological) or from biobanked human tissue samples, or the combi-
nation of these approaches.27 In addition, several omics technologies such
as transcriptomics, metabolomics, and proteomics have added an import-
ant aspect to biomarker research.12 More recently, epigenomics, which is
the study of changes in gene activity not attributed to DNA sequence alter-
ations, has been shown to have increased importance in disease causality
research.12 These technologies and data produced, along with large data-
sets of high-throughput screening data, essentially changed the process of
defining biomarkers. The process of discovering or inferring biomarkers
through computational means involves the identification or prediction of
the molecular target(s) of the chemical, which in many cases can be sec-
ondary or undesirable targets and the association of these targets with
perturbed biological pathways. The integration of these approaches with
the quantitative analysis of chemically induced molecular and functional
changes has brought to fruition the goals originally outlined in the 2007
NRC report.9
View Online
1.4 Environmental Toxicology

The concepts of environmental chemical toxicity are different to the con-
cepts of drug toxicity, as with environmental exposures there are only risk
considerations, with virtually no benefit associated with chemical exposure.
Currently there are more than 80 000 chemicals on the market and/or reach
the environment, and ∼2000 new chemicals are introduced each year. Unlike
drugs, for the majority of these compounds, there is limited or inadequate
toxicological information with which to make rational evaluations of risk.2
Where information exists or is associated from similar structures of anal-
ogous compounds, a risk assessor may arrive at various hazard reference
values, such as a derived no-effect level, to estimate an acceptable level of
protection of human or wildlife health and the environment.5 Depending
on the context and urgency of the risk assessment, which could include the
classification of a chemical in terms of hazard severity and risk management
assessment, several assumptions must be made which could cause the level
of uncertainty to increase.
1.4.1 Adverse Outcome Pathway

The concept of the AOP was a necessary enhancement to the Toxicity Testing
in the Twenty-first Century report, made to more adequately support ecologi-
cal risk assessment.6 After the first publication in 2010, and subsequent pub-
lications by scientists at the EPA,10,11 the AOP concept and developing case
studies have become a primary force in the progression of the computational
systems toxicology approach in environmental risk assessment. Unlike work
in drug discovery and development, which always has a confidential busi-
ness information component and therefore results are not fully publically
available, AOPs are developed in a fully open-access mode and are supported
by publicly available databases updated by EPA scientists. The AOP con-
cept highlights existing knowledge that links the direct molecular initiating
event, of which in theory is the interaction or modulation of a molecular bio-
molecule or target with a xenobiotic, and an adverse outcome at a biological
organization that spans multiple levels of biological organization including
the following general examples from Ankley and colleagues.6 These events
are outlined below.

(1) Macro-molecular interactions, such as receptor–ligand interac-
tions including agonism and antagonism, DNA binding, and protein
oxidation.
(2) Cellular responses, such as gene activation, protein production, alter-
ations in signaling, and protein depletion.
(3) Organ responses, such as disrupted homeostasis, alterations in tissue
development and/or function, and altered physiology.
(4) Organism responses, such as mortality, impaired reproductive and
developmental function, and development of diseases, such as cancer.
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10 Chapter 1
(5) Population responses, such as alterations in the structure of a popu-
lation and potential extinction of species within regional and global
environments.

In defining the key aspects of an AOP, macro-molecular interactions (1)
are considered the initiating event, which is called “anchor 1”, and the organ
and population responses (4 and 5) are considered adverse outcomes at the
organism or population level, collectively called “anchor 2”. The aspects of
connecting the initiating events to outcomes can take various forms, depend-
ing on the chemical itself and the amount of information available, includ-
ing in vivo, in vitro, and computational sources. These various linkages also
help to define key assays and technologies to enhance information collection
and usage for each individual AOP. Ankley and colleagues6 provide five case
studies that illustrate these points. Events occurring in the information flow
between the molecular initiating event and adverse outcome are called inter-
mediate events.28 When an intermediate event represents a biological event
that is necessary for an adverse outcome to occur and is quantitatively mea-
surable, it is considered to be a key event. In a systems toxicology approach,
key event relationships between adjacent molecular initiating events, key
events and adverse outcomes help define alternative approaches to assess
environmental hazards. In a signaling pathway, this could be upstream or
downstream events that help define more suitable assays or test systems and
provide a faster quantitative evaluation of potential adverse outcomes. One of
the challenges in the AOP process is to define or estimate the exposure of the
xenobiotic in the relevant species under consideration for risk assessment.
1.4.2 Expanding Exposure Concepts

As discussed earlier, measurement of exposure, toxicokinetics, system-
ically and importantly, at the critical site of action (anchor 1) is an essen-
tial piece of information. Unlike pharmaceutical compounds, it is highly
unlikely that there would ever be controlled human toxicokinetics data for
industrial and environmental chemicals.29 Extrapolating toxicokinetic mod-
els from in vitro data has been used with pharmaceutical compounds, and
this is termed in vitro to in vivo extrapolation methodology. These models
have been used with some success for environmental and industrial chem-
icals using high-throughput toxicokinetics (HTTK) models. Several exam-
ples of HTTK methodology have been published, including lecture series
by scientists from the United States EPA, the National Center for Compu-
tational Toxicology, and the Hamner Institutes for Health Sciences.29,30 The
primary methodology is termed “reverse dosimetry”, which uses concentra-
tions that produce bioactivity in in vitro assays to estimate doses (mg kg−1
per day) sufficient to produce steady-state plasma concentrations (Css) in
µM. These approaches assume 100% bioavailability and a linear relationship
between Css and dose. Another approach, called probabilistic reverse dosim-
etry approaches for estimating exposure distributions (PROcEED)30 uses
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exertion of the morning, hurried her off to bed, promising to have
“something hearty” sent up on a tray.
To Isabella Weeks it was untold luxury to be so fussed over and

cared for. She tried several times to express her gratitude, but
emotion so choked her that the words would not come.
Once when Betty was starting to leave the room, she caught at
the girl’s hand, pressing it for a moment to her withered old cheek.
“I was right,” she murmured. “Your mother is very lovely, dear

child; and you are just like her.”
Then followed days of house hunting and furniture selection that

were pure joy to the Outdoor Girls. Although the little old lady was
too frail to go with them on their shopping trips, each evening they
talked over the adventures of the day with her, telling her just what
they had bought and submitting long lists, with the price opposite
each article, for her inspection.
They found exactly the right kind of house, a little four-room

bungalow with a broad, low porch and window boxes in every
window. This they furnished gayly with wicker and cretonne and
comfortable cushions heaped up everywhere.
When it was all ready—complete even to the maid with white cap
and apron—they proudly bore the old lady to her new home,
triumphantly exhibiting the results of their work.
The old lady seemed completely carried away with delight. And so
they were taken totally unawares when after an inspection of the
four rooms the owner of the pretty bungalow dropped into a deep-
seated, gayly-cushioned chair and, covering her face with her hands,
began to weep silently.
Disconcerted, utterly bewildered, the girls stared at her. But

suddenly the little old lady lifted a face to them that was radiant
through the tears.
“Don’t be alarmed, my dears,” she said, in her quaint, wistful way.

“I’m not ill. I don’t believe joy ever made any one ill, do you?”
“Not ever in the world!” answered the Little Captain, happily.
Days followed during which the girls were almost always with
Isabella Weeks. Through all the red tape of legal procedure she
insisted on their presence. And though her health seemed to
improve daily, owing to good food and good care and lack of worry,
the girls noticed that she was restless and uneasy, seeming always
to listen for some one who did not come.
“She’s waiting for James Barton,” thought Betty, adding softly: “I

hope we hear good news from Allen soon.”
Betty heard from the young lawyer nearly every day, but he gave
no assurance that he would be able to locate James Barton. In fact,
he was so noncommittal about the result of his search that the girls
finally began to believe the worst.
Then one evening, as Betty read to the old lady and the rest of
the girls lounged about the pretty living room, there was a sudden
sounding of a motor horn from without the house that drew them all
to their feet.
The little old lady turned suddenly white, her hand flew to her
throat. Betty, having glanced out the window, came over and laid a
quieting hand on the old lady’s shoulder. One would never have told
from Betty’s voice how her heart was thumping.
“It’s Allen,” she said, softly. “And he has some one with him.”
The next moment the door was flung open and Allen himself
stepped inside the room. Beside him was one of the handsomest old
gentlemen the girls had ever seen. Erect and soldierly in his bearing,
broad-shouldered and ruddy of face, with a mass of curly iron gray
hair, he was the kind of man one instinctively turns and stares after
in the street.
There was a moment of tense silence while the two who had been
lovers in their youth looked deep into each other’s eyes. Then James
Barton started forward, eager hands outstretched.
“Isabella!” he cried. “After all the wasted years I’ve come to you!
Are you glad?”
“Oh, my dear!” the words seemed wrung from the little old lady as
she lifted her face to him. “All my life—I think—I’ve waited for this
moment——”
Stumblingly, eyes blinded by tears, the girls found themselves

outside the house. Somehow Betty’s hand slipped into Allen’s.
“You—you’re wonderful, Allen!” she whispered. “How did you ever

do it?”
The young lawyer leaned close to her.
“I promised I would, didn’t I?” said he.
Two weeks later on a gloriously sunshiny morning, within the dim

interior of “the little church around the corner” before the minister
stood a pair of lovers, old in years but possessing the priceless gift
of hearts that will always be young.
The slender, blue-veined hand of the little Old Maid of the

Mountains trembled in the grip of James Barton but her voice was
sweet and resolute as she answered clearly, “I do.”
Back in the pew where four Outdoor Girls and four stalwart lads
were gathered, there sounded a muffled little sob. It was Amy who
was crying and Will quite openly and shamelessly held her hand.
Then gently, as though unconsciously, Allen’s arm stole about the

Little Captain, drawing her close to him. And because of the warmth
about her heart—perhaps because of other reasons too, who knows?
—Betty did not draw away.
THE END
This Isn’t All!
Would you like to know what became of the good friends you have
made in this book?
Would you like to read other stories continuing their adventures

and experiences, or other books quite as entertaining by the same
author?
On the reverse side of the wrapper which comes with this book,
you will find a wonderful list of stories which you can buy at the
same store where you got this book.
Don’t throw away the Wrapper

Use it as a handy catalog of the books you want some day to have.
But in case you do mislay it, write to the Publishers for a complete
catalog.
THE OUTDOOR GIRLS SERIES
By LAURA LEE HOPE
Author of “The Blythe Girls Books.”
Every Volume Complete in Itself.
These are the adventures of a group of bright, fun-loving, up-to-

date girls who have a common bond in their fondness for outdoor
life, camping, travel and adventure. There is excitement and humor
in these stories and girls will find in them the kind of pleasant
associations that they seek to create among their own friends and
chums.
THE OUTDOOR GIRLS OF DEEPDALE

THE OUTDOOR GIRLS AT RAINBOW LAKE
THE OUTDOOR GIRLS IN A MOTOR CAR
THE OUTDOOR GIRLS IN A WINTER CAMP
THE OUTDOOR GIRLS IN FLORIDA
THE OUTDOOR GIRLS AT OCEAN VIEW
THE OUTDOOR GIRLS IN ARMY SERVICE
THE OUTDOOR GIRLS ON PINE ISLAND
THE OUTDOOR GIRLS AT THE HOSTESS HOUSE
THE OUTDOOR GIRLS AT BLUFF POINT
THE OUTDOOR GIRLS AT WILD ROSE LODGE
THE OUTDOOR GIRLS IN THE SADDLE
THE OUTDOOR GIRLS AROUND THE CAMPFIRE
THE OUTDOOR GIRLS ON CAPE COD
THE OUTDOOR GIRLS AT FOAMING FALLS
THE OUTDOOR GIRLS ALONG THE COAST
THE OUTDOOR GIRLS AT SPRING HILL FARM
THE OUTDOOR GIRLS AT NEW MOON RANCH
THE OUTDOOR GIRLS ON A HIKE
THE OUTDOOR GIRLS ON A CANOE TRIP
THE OUTDOOR GIRLS AT CEDAR RIDGE
THE OUTDOOR GIRLS IN THE AIR
GROSSET & DUNLAP, Publishers, NEW YORK

The
OUTDOOR GIRLS
By LAURA LEE HOPE
Author of The Bobbsey Twins
The Bunny Brown Series, Etc.
These tales tell of the exciting adventures enjoyed by several

bright, up-to-date girls who love outdoor life.
The Outdoor Girls of Deepdale

The Outdoor Girls at Rainbow Lake
The Outdoor Girls in a Motor Car
The Outdoor Girls in a Winter Camp
The Outdoor Girls in Florida
The Outdoor Girls at Ocean View
The Outdoor Girls on Pine Island
The Outdoor Girls in Army Service
The Outdoor Girls at Hostess House
The Outdoor Girls at Bluff Point
The Outdoor Girls at Wild Rose Lodge
The Outdoor Girls in the Saddle
The Outdoor Girls Around the Campfire
The Outdoor Girls on Cape Cod
The Outdoor Girls at Foaming Falls
The Outdoor Girls Along the Coast
The Outdoor Girls at Spring Hill Farm
The Outdoor Girls at New Moon Ranch
The Outdoor Girls on a Hike
The Outdoor Girls on a Canoe Trip
The Outdoor Girls at Cedar Ridge
The Outdoor Girls in the Air
GROSSET & DUNLAP, NEW YORK

Mystery Stories
for Girls
By LILIAN GARIS
BARBARA HALE
It was Barbara’s sympathy and understanding that helped her

unravel the mystery that surrounded the fascinating little Italians,
Nicky and Vicky—and that helped her recover the “Santa Maria”
model for the elderly Davis twins.
BARBARA HALE’S MYSTERY FRIEND
One dark, dreary night, in the pouring rain, a little girl comes
tapping at the door of Barbara’s home. Who is she? Where is she
from? Have the strange Armenians with their beautiful embroideries
anything to do with her? Barbara has many anxious moments
before she finds the answers to these questions.
NANCY BRANDON
Running a successful “Whatnot Shop” during her vacation did not

keep Nancy too busy to try to solve the mystery of the
“disappearing” Mr. Sanders, who had the whole town upset by his
strange behavior.
NANCY BRANDON’S MYSTERY
Nancy’s summer vacation in the New Hampshire mountains

proves an exciting one—for she determines to protect her cousin
Rosa from the bad influence of the mysterious, fiery tempered and
bitter Orilla. And Nancy has a real surprise when she discovers
Orilla’s secrets.
JUDY JORDAN
Judy seeks a writing career in New York City and makes many
interesting friends—the wealthy Estelle who wants to run away for
excitement, “Lord Dinny” who wants to write, too—and Dave Lane,
a successful and friendly reporter.
JUDY JORDAN’S DISCOVERY
The mysterious but attractive man living alone in the Old Stewart
place piques Judy’s curiosity—and when she finally discovers his
true identity she has the surprise of her life.
GROSSET & DUNLAP, New York

By
CAROLYN
KEENE
Solve these thrilling mysteries

with Nancy Drew!
Nancy Drew Mystery Stories

THE SECRET OF THE OLD CLOCK—Nancy seeks to find a
missing will and an old clock plays a big part in the search.
THE HIDDEN STAIRCASE—The discovery of a hidden staircase in

an old mansion helps to solve the secret of some mysterious
happenings.
THE BUNGALOW MYSTERY—Nancy has some weird experiences

around a deserted bungalow while trying to help a girl friend out of
a dangerous situation.
THE MYSTERY AT LILAC INN—The strange mystery that had its

beginning at Lilac Inn needed quick thinking and instant action.
THE SECRET AT SHADOW RANCH—On a vacation in Arizona

Nancy uncovers an old mystery and follows a faint clue.
THE SECRET OF RED GATE FARM—Nancy becomes suspicious

of a secret society which meets on an old farm on a hillside.
NANCY’S MYSTERIOUS LETTER—A thrilling story that centers

around the contents of a mysterious letter.
THE SIGN OF THE TWISTED CANDLES—A chance stop at a

little country inn leads Nancy into a mysterious plot that involves a
family feud and a hidden will.
GROSSET & DUNLAP Publishers NEW YORK

Transcriber’s Note:
Variations in spelling and hyphenation

have been retained as they appear in the
original publication. Punctuation has
been standardised.
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Computational Systems Pharmacology and Toxicology Johnson 2024 Scribd Download

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Download the full version of the textbook now at textbookfull.

Computational systems pharmacology and

Explore and download more textbook at https://textbookfull.com

Computational Toxicology Orazio Nicolotti

Studies on Experimental Toxicology and Pharmacology 1st

Advances in Computational Toxicology Methodologies and

Principles of Risk Analysis: Decision Making Under

Animal Biotechnology 2 Heiner Niemann

Postcolonial Screen Adaptation and the British Novel

The Chemistry of Mycotoxins 1st Edition Stefan Bräse

Spider Web: The Birth of American Anticommunism 1st

Computational Systems Pharmacology and Toxicology

Timothy C. Marrs, Edentox Associates, UK

Titles in the Series:

26: Chemical Warfare Toxicology, Volume 1: Fundamental Aspects

31: Computational Systems Pharmacology and Toxicology

How to obtain future titles on publication:

For further information please contact:

Issues in Toxicology No. 31

Print ISBN: 978-1-78262-332-8

© The Royal Society of Chemistry 2017

All rights reserved

For further information see our web site at www.rsc.org

Our motivation for bringing about a book on systems computational

Issues in Toxicology No. 31

Chapter 1 Systems Biology Approaches in Pharmacology and

Issues in Toxicology No. 31

2.2 Categorized Lists of Databases for Systems Toxicology  21

Chapter 3 Tools for Green Molecular Design to Reduce

Chapter 4 Linking Environmental Exposure to Toxicity  60

4.4 The AEP Framework: An Organizing Principle for

Chapter 5 Linking Drug or Phytochemical Exposure to Toxicity  89

Chapter 6 Chemical Similarity, Shape Matching and QSAR  120

6.1 I ntroduction  120

6.4 Conclusion  153

Chapter 7 In silico Chemical–Protein Docking and Molecular

7.1 I ntroduction  174

Chapter 8 Computational Tools for Chemical Toxicity Testing

8.1 I ntroduction  191

8.6.4 Case Studies  203

Chapter 9 In silico Toxicology: An Overview of Toxicity Databases,

9.1 I ntroduction  209

Chapter 10 Data Sources for Herbal and Traditional Medicines  243

10.1 I ntroduction  243

Text Mining)  248

Chapter 11 Network Pharmacology Research Approaches for

11.1 I ntroduction  261

Chapter 12 Chemical–Disease Category Linkage (CDCL):

12.1 I ntroduction  279

12.5 Combination Therapies and Future Directions  294

Chapter 13 Educational Programs for Computational Toxicology

13.1 I ntroduction  300

Subject Index  324

Systems Biology Approaches in

Issues in Toxicology No. 31

new approaches and move away from an overdependence on in vivo animal

1.2 Systems Toxicology

Systems Biology Approaches in Pharmacology and Toxicology 3

national Consortium for Innovation and Quality in Pharmaceutical Develop-

Chapter 1 Systems Biology Approaches in Pharmacology and

2.2 Categorized Lists of Databases for Systems Toxicology 21

Chapter 3 Tools for Green Molecular Design to Reduce

Chapter 4 Linking Environmental Exposure to Toxicity 60

4.4 The AEP Framework: An Organizing Principle for

Chapter 5 Linking Drug or Phytochemical Exposure to Toxicity 89

Chapter 6 Chemical Similarity, Shape Matching and QSAR 120

6.1 I ntroduction 120

6.4 Conclusion 153

Chapter 7 In silico Chemical–Protein Docking and Molecular

7.1 I ntroduction 174

Chapter 8 Computational Tools for Chemical Toxicity Testing

8.1 I ntroduction 191

8.6.4 Case Studies 203

Chapter 9 In silico Toxicology: An Overview of Toxicity Databases,

9.1 I ntroduction 209

Chapter 10 Data Sources for Herbal and Traditional Medicines 243

10.1 I ntroduction 243

Text Mining) 248

Chapter 11 Network Pharmacology Research Approaches for

11.1 I ntroduction 261

Chapter 12 Chemical–Disease Category Linkage (CDCL):

12.1 I ntroduction 279

12.5 Combination Therapies and Future Directions 294

Chapter 13 Educational Programs for Computational Toxicology

13.1 I ntroduction 300

Subject Index 324

1.2 Systems Toxicology

1.3 Chemical Toxicities

1.3.2 Toxicological Profiling for Potential Adverse Reactions

1.3.3 Toxicological Concepts for Safer Chemical Design

1.4 Environmental Toxicology

1.4.1 Adverse Outcome Pathway

1.4.2 Expanding Exposure Concepts