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Challenges and Advances
in Computational Chemistry and Physics 30
Series Editor: Jerzy Leszczynski
Huixiao Hong Editor
Advances in
Computational
Toxicology
Methodologies and Applications in
Regulatory Science
Challenges and Advances in Computational
Chemistry and Physics
Volume 30
Series Editor
Jerzy Leszczynski
Department of Chemistry and Biochemistry
Jackson State University, Jackson, MS, USA
This book series provides reviews on the most recent developments in computa-
tional chemistry and physics. It covers both the method developments and their
applications. Each volume consists of chapters devoted to the one research area.
The series highlights the most notable advances in applications of the computa-
tional methods. The volumes include nanotechnology, material sciences, molecular
biology, structures and bonding in molecular complexes, and atmospheric
chemistry. The authors are recruited from among the most prominent researchers
in their research areas. As computational chemistry and physics is one of the most
rapidly advancing scientific areas such timely overviews are desired by chemists,
physicists, molecular biologists and material scientists. The books are intended for
graduate students and researchers.
All contributions to edited volumes should undergo standard peer review to
ensure high scientific quality, while monographs should be reviewed by at least two
experts in the field. Submitted manuscripts will be reviewed and decided by the
series editor, Prof. Jerzy Leszczynski.
More information about this series at http://www.springer.com/series/6918

Huixiao Hong
Editor
Advances in Computational
Toxicology
Methodologies and Applications
in Regulatory Science
123
Editor
Huixiao Hong
National Center for Toxicological Research
US Food and Drug Administration
Jefferson, AR, USA
ISSN 2542-4491 ISSN 2542-4483 (electronic)

Challenges and Advances in Computational Chemistry and Physics
ISBN 978-3-030-16442-3 ISBN 978-3-030-16443-0 (eBook)
https://doi.org/10.1007/978-3-030-16443-0
Library of Congress Control Number: 2019935555
© Springer Nature Switzerland AG 2019

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Foreword
Given the ever-increasing panoply of human and animal drugs, food products, and
environmental chemicals, the need for science-based risk/safety regulation is
greater than ever. From a pharmaceutical perspective, accurate and effective toxicity
evaluation is critical in several areas such as dose–response characteristics including
organ exposure and first-in-human dosages, reproductive and carcinogenicity tox-
icity, exposure assessment, and biological pathway characterization. Food product
assessment requires understanding of gastrointestinal delivery, metabolic break-
down into metabolites, context of use, and dietary exposures. Lastly, environmental
toxicity necessitates system-level approaches considering chemical mixtures and
chemical transport into target organs in multiple species. Despite these extensive
efforts, idiosyncratic toxicities can occur, suggesting the need for personalized
toxicity approaches.
Conventional approaches along with some new methodologies like “organ-
or-a-chip” have been developed to address key questions in this area. Many of these
approaches are limited in cost, time, translational accuracy, and scalability.
Consequently, scientific endeavors in the computational space have inspired new
and powerful tools, ushering in the era of computational toxicology. This exciting
field facilitates the paradigm shift from bench-based toxicology to the computa-
tional assessment and will provide regulators globally with the benefit of fast,
accurate, and low-cost methods to supplement conventional toxicity assessment.
Moreover, integrative predictive approaches may enhance personalized toxicolog-
ical prediction to prevent idiosyncratic events.
To inform not only regulators around the world but also key stakeholders,
industry, and academic trainees, this textbook provides a deep dive into compu-
tational toxicological approaches needed to advance toxicological regulation
through research. It includes sections outlining theory, methods, applications, as
well as tangible examples and covers development through implementation.
Information in this book will apprise the reader with a greater understanding of
computer-based toxicological predictive capabilities. Information in this book will
also enable the reader to develop their own cutting-edge computational strategy to
address a toxicological question of interest. The provided information may also
v
vi Foreword
foster collaboration by providing inspiration for scientific discourse among readers

with diverse training backgrounds.
Currently, computational toxicology has gained acceptance as an “alternative”
testing method compared to traditional approaches for rapid toxicity assessment.
The toxicology community of scientists and regulators look forward to the vali-
dation of computational methods that may supplement and, in some cases, replace
traditional assays. The contents of this textbook, inspired by new computational
methods and approaches, provides a comprehensive overview of the representative
methodologies in the land of computational toxicology with an emphasis on reg-
ulatory science research.
Jefferson, AR, USA William Slikker Jr. Ph.D.

Director, National Center for Toxicological Research
Preface
In comparison with the field of toxicology which dates back to ancient civilizations,
the field of computer science is just coming of age. After many years of focused
development, computational tools, methods, hardware, and knowledge have
advanced enough to be of utility in other fields. Computational techniques are now
employed in toxicology for regulatory, research, and development purposes. We
compiled this book with the ambition to capture the latest advancements at the
intersection of computer science and toxicology together in one location.
Our motivation in creating this book was twofold. First of all, the number of new
chemical entities being developed by the ever-growing pharmaceutical, biotech-
nology, and food industry is dizzying. Absolutely all of these products must be
screened for safety at various stages of development. Secondly, the ecosystem of
our planet is increasingly bathed in an assortment of molecules, many of which
nature has never experienced before. The surge of new molecules and entities
entering the human body and the environment presents an insurmountable chal-
lenge to traditional toxicology. Impressively, the novel computational toxicology
methods described herein are rising to meet the challenge.
Machine learning, artificial intelligence, quantitative structure–activity relation-
ship (QSAR), bioinformatics, genomics, proteomics, molecular dynamics, and
more are described via examples of applications to toxicology. Both safety eval-
uation and risk assessment are topics of consideration across multiple chapters.
A background introduction followed by details is provided for computational
toxicology methods, as well as applications. Toxicology from the perspective of
medicines, food products, and the environment is described in multiple chapters.
This book is intended as a text for established computer scientists looking to
enter the toxicology field, experienced toxicologists seeking to enable research
through computational methods, or students and trainees curious about stepping
into the field. Thus, this book includes not only introductory sections to help readers
become familiar with new concepts but also detailed actionable methods which can
be deployed by the reader. Each chapter of this book can stand alone to update the
reader on a specific topic of interest. Alternatively, this textbook can be read in
sections as chapters that are roughly organized in topical order. For a graduate
vii
viii Preface
course on computational toxicology, this book would provide excellent reading

material. Studying the entire book will provide the reader with not only a broad but
also a deep understanding of the field.
While this book does focus on computational toxicology, it does not contain any
learning exercises, quizzes, or snippets of computer code for the reader to advance
and test knowledge. In the case of the classroom setting, these materials would be
left to the course instructor. Moreover, herein we do not review basic toxicology
concepts as they are effectively covered by other established bodies of work. We
would be appreciative of any corrections, feedback, comments, or criticism from
readers on how to improve for a future body of work.
Inspired by how computational toxicology is rising to meet the challenges
currently facing traditional toxicology methods, we put forth this book for the
community as an educational tool. The broad scope and deep depth of this textbook
would not be possible without the herculean efforts of and tremendous cooperation
from the authors, for which we are tremendously appreciative. This book also
would not have been possible without the support and vision of Springer, who we
acknowledge for having a visionary understanding of the importance of the topic at
hand.
This preface reflects the views of the authors and should not be construed to
represent the FDA’s views or policies.
Cambridge, MA, USA Rebecca Kusko, Ph.D.

Senior Vice President and Head of R&D
Immuneering Corporation
Jefferson, AR, USA Huixiao Hong, Ph.D.
Chief, Bioinformatics Branch
Division of Bioinformatics and Biostatistics
National Center for Toxicological Research
Contents
1 Computational Toxicology Promotes Regulatory Science . . . . . . . . 1

Rebecca Kusko and Huixiao Hong
Part I Methods in Computational Toxicology

2 Background, Tasks, Modeling Methods, and Challenges
for Computational Toxicology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15
Zhongyu Wang and Jingwen Chen
3 Modelling Simple Toxicity Endpoints: Alerts, (Q)SARs
and Beyond . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 37
Richard Williams, Martyn Chilton, Donna Macmillan, Alex Cayley,
Lilia Fisk and Mukesh Patel
4 Matrix and Tensor Factorization Methods for Toxicogenomic
Modeling and Prediction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 57
Suleiman A. Khan, Tero Aittokallio, Andreas Scherer,
Roland Grafström and Pekka Kohonen
5 Cardio-oncology: Network-Based Prediction of Cancer
Therapy-Induced Cardiotoxicity . . . . . . . . . . . . . . . . . . . . . . . . . . . 75
Feixiong Cheng
6 Mode-of-Action-Guided, Molecular Modeling-Based Toxicity
Prediction: A Novel Approach for In Silico Predictive
Toxicology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 99
Ping Gong, Sundar Thangapandian, Yan Li, Gabriel Idakwo,
Joseph Luttrell IV, Minjun Chen, Huixiao Hong and Chaoyang Zhang
7 A Review of Feature Reduction Methods for QSAR-Based
Toxicity Prediction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 119
Gabriel Idakwo, Joseph Luttrell IV, Minjun Chen, Huixiao Hong,
Ping Gong and Chaoyang Zhang
ix
x Contents
8 An Overview of National Toxicology Program’s Toxicogenomic

Applications: DrugMatrix and ToxFX . . . . . . . . . . . . . . . . . . . . . . 141
Daniel L. Svoboda, Trey Saddler and Scott S. Auerbach
9 A Pair Ranking (PRank) Method for Assessing Assay
Transferability Among the Toxicogenomics Testing Systems . . . . . 159
Zhichao Liu, Brian Delavan, Liyuan Zhu, Ruth Robert
and Weida Tong
10 Applications of Molecular Dynamics Simulations
in Computational Toxicology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 181
Sugunadevi Sakkiah, Rebecca Kusko, Weida Tong and Huixiao Hong
Part II Applications in Regulatory Science

11 Applicability Domain: Towards a More Formal Framework
to Express the Applicability of a Model and the Confidence
in Individual Predictions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 215
Thierry Hanser, Chris Barber, Sébastien Guesné,
Jean François Marchaland and Stéphane Werner
12 Application of Computational Methods for the Safety Assessment
of Food Ingredients . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 233
Patra Volarath, Yu (Janet) Zang and Shruti V. Kabadi
13 Predicting the Risks of Drug-Induced Liver Injury in Humans
Utilizing Computational Modeling . . . . . . . . . . . . . . . . . . . . . . . . . 259
Minjun Chen, Jieqiang Zhu, Kristin Ashby, Leihong Wu,
Zhichao Liu, Ping Gong, Chaoyang (Joe) Zhang, Jürgen Borlak,
Huixiao Hong and Weida Tong
14 Predictive Modeling of Tox21 Data . . . . . . . . . . . . . . . . . . . . . . . . . 279
Ruili Huang
15 In Silico Prediction of the Point of Departure (POD)
with High-Throughput Data . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 299
Dong Wang
16 Molecular Modeling Method Applications: Probing
the Mechanism of Endocrine Disruptor Action . . . . . . . . . . . . . . . . 315
Xianhai Yang, Huihui Liu and Rebecca Kusko
17 Xenobiotic Metabolism by Cytochrome P450 Enzymes:
Insights Gained from Molecular Simulations . . . . . . . . . . . . . . . . . 337
Zhiqiang Fu and Jingwen Chen
Contents xi
18 Integrating QSAR, Read-Across, and Screening Tools:

The VEGAHUB Platform as an Example . . . . . . . . . . . . . . . . . . . . 365
Emilio Benfenati, Alessandra Roncaglioni, Anna Lombardo
and Alberto Manganaro
19 OpenTox Principles and Best Practices for Trusted Reproducible
In Silico Methods Supporting Research and Regulatory
Applications in Toxicological Science . . . . . . . . . . . . . . . . . . . . . . . 383
Barry Hardy, Daniel Bachler, Joh Dokler, Thomas Exner,
Connor Hardy, Weida Tong, Daniel Burgwinkel
and Richard Bergström
Index . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 405
Editor and Contributors
About the Editor
Huixiao Hong is Chief of Bioinformatics Branch, Division of Bioinformatics and

Biostatistics, National Center for Toxicological Research (NCTR), US Food and
Drug Administration (FDA), working on the scientific bases for regulatory appli-
cations of bioinformtics. Before joining the FDA, he was Manager of
Bioinformatics Division of Z-Tech, an ICFI company. He was Research Scientist at
Sumitomo Chemical Company in Japan and Visiting Scientist at National Cancer
Institute at National Institutes of Health. He was also Associate Professor and
Director of Laboratory of Computational Chemistry at Nanjing University in China.
He is Member of steering committee of OpenTox, Member of board directors of US
MidSouth Computational Biology and Bioinformatics Society, and in the leader-
ship circle of US FDA modeling and simulation working group. He published more
than 180 scientific papers and served as Editor-in-Chief and Editorial Board
member for multiple peer-reviewed journals. He received his Ph.D. from Nanjing
University in China in 1990 and conducted research in University of Leeds in
England in 1990–1992. e-mail: Huixiao.Hong@fda.hhs.gov
Contributors
Tero Aittokallio Institute for Molecular Medicine Finland, University of Helsinki,

Helsinki, Finland;
Department of Mathematics and Statistics, University of Turku, Turku, Finland
Kristin Ashby Division of Bioinformatics and Biostatistics, National Center for
Toxicological Research, US Food and Drug Administration (FDA), Jefferson, AR,
USA
xiii
xiv Editor and Contributors
Scott S. Auerbach Division of the National Toxicology Program, National

Institute of Environmental Health Sciences, National Institutes of Health, Durham,
NC, USA
Daniel Bachler Edelweiss Connect GmbH, Technology Park Basel, Basel,
Switzerland
Chris Barber Lhasa Limited, Leeds, UK
Emilio Benfenati Istituto di Ricerche Farmacologiche Mario Negri – IRCCS,
Milano, Italy
Richard Bergström Bergstroem Consulting GmbH, Zug, Switzerland
Jürgen Borlak Hannover Medical School, Center of Pharmacology and
Toxicology, Hannover, Germany
Daniel Burgwinkel Guardtime AS, Basel, Switzerland
Alex Cayley Lhasa Limited, Leeds, UK
Jingwen Chen Key Laboratory of Industrial Ecology and Environmental
Engineering (Ministry of Education), School of Environmental Science and
Technology, Dalian University of Technology, Dalian, China
Minjun Chen Division of Bioinformatics and Biostatistics, National Center for
USA
Feixiong Cheng Genomic Medicine Institute, Lerner Research Institute,
Cleveland Clinic, Cleveland, OH, USA;
Department of Molecular Medicine, Cleveland Clinic Lerner College of Medicine,
Case Western Reserve University, Cleveland, OH, USA;
Case Comprehensive Cancer Center, Case Western Reserve University School of
Medicine, Cleveland, OH, USA
Martyn Chilton Lhasa Limited, Leeds, UK
Brian Delavan Division of Bioinformatics and Biostatistics, National Center for
USA;
Department of Biosciences, University of Little Rock, Little Rock, AR, USA
Joh Dokler Edelweiss Connect GmbH, Technology Park Basel, Basel,
Switzerland
Thomas Exner Edelweiss Connect GmbH, Technology Park Basel, Basel,
Switzerland
Lilia Fisk Lhasa Limited, Leeds, UK
Editor and Contributors xv
Zhiqiang Fu Key Laboratory of Industrial Ecology and Environmental

Ping Gong Environmental Laboratory, US Army Engineer Research and
Development Center, Vicksburg, MS, USA
Roland Grafström Institute of Environmental Medicine, Karolinska Institutet,
Stockholm, Sweden;
Predictomics AB, Stockholm, Sweden;
Misvik Biology Oy, Turku, Finland
Sébastien Guesné Lhasa Limited, Leeds, UK
Thierry Hanser Lhasa Limited, Leeds, UK
Barry Hardy Edelweiss Connect GmbH, Technology Park Basel, Basel,
Switzerland
Connor Hardy Edelweiss Connect GmbH, Technology Park Basel, Basel,
Switzerland
Huixiao Hong Division of Bioinformatics and Biostatistics, National Center for
USA
Ruili Huang National Center for Advancing Translational Sciences, NIH,
Rockville, MD, USA
Gabriel Idakwo School of Computing Sciences and Computer Engineering,
University of Southern Mississippi, Hattiesburg, MS, USA
Shruti V. Kabadi FDA/CFSAN/OFAS, College Park, MD, USA
Suleiman A. Khan Institute for Molecular Medicine Finland, University of
Helsinki, Helsinki, Finland
Pekka Kohonen Institute of Environmental Medicine, Karolinska Institutet,
Stockholm, Sweden;
Predictomics AB, Stockholm, Sweden;
Misvik Biology Oy, Turku, Finland
Rebecca Kusko Immuneering Corporation, Cambridge, MA, USA
Yan Li Bennett Aerospace, Inc., Cary, NC, USA
Huihui Liu Jiangsu Key Laboratory of Chemical Pollution Control and Resources
Reuse, School of Environmental and Biological Engineering, Nanjing University of
Science and Technology, Nanjing, China
Zhichao Liu Division of Bioinformatics and Biostatistics, National Center for
USA
xvi Editor and Contributors
Anna Lombardo Istituto di Ricerche Farmacologiche Mario Negri – IRCCS,

Milano, Italy
Joseph Luttrell IV School of Computing Sciences and Computer Engineering,
Donna Macmillan Lhasa Limited, Leeds, UK
Alberto Manganaro KODE, Pisa, Italy
Jean François Marchaland Lhasa Limited, Leeds, UK
Mukesh Patel Lhasa Limited, Leeds, UK
Ruth Robert ApconiX, BioHub at Alderley Park, Alderley Edge, UK;
Department of Biosciences, University of Birmingham, Birmingham, UK
Alessandra Roncaglioni Istituto di Ricerche Farmacologiche Mario
Negri – IRCCS, Milano, Italy
Trey Saddler Kelly Government Solutions, Durham, NC, USA
Sugunadevi Sakkiah National Center for Toxicological Research, US Food and
Drug Administration, Jefferson, AR, USA
Andreas Scherer Institute for Molecular Medicine Finland, University of
Helsinki, Helsinki, Finland
Daniel L. Svoboda Sciome LLC, Durham, NC, USA
Sundar Thangapandian Environmental Laboratory, US Army Engineer Research
and Development Center, Vicksburg, MS, USA
Weida Tong Division of Bioinformatics and Biostatistics, National Center for
USA
Patra Volarath FDA/CFSAN/OFAS, College Park, MD, USA
Dong Wang Division of Bioinformatics and Biostatistics, National Center for
USA
Zhongyu Wang Key Laboratory of Industrial Ecology and Environmental
Stéphane Werner Lhasa Limited, Leeds, UK
Richard Williams Lhasa Limited, Leeds, UK
Leihong Wu Division of Bioinformatics and Biostatistics, National Center for
USA
Editor and Contributors xvii
Xianhai Yang Jiangsu Key Laboratory of Chemical Pollution Control and

Resources Reuse, School of Environmental and Biological Engineering, Nanjing
University of Science and Technology, Nanjing, China
Yu (Janet) Zang FDA/CFSAN/OFAS, College Park, MD, USA
Chaoyang Zhang School of Computing Sciences and Computer Engineering,
Chaoyang (Joe) Zhang School of Computing Sciences and Computer
Engineering, University of Southern Mississippi, Hattiesburg, MS, USA
Jieqiang Zhu Division of Bioinformatics and Biostatistics, National Center for
USA
Liyuan Zhu Division of Bioinformatics and Biostatistics, National Center for
USA
Chapter 1
Computational Toxicology Promotes
Regulatory Science
Rebecca Kusko and Huixiao Hong
Abstract New tools have become available to researchers and regulators includ-
ing genomics, transcriptomics, proteomics, machine learning, artificial intelligence,
molecular dynamics, bioinformatics, systems biology, and other advanced tech-
niques. These new advanced approaches originated elsewhere but over time have
perfused into the toxicology field, enabling more efficient risk assessment and safety
evaluation. While traditional toxicological methods remain in full swing, the contin-
uing increase in the number of chemicals introduced into the environment requires
new toxicological methods for regulatory science that can overcome the shortcoming
of traditional toxicological methods. Computational toxicology is a new toxicolog-
ical method which is much faster and cheaper than traditional methods. A variety
of methods have been developed in computational toxicology and some have been
adopted in regulatory science. This book summarizes some methods in computa-
tional toxicology and reviews multiple applications in regulatory science, indicating
that computational toxicology promotes regulatory science.
Keywords Computational toxicology · Regulatory science · Risk assessment ·

Safety evaluation · Chemicals
Abbreviations
3D Three dimensional
AI Artificial intelligence
R. Kusko
Immuneering Corporation, Cambridge, MA, USA
e-mail: bkusko@immuneering.com
H. Hong (B)
National Center for Toxicological Research, U.S. Food and Drug Administration,
Jefferson, AR, USA
e-mail: Huixiao.Hong@fda.hhs.gov
© This is a U.S. government work and not under copyright protection in the U.S.; foreign 1
copyright protection may apply 2019
H. Hong (ed.), Advances in Computational Toxicology, Challenges and Advances
in Computational Chemistry and Physics 30,
https://doi.org/10.1007/978-3-030-16443-0_1
2 R. Kusko and H. Hong
CYP Cytochrome P450 enzyme

DA Department of Agriculture
DILI Drug-induced liver injury
EDC Endocrine disrupting chemical
EDSP Endocrine disruptor screening program
EPA Environment Protection Agency
FDA Food and Drug Administration
ML Machine learning
MD Molecular dynamics
MDDT Medical Device Development Tools
MOA Mechanism of Action
MoA Mode of Action
NCATS National Center for Advancing Translational Sciences
NIEHS National Institute of Environmental Health Sciences
NN Neural Networks
POD Point of Departure
QSAR Quantitative structure–activity relationship
REACH Registration, Evaluation, Authorisation and Restriction of Chemicals
TsTKB Target-specific Toxicity Knowledgebase
US United States
1.1 Computational Toxicology
Toxicology as a broad field seeks to predict and eliminate substances which may cause
a living body harm, including pharmaceuticals, natural products, food products, and
environmental substances. Toxicology has been performed since the ancient Greeks
and Chinese [1]. It is currently a major field of study around the world. The study of
toxicology is of importance not only to governmental regulatory agencies, but also
to the pharmaceutical/biotech industry, the veterinary industry, food manufactur-
ers, and academics. Toxicology also spans many sub-disciplines as it must consider
the entire path of a potential toxicant, including exposure, absorption, distribution,
metabolism, excretion, as well as interactions with cellular machinery throughout
this entire pathway (Fig. 1.1). Pinpointing the exact mechanism or mode of toxicity
as a potential toxicant interacts with a living organism is paramount. Adding to an
already complex system, nearly any known substance can be toxic at a high enough
exposure. Moreover, toxicity is dependent on an array of other factors including
organism size, species, age, sex, genetics, diet, combination with other chemicals,
overall health, and/or environmental context.
Toxicological methods can be classed into experimental and computational [2].
Experimental methods consist of two types: in vivo and in vitro experiments indicated
by the blue arrows in Fig. 1.1. Traditional experiments in toxicology are conducted
on non-human animals such and mice and rats [3]. Though in vivo experiments are
generally treated as the gold standard method in toxicological studies and remain as
1 Computational Toxicology Promotes Regulatory Science 3
Fig. 1.1 Predictive toxicology schematic. A potential route of a toxicant is represented as black
arrows. In vivo and in vitro toxicology as well as connections between components are represented
as blue arrows. Computational toxicology’s key role is represented as red arrows. Arrows are labeled
by actions that achieve the arrow targets
a major approach of estimating human effects of substances, ethical, economic, and

technical concerns on use of animals make toxicologists search for alternative testing
methods [4–6]. Computational toxicology, an emerging component in toxicology,
is an alternative method where computational methods are used to understand and
predict toxicological effects of substances in the environment such as drugs, food, and
environmental chemicals [7–9]. Many computational methods have been developed
for predicting absorption, metabolism of chemicals, estimating in vitro and in vivo
experimental data, and assessing human risk solely based on chemical structures as
illustrated by the red arrows in Fig. 1.1 [10–17].
Given impressive advances recently in computing power as well as developments
in advanced computational algorithms, many toxicologists are now reaching out to
computer science to enable prediction of toxicological effects or outcomes. Thus,
the intersection of computer science and toxicology is what we here call “Compu-
tational Toxicology.” Computational toxicology integrates both the long-standing
computational methods and the newer approaches including neural networks (NNs)
and artificial intelligence (AI). Rather than individual scientists and researchers trying
to understand multiple complex phenomena via bench experiments, these complex
biological systems can now be modeled and predicted in the computational space.
Issues which may have previously seemed impossible or intractable are increasingly
becoming solvable due to the scalability of computational toxicology.
1.2 Domain of Computational Toxicology
Safe drugs, safe food products, and a safe environment for living organisms are of
concern in all countries around the world. Toxicology leadership usually stems from
governmental regulatory agencies, in the USA including the FDA (Food and Drug
Administration), EPA (Environment Protection Agency), DA (Department of Agri-
culture), NCATS (National Center for Advancing Translational Sciences), NIEHS
(National Institute of Environmental Health Sciences) and others. These regulatory
agencies are responsible for maintaining the health and well-being of a population
and actively seek to prevent any exposures to toxic chemicals. Additionally, the phar-
maceutical and biotechnology industry strive to improve patient lives by bringing
both new and generic medicines to the market and must do so while minimizing harm
to human life. Safety and toxicity screening is critical throughout the steps of any
drug development program, starting from the preclinical stage, during clinical trials,
and even in post-market surveillance. For the food and agriculture industry, safety
screening is also a key step in establishing safe exposure levels to new additives or
pesticides. Academics, while rarely developing a product for commercial purposes,
do seek to create and test toxicity screens and also assess toxicity mechanism of
action (MOA) or mode of action (MoA). This textbook emphasizes the methods of
computational toxicology and their potential applications in regulatory science, but
the topic is clearly relevant across sectors and around the world.
1.3 Need for Computational Toxicology
The field of computational toxicology has been blooming due to the fundamental lim-
itations of experimental toxicology. While a dizzying array of novel chemical matter
is being created every day, traditional experiments are bottlenecked by throughput
and cost. In other words, the need for fast toxicity screening and prediction is ever
increasing and traditional in vivo and in vitro approaches cannot keep pace. More-
over, there is a global push to avoid the use of animals for experimental testing.
Traditional approaches are also limited in the number of doses, time points, organ
systems, and combinations that can possibly be tested sanely in one experiment or
laboratory.
When using research to guide toxicology regulation, reproducible and rigorous

analysis are absolutely required. Bench experiments often have many variables which
are difficult to control, including variations in technician, machinery, laboratories,
reagent lots, reagent age, or other protocol subtleties. Advances in computer science
offer not only faster experiments, but also more reproducible ones. For example, a
computational analysis can be exactly repeated by an independent scientist provided
that the raw data is available, code is captured in a publicly available source such as
GitHub and the compute environment is dockerized. The ease of sharing experiments
not only allows computational toxicology to be more rigorous and reproducible, but
fosters collaboration between researchers as protocols are readily shared.
1.4 Methods in Computational Toxicology
Many computational techniques, including the ones originated from other fields
such as computational chemistry and pure computer science, have been developed
and applied in toxicology. To summarize, this book solicited chapters to review some
popular methods in computational toxicology that can be used to assess risk, evaluate
safety, and/or predict toxicology of a drug or other substance.
Chapter 2 introduced the modeling framework of computational toxicology,
defined its scope, listed the major tasks, reviewed the methods, and discussed the
challenges in computational toxicology.
Structural alerts and quantitative structure–activity relationship (QSAR) models
are two of the most popular methods for predicting toxicological activity of chemi-
cals, especially for the simple toxicological endpoints [18, 19]. Chapter 3 reviewed
the applications of structural alerts and QSAR models in computational toxicology
and summarized some lessons learned from some successful models. It also dis-
cussed some challenges such as making negative predictions, moving to quantitative
predictions and weight of evidence approaches.
Emerging technologies such as next-generation sequencing enable fast genera-
tion of huge amounts of data. Computational analysis is challenging and crucial to
extract knowledge from such big data [20]. Machine learning algorithms have been
developed and applied in computational toxicology for prediction of unexpected,
toxic effects of chemicals. Moreover, computer science has enabled computational
prediction to scale to supermassive sizes. For example, the field of machine learning
has birthed matrix and tensor factorization. These two approaches have been used
to analyze >2.5 × 108 data points spanning 1300 compounds. It would be abso-
lutely impossible to analyze such a dataset in a simple traditional program such as
Microsoft Excel! Chapter 4 reviewed the recent progresses in machine learning-based
computational methods and tools and further detailed matrix and tensor factorization
approaches.
One feature of modern science is diverse data for a specific scientific question
such as specific risk of chemicals to humans and the environment. Thus, integrat-
ing diverse data sources from toxicological research to extract more consistent and
reliable knowledge than that provided by any individual data source for risk assess-
ment of chemicals attracts attention of computational toxicologists [21]. Network
analysis-based algorithms have been developed for analyzing such large, diverse,
and sparse data in computational toxicology [22, 23]. To shed insight into this new
method, Chap. 5 presented a network-based systems pharmacology approach that
integrates the networks of proteins, genes, drug target, and the human protein–pro-
tein interactome for assessing the risk of drug-induced cardiotoxicity in humans.
MoA is the functional or anatomical change caused by chemicals, at the cellular
level or at the molecular level that is often used as mechanism of action [24]. It is
important knowledge for understanding toxicology of chemicals when the molecu-
lar target of chemicals has not yet been determined. It can be used to guide devel-
opment of predictive models in computational toxicology. Chapter 6 introduced a
MoA-guided novel computational toxicology approach that is based on molecular
modeling and is implemented in the target-specific toxicity knowledgebase (TsTKb)
that contains a pre-categorized database of MoA for chemicals and provides pre-built
and category-specific predictive models.
Predictive models in computational toxicology are often developed based on many
molecular descriptors using different machine algorithms [25]. One of the key steps in
development is to select important descriptors. Chapter 7 discussed different meth-
ods for removal of redundant and irrelevant molecular descriptors to improve the
performance and interpretability of the model. The strengths and shortcomings of
some feature selection and extraction methods in current computational toxicology
practices were summarized.
Genomics is the study of genomes, including all molecules such as DNA and RNA
and their structures and functions. Adverse effect of a chemical could be caused by
the interactions between the chemical and the target genome such as human genome,
such is the scope of toxicogenomics [26]. Toxicogenomics has been widely applied
in current toxicology practices. A database spanning disciplines of toxicogenomics
is the DrugMatrix, which includes gene expression of some 600 therapeutics at
multiple doses and 96 signatures relating to phenotypes. Chapter 8 gave a com-
prehensive description of a legacy resource of toxicogenomics, DrugMatrix and its
automated toxicogenomics reporting system, the largest molecular toxicology refer-
ence database and informatics systems, which contains thousands of gene expression
datasets generated using different microarray platforms.
Given the increasing prevalence of toxicogenomics resources such as the Drug-
Matrix database, a methodology known as pair ranking was developed to compare
transferability between the systems used for testing. Chapter 9 introduced the pair
ranking (PRank) method that is developed for quantitative evaluation of assay trans-
ferability between the different toxicogenomics platforms.
Several computational toxicology approaches have emerged as a hybrid with com-
putational chemistry. For example, molecular dynamics (MD) simulation was orig-
inally used in chemistry to detail interactions between chemicals and biological
molecules (including DNA and proteins). For computational toxicologists, MD sim-
ulation allows for surveillance of potential fluctuations or conformational changes
that a chemical might induce on a biomolecule [27]. Chapter 10 reviewed available
software tools for MD simulations and the challenges to apply these software tools
to computational toxicology and summarized key protocols to run MD simulations.
The applicability domain of a prediction model is defined as the structural space
that is covered by the chemicals of the training set. It is expected that the predictions
from the model for new compounds within the structural space are more accurate than
the predictions of chemicals out of the space. Analysis of applicability domains in
computational toxicology is important for assessing QSAR models [28]. Chapter 11
reviewed different perspectives of the applicability domain and the existing meth-
ods for analysis of applicability domain. It also formalized a holistic approach for
utilization of the applicability domain in computational toxicology.
1.5 Potential Applications of Computational Toxicology

in Regulatory Science
Computational toxicology has been accepted in the regulation of products. One of

the examples is the International Council for Harmonisation M7 (ICH M7) guide-
line that describes the assessment of carcinogenic risk of mutagenic impurities in
drug products [29]. This indicates the state of the art of a computational toxicology
method and is the milestone for regulatory acceptance of computational toxicology
for pharmaceutical products [30, 31]. In the USA, the FDA accepted QSAR model-
ing results for impurities in applications of drug products. The FDA developed the
Medical Device Development Tools (MDDT) program to qualify tools that can be
used in evaluation of medical devices [32]. In the newly released FDA’ predictive
toxicology roadmap, computational toxicology is listed as one of the new technolo-
gies might be able to address some of the needs in regulatory science [33]. The EPA’s
Endocrine Disruptor Screening Program (EDSP) in the twenty-first century is using
computational toxicology, coupling with in vitro methodologies, to prioritize and
identify EDSP Tier 1 information needs for pesticide active ingredients that will be
included in the registration review program [34]. In Europe, read-across, a commonly
used computational toxicology method, is adopted for data gap filling in registrations
submitted under the REACH regulation [35]. Computational toxicology is gaining
attention in chemical risk assessment and management in China [36]. This book’s
solicited chapters shed lights on examples of potential applications of computational
toxicology in regulatory science in USA, Europe, and China.
In terms of consumer food safety, toxicokinetics, QSAR modeling, and bioinfor-
matics approaches are currently in use. Over time, certainly many more approaches
will be added to screen for toxic food products. Chapter 12 reviewed quantitative
structure–activity relationships, toxicokinetic modeling and simulation, and bioin-
formatics in the FDA’s Center for Food Safety and Applied Nutrition in-house food
ingredient knowledgebase to show the scientific utility of computational toxicology
for improving regulatory review efficiency.
In the space of drug development, log regression analysis has predicted drug-
induced liver injury, which has proven challenging for both the pharmaceutical indus-
try and regulators. Chapter 13 briefed the drug-induced liver injury (DILI) research
efforts at the National Center for Toxicological Research (NCTR), FDA, including
drug-label-based-approach to annotate the DILI risk associated with individual drugs
including a series of models developed to assess the potential of DILI risk.
Alternative methods including computational toxicology have been considered to
inform regulation of drugs, foods, and environmental chemicals. Spanning all three of
these fields, a collaborative project across US governmental agencies known as Tox21
screened 10 k chemicals against a large panel of cell-based assays in a quantitative
high-throughput screen [37]. Chapter 14 described the efforts to build in vivo toxicity
prediction models based on the Tox21 in vitro activity profiles of compounds and
discussed the limitations of the current data and strategies for selection of optimal
assays to improve the performance of the developed models. The Tox21 project
served as powerful fuel for computational predictive modeling across many projects
and institutions including predicting point of departure (POD). Chapter 15 reviewed
common data modeling approaches that use gene expression profiles to estimate the
PODs and compared with the PODs determined using Tox21 data.
From an environmental perspective, endocrine disrupting chemicals (EDCs) are of
grave concern and the MOA has been effectively detailed by target-based molecular
modeling methods. Computational toxicology methods are an essential and pow-
erful tool to elucidate the MOA of endocrine disruptors. Chapter 16 reviewed the
critical processes to perform the molecular modeling of EDCs, including preparation
of three-dimensional (3D) structures of the biomacromolecules and EDCs, genera-
tion and optimization of the structures of EDC–biomacromolecule complexes, and
investigation of the underlying interaction mechanism.
The metabolism of xenobiotics by cytochrome P450 enzymes (CYPs) repre-
sents an important mechanism for in vivo compound processing via environmental
exposure. Density functional theory (DFT) calculations have been used to highlight
the underpinnings of the mechanisms of various environmental toxicants by CYPs
including brominated flame retardants. Chapter 17 reviewed the recent progress in
molecular simulations of xenobiotic metabolism catalyzed by the typical phase I
enzyme CYPs.
Computational toxicology methods including QSAR and read-across are gaining
acceptance in regulatory science in the USA, Europe, and Japan [38]. To facilitate the
applications of computational toxicology in regulatory science, tools for utilization
of QSAR models and read-across have been developed. Chapter 18 introduced a tool
(VEGA) that was designed to reduce the barriers between the different read-across
and QSAR models for the evaluation of specific chemicals for the assessment of
populations of substances. VEGA provides multiple tools for different purposes.
Rigorous and reproducible in silico workflows are needed for toxicological
databases and analysis to be successful. OpenTox is stepping in to fill this gap. Open-
Tox advocates the establishment of good practice and guidance for tracking compu-
tational toxicology models to enhance reproducibility, a very important parameter
for acceptance of the computational models in regulatory science. Chapter 19 dis-
cussed the implementations of workflows for assessing trusted reproducible in silico

evidence supported within OpenTox and OpenRiskNet.
1.6 Conclusions
Translating computational approaches into the complex and intricate field of toxicity
is not a simple task. Working together as a community across countries, disciplines,
and organizations, computational toxicology was born and has been taking flight. As
the field advances, open communication must continue across international borders
as well as between regulators and researchers to continually move toward more
efficient and effective toxicology.
Disclaimer This article reflects the views of the authors and should not be construed to represent
the FDA’s views or policies.
References
1. Wennig R (2009) Back to the roots of modern analytical toxicology: Jean Servais Stas and the
Bocarmé murder case. Drug Test Anal 1(4):153–155
2. de Bruin YB, Eskes C, Langezaal I, Coecke S, Kinsner-Ovaskainen A, Hakkinen PJ (2009)
In: Wexler P, Hakkinen PJ, Mohapatra A, and Gilbert SG (eds) Testing methods and toxicity
assessment (including alternatives), in information resources in toxicology, 4th edn. Elsevier,
pp 497–513
3. Kolar R (1998) OECD pushes antiquated animal test for endocrine disrupting activity. Altex
15(4):215–217
4. Bruner LH (1992) Alternatives to the use of animals in household product and cosmetic testing.
J Am Vet Med Assoc 200(5):669–673
5. Indans I (2002) The use and interpretation of in vitro data in regulatory toxicology: cosmetics,
toiletries and household products. Toxicol Lett 127(1–3):177–182
6. McNamee P1, Hibatallah J, Costabel-Farkas M, Goebel C, Araki D, Dufour E, Hewitt NJ, Jones
P, Kirst A, Le Varlet B, Macfarlane M, Marrec-Fairley M, Rowland J, Schellauf F, Scheel J.
(2009) A tiered approach to the use of alternatives to animal testing for the safety assessment
of cosmetics: eye irritation. Regul Toxicol Pharmacol 54(2):197–209
7. Reisfeld B1, Mayeno AN (2012) What is computational toxicology? Methods Mol Biol 929:3–7
8. Kavlock RJ, Ankley G, Blancato J, Breen M, Conolly R, Dix D, Houck K, Hubal E, Judson
R, Rabinowitz J, Richard A, Setzer RW, Shah I, Villeneuve D, Weber E (2008) Computational
toxicology—a state of the science mini review. Toxicol Sci 103:14–27
9. Benfenati E (2007) Predicting toxicity through computers: a changing world. Chem Central J
1:32
10. Hong H, Neamati N, Winslow HE, Christensen JL, Orr A, Pommier Y, Milne GWA (1998)
Identification of HIV-1 integrase inhibitors based on a four-point pharmacophore. Antiviral
Chem Chemother 9:461–472
11. Shen J, Zhang W, Fang H, Perkins R, Tong W, Hong H (2013) Homology modeling, molecular
docking, and molecular dynamics simulations elucidated α-fetoprotein binding modes. BMC
Bioinform 14:S6
12. Ng HW, Doughty SW, Luo H, Ye H, Ge W, Tong W, Hong H (2015) Development and validation
of decision forest model for estrogen receptor binding prediction of chemicals using large data
sets. Chem Res Toxicol 28:2343–2351
13. Sakkiah S, Ng HW, Tong W, Hong H (2016) Structures of androgen receptor bound with ligands:
advancing understanding of biological functions and drug discovery. Expert Opin Ther Targets
20(10):1267–1282
14. Hong H, Shen J, Ng HW, Sakkiah S, Ye H, Ge W, Gong P, Xiao W (2016) A rat α-fetoprotein
binding activity prediction model to facilitate assessment of the endocrine disruption potential
of environmental chemicals. Int J Environ Res Public Health 13(4):372
15. Luo H, Ye H, Ng HW, Sakkiah S, Mendrick DL, Hong H (2016) sNebula, a network-based
algorithm to predict binding between human leukocyte antigens and peptides. Sci Rep 6:32115
16. Hong H, Thakkar T, Chen M, Tong W (2017) Development of decision forest models for
prediction of drug-induced liver injury in humans using a large set of FDA-approved drugs.
Sci Rep 7(1):17311
17. Selvaraj C, Sakkiah S, Tong W, Hong H (2018) Molecular dynamics simulations and applica-
tions in computational toxicology and nanotoxicology. Food Chem Toxicol 112:495–506
18. Ashby J, Tennant RW (1988) Chemical structure, Salmonella mutagenicity and extent of car-
cinogenicity as indicators of genotoxic carcinogenesis among 222 chemicals tested in rodents
by the U.S. NCI/NTP. Mutat Res 204:17–115
19. Hong H, Tong W, Fang H, Shi L, Xie Q, Wu J, Perkins R, Walker JD, Branham W, Sheehan
DM (2002) Prediction of estrogen receptor binding for 58,000 chemicals using an integrated
system of a tree-based model with structural alerts. Environ Health Perspect 110(1):29–36
20. Hong H, Zhang W, Shen J, Su Z, Ning B, Han T, Perkins R, Shi L, Tong W (2013) Critical
role of bioinformatics in translating huge amounts of next-generation sequencing data into
personalized medicine. Sci China Life Sci 56(2):110–118
21. Haghighat M, Abdel-Mottaleb M, Alhalabi W (2016) Discriminant correlation analysis: real-
time feature level fusion for multimodal biometric recognition. IEEE Trans Inf Forensics Secur
11(9):1984–1996
22. Ye H, Luo H, Ng HW, Meehan J, Ge W, Tong W, Hong H (2016) Applying network analysis
and Nebula (neighbor-edges based and unbiased leverage algorithm) to ToxCast data. Environ
Int 89–90:81–92
23. Luo H, Ye H, Ng H, Shi L, Tong W, Mattes W, Mendrick D, Hong H (2015) Understanding
and predicting binding between human leukocyte antigens (HLAs) and peptides by network
analysis. BMC Bioinform 16(Suppl 13):S9
24. US EPA. Mechanisms and mode of dioxin action. Retrieved from https://web.archive.org/
web/20150226023800/, http://www.epa.gov/ncea/pdfs/dioxin/nas-review/pdfs/part3/dioxin_
pt3_ch03_oct2004.pdf. Accessed on 24 Nov 2018
25. Hong H, Xie Q, Ge W, Qian F, Fang H, Shi L, Su Z, Perkins R, Tong W (2008) Mold2, molecular
descriptors from 2D structures for chemoinformatics and toxicoinformatics. J Chem Inf Model
48(7):1337–1344
26. Wang C, Gong B, Bushel PR, Thierry-Mieg J et al (2014) The concordance between RNA-seq
and microarray data depends on chemical treatment and transcript abundance. Nat Biotechnol
32(9):926–932
27. Sakkiah S, Kusko R, Pan B, Guo W, Ge W, Tong W, Hong H (2018) Structural changes due to
antagonist binding in ligand binding pocket of androgen receptor elucidated through molecular
dynamics simulations. Front Pharmacol 9:492
28. Tetko IV, Sushko I, Pandey AK, Zhu H, Tropsha A, Papa E, Oberg T, Todeschini R, Fourches
D, Varnek A (2008) Critical assessment of QSAR models of environmental toxicity against
Tetrahymena pyriformis: focusing on applicability domain and overfitting by variable selection.
J Chem Inf Model 48(9):1733–1746
29. International Council for Harmonisation of Technical Requirements for Pharmaceuticals
for Human use (ICH). Assessment and control of DNA reactive (mutagenic) impurities
in pharmaceuticals to limit potential carcinogenic risk. Retrieved from https://www.ich.
org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Multidisciplinary/M7/M7_R1_
Addendum_Step_4_2017_0331.pdf. Accessed on Nov 26 2018
30. Amberg A, Beilke L, Bercu J et al (2016) Principles and procedures for implementation of ICH
M7 recommended (Q)SAR analyses. Regul Toxicol Pharmacol 77:13–24
31. Barber C, Amberg A, Custer L et al (2015) Establishing best practice in the application of
expert review of mutagenicity under ICH M7. Regul Toxicol Pharmacol 73:367–377
32. FDA. Qualification of medical device development tools- guidance for industry, tool develop-
ers, and food and drug administration staff. Retrieved from https://www.fda.gov/downloads/
MedicalDevices/DeviceRegulationandGuidance/GuidanceDocuments/UCM374432.pdf.
Accessed on 26 Nov 2018
33. FDA. FDA’ predictive toxicology roadmap. Retrieved from https://www.fda.gov/downloads/
scienceresearch/specialtopics/regulatoryscience/ucm587831.pdf. Accessed on 26 Nov 2018
34. EPA. Endocrine disruptor screening program (EDSP) in the 21st century. Retrieved from
https://www.epa.gov/endocrine-disruption/endocrine-disruptor-screening-program-edsp-
21st-century. Accessed on 26 Nov 2018
35. European Chemical Agency. Read-across assessment framework (RAAF). Retrieved from
https://echa.europa.eu/documents/10162/13628/raaf_en.pdf. Accessed on 26 Nov 2018
36. Solid Waste and Chemicals Management Center, MET, China. Latest progress of chemicals
management in China. Retrieved from http://chemical-net.env.go.jp/pdf/20180123_Seminar1.
pdf. Accessed on 26 Nov 2018
37. Huang R, Xia M, Sakamuru S, Zhao J, Shahane SA, Attene-Ramos M, Zhao T, Austin CP,
Simeonov A (2016) Modelling the Tox21 10K chemical profiles for in vivo toxicity prediction
and mechanism characterization. Nat Commun 7:10425
38. Chesnut M, Yamada T, Adams T, Knight D, Kleinstreuer N, Kass G, Luechtefeld T, Hartung
T (2018) Regulatory acceptance of read-across. Altex 35(3):413–419
Rebecca Kusko is the SVP and Head of R&D at Immuneering Corporation. She completed
her undergraduate degree at MIT in Biological Engineering and earned a Ph.D. in Genetics and
Genomics from BU before joining Immuneering in 2014. At Immuneering, she has been acceler-
ating pharma R&D using advanced algorithms. Additionally, she is a board member of the MAQC
Society, an initiative around best practices for big data analysis.
Huixiao Hong is Chief of Bioinformatics Branch, Division of Bioinformatics and Biostatistics,

National Center for Toxicological Research (NCTR), US Food and Drug Administration (FDA),
working on the scientific bases for regulatory applications of bioinformatics. Before joining the
FDA, he was Manager of Bioinformatics Division of Z-Tech, an ICFI company. He was a research
scientist position at Sumitomo Chemical Company in Japan and a visiting scientist at National
Cancer Institute at National Institutes of Health. He was also Associate Professor and the Direc-
tor of Laboratory of Computational Chemistry at Nanjing University in China. Dr. Hong is the
member of steering committee of OpenTox, the member of board directors of US MidSouth Com-
putational Biology and Bioinformatics Society, and in the leadership circle of US FDA modeling
and simulation working group. He published more than 180 scientific papers and served as Editor-
in-Chief and Editorial Board member for multiple peer-reviewed journals. He received his Ph.D.
from Nanjing University in China in 1990 and conducted research in Leeds University in England
in 1990–1992.
Part I
Methods in Computational Toxicology
Another random document with
no related content on Scribd:
The Project Gutenberg eBook of El terror de 1824
This ebook is for the use of anyone anywhere in the United States and
most other parts of the world at no cost and with almost no restrictions
whatsoever. You may copy it, give it away or re-use it under the terms
of the Project Gutenberg License included with this ebook or online at
www.gutenberg.org. If you are not located in the United States, you will
have to check the laws of the country where you are located before
using this eBook.
Title: El terror de 1824
Author: Benito Pérez Galdós
Release date: October 12, 2023 [eBook #71861]
Language: Spanish
Original publication: Madrid: Obras de Pérez Galdós, 1904
Credits: Ramón Pajares Box. (This file was produced from images
generously made available by The Internet Archive/Canadian
Libraries.)
*** START OF THE PROJECT GUTENBERG EBOOK EL TERROR DE

1824 ***
Índice: I, II, III, IV, V, VI, VII, VIII, IX, X, XI, XII, XIII, XIV, XV, XVI, XVII,
XVIII, XIX, XX, XXI, XXII, XXIII, XXIV, XXV, XXVI, XXVII, XXVIII, XXIX.
Nota de transcripción
Los errores de imprenta han sido corregidos.

La ortografía del texto original ha sido modernizada de acuerdo con las normas
publicadas en 2010 por la Real Academia Española.
Las rayas intrapárrafos han sido espaciadas según los modernos usos
ortotipográficos.
Las notas a pie de página han sido renumeradas y colocadas al final del párrafo en
que se las llama.
EPISODIOS NACIONALES
EL TERROR DE 1824
Es propiedad. Queda hecho el depósito
que marca la ley. Serán furtivos los
ejemplares que no lleven el sello del autor
B. PÉREZ GALDÓS
EPISODIOS NACIONALES
SEGUNDA SERIE
EL TERROR DE 1824
32.000
MA DRID
O B RAS DE P É RE Z G AL DÓ S
132, Hortaleza
1904
EST. TIP. DE LA VIUDA E HIJOS DE TELLO
IMPRESOR DE CÁMARA DE S. M.
C. de San Francisco, 4.
EL TERROR DE 1824
En la tarde del 2 de octubre de 1823 un anciano bajaba con paso

tan precipitado como inseguro por las afueras de la Puerta de Toledo
en dirección al puente del mismo nombre. Llovía menudamente, sin
cesar, según la usanza del hermoso cielo cuando se enturbia, y la
ronda podía competir en lodos con su vecino Manzanares, el cual
hinchándose como la madera cuando se moja, extendía su saliva
fangosa por gran parte del cauce que le permiten los inviernos. E
anciano transeúnte marchaba con pie resuelto, sin que le causara
estorbo la lluvia, con el pantalón recogido hasta la pantorrilla
chapoteando sin embarazo en el lodo con las destrozadas botas. Iba
estrechamente forrado, como tizona en vaina, en añoso gabán oscuro
cuyo borde y solapa se sujetaba con alfileres allí donde no había
botones, y con los agarrotados dedos en la parte del pecho, como la
más necesitada de defensa contra la humedad y el frío. Hundía la
barba y media cara en el alzacuello, tieso como una pared
cubriéndose con él las orejas y el ala posterior del sombrero, que
destilaba agua como cabeza de tritón en fuente de Reales Sitios. No
llevaba paraguas ni bastón. Mirando sin cesar al suelo, daba unos
suspiros que competían con las ráfagas de aire. ¡Infelicísimo varón
¡Cuán claramente pregonaban su desdichada suerte el roto vestido
las horadadas botas, el casquete húmedo, la aterida cabeza, y aque
continuo suspirar casi al compás de los pasos! Parecía un
desesperado que iba derecho a descargar sobre el río el fardo de una
vida harto enojosa para llevarla más tiempo. No obstante, pasó por e
puente sin mirar al agua, y no se detuvo hasta el parador situado en la
divisoria de los caminos de Toledo y Andalucía.
Bajo el cobertizo destinado a los alcabaleros y gente del fisco
había hasta dos docenas de hombres de tropa, entre ellos algunos
oficiales de línea y voluntarios realistas de nuevo cuño en tales días
Los paradores cercanos albergaban una fuerza considerable, cuya
misión era guardar aquella principalísima entrada de la corte, ignorante
aún de los sucesos que en el último confín de la Península habían
cambiado el gobierno de constitucional dudoso en absoluto verídico y
puro, poniendo fin entre bombas certeras y falaces manifiestos a los
tres llamados años. En aquel cuerpo de guardia eran examinados los
pasaportes, vigilando con exquisito esmero las entradas y las salidas
mayormente estas últimas, a fin de que no escurriesen el bulto los
sospechosos ni se pusieran en cobro los revolucionarios, cuya última
cuenta se ajustaría pronto en el tremendo Josafat del despotismo.
Acercose el vejete al grupo de oficiales, y reconociendo
prontamente al que sin duda buscaba, que era joven, adusto y
morenote, bastante adelantado en su marcial carrera como
proclamaban las insignias, díjole con mucho respeto:
—Aquí estoy otra vez, señor coronel Garrote. ¿Tiene vuecencia
alguna buena noticia para mí?
—Ni buena ni mala, señor... ¿cómo se llama usted? —repuso e
militar.
—Patricio Sarmiento, para servir a vuecencia y la compañía
Patricio Sarmiento, el mismo que viste y calza, si esto se puede deci
de mi traje y de mis botas. Patricio Sarmiento, el...
—Pase usted adentro —díjole bruscamente el militar, tomándole po
un brazo y llevándole bajo el cobertizo—. Está usted como una sopa.
Un rumor, del cual podía dudarse si era de burla o de lástima, y
quizás provenía de las dos cosas juntamente, acogió la entrada de
infeliz preceptor en la compañía de los militares.
—Sí, señor Garrote —añadió Sarmiento—; soy, como decía, e
hombre más desgraciado de todo el globo terráqueo. Ese cielo que
nos moja no llora más que lloro en estos días, desde que me han
anunciado como probable, como casi cierta, la muerte de mi querido
hijo Lucas, de mi niño adorado, de aquel que era manso cordero en e
hogar paterno y león indómito en los combates... ¡Ah, señores
¡Ustedes no saben lo que es tener un hijo único, y perderlo en una
escaramuza de Andalucía, por descuidos de un general, o po
intrepidez imprudente de un oficialete!... ¿Pero hay esperanzas
todavía de que tan horrible noticia resulte incierta? ¿Se ha sabido
algo? Por Dios, señor Garrote, ¿ha sabido vuecencia si mi idolatrado
unigénito vive aún, o si feneció en esas tremendas batallas?... ¿Hay
algún parte que lo mencione?..., porque Lucas no podía morir como
cualquiera, no: había de morir ruidosa y gloriosísimamente, de una
manera tal, que dé gusto y juego a los historiadores... ¿Ha sabido algo
vuecencia de ayer acá?
—Nada —repuso Garrote fríamente.
—Ha seis días que vengo todas las tardes, y siempre me dice
vuecencia lo mismo —murmuró Sarmiento con angustia—. ¡Nada!
—Desde el primer día manifesté a usted qué nada podía saber.
—Pero a todas horas entran heridos, soldados dispersos, paisanos
correos que vienen de las Andalucías. ¿Se ha olvidado usted de
preguntar?
—No me he olvidado —indicó el coronel con semblante y tono más
compasivos—; pero nadie, absolutamente nadie, tiene noticia de
miliciano Lucas Sarmiento.
—¡Todo sea por Dios! —exclamó el preceptor mirando al cielo—
¡Qué agonía! Unos me dicen que sucumbió, otros que está herido
gravemente... ¿Han entrado hoy muchos milicianos prisioneros?
—Algunos.
—¿No venía Pujitos?
—¿Y quién es Pujitos?
—¡Oh! Vuecencia no conoce a nuestra gente.
—Soy forastero en Madrid.
—¡Oh! Pasaron aquellos tiempos de gloria —exclamó don Patricio
con lágrimas en los ojos, y declamando con cierto énfasis que no
cuadraba mal a su hueca voz y alta figura—. ¡Todo ha caído, todo es
desolación, muerte y ruinas! Aquellos adalides de la libertad, que
arrancaron a la madre España de las garras del despotismo; aquellos
fieros leones matritenses, que con solo un resoplido de su augusta
cólera desbarataron a la Guardia real, ¿qué se hicieron? ¿Qué se hizo
de la elocuencia que relampagueaba tronando en los cafés, con luz y
estruendo sorprendentes? ¿Qué se hizo de aquellas ideas de
emancipación que inundaban de gozo nuestras corazones? Todo cayó
todo se desvaneció en tinieblas, como lumbre extinguida por la
corriente de las aguas. La oleada de fango frailesco ha venido
arrasándolo todo. ¿Quién la detendrá volviéndola a su inmundo
cauce? ¡Estamos perdidos! La patria muere ahogada en lodaza
repugnante y fétido. Los que vimos sus días gloriosos, cuando al son
de patrióticos himnos eran consagradas públicamente las ideas de
libertad y nos hacíamos todos libres, todos igualmente soberanos, los
recordamos como un sueño placentero que no volverá. Despertamos
en la abyección, y el peso y el rechinar de nuestras cadenas nos
indican que vivimos aún. Las iracundas patas del déspota nos
pisotean, y los frailes nos...
—Basta —gritó una formidable voz interrumpiendo bruscamente a
infeliz dómine—. Para sainete basta ya, señor Sarmiento. Si abusa
usted de la benignidad con que se le toleran sus peroratas en atención
al estado de su cabeza, nos veremos obligados a retirarle las licencias
Esto no se puede resistir. Si los desocupados de Madrid le consienten
a usted que vaya de esquina en esquina y de grupo en grupo
divirtiéndoles con sus necedades y reuniendo tras de sí a los chicos
yo no permito que con pretexto de locura o idiotismo se insulte a
orden político que felizmente nos rige...
—¡Ah, señor Garrote, señor Garrote! —dijo Sarmiento moviendo
tristemente la cabeza y sacudiendo menudas gotas de agua sobre los
circunstantes—. Vuecencia me tapa la boca, que es el único desahogo
de mi alma abrasada... Callaré; pero deme vuecencia nuevas de m
hijo, aunque sean nuevas de su muerte.
Garrote encogió los hombros y ofreció una silla al pobre hombre
que, despreciando el asiento, juzgó más eficaz contra la humedad y e
fresco pasearse de un rincón a otro del cobertizo, dando fuertes
patadas y girando rápidamente, como veleta, al dar las vueltas. Los
demás militares y paisanos armados no ocultaban su regocijo ante la
grotesca figura y ditirámbico estilo del anciano, y cada cual imaginaba
un tema de burla con que zaherirle, mortificándole también en su
persona. Este le decía que Su Majestad pensaba nombrarle ministro
de Estado y llavero del reino; aquel que un ejército de carbonarios
venía por la frontera derecho a restablecer la Constitución; uno le
ponía una banqueta delante para que al pasar tropezase y cayese
otro le disparaba con cerbatana un garbanzo haciendo blanco en e
cogote o la nariz. Pero Sarmiento, atento a cosas más graves que
aquel juego importuno, hijo de un sentimiento grosero y vil, no hacía
caso de nada, y solo contestaba con monosílabos, o llevándose la
mano a la parte dolorida.
Había pasado más de un cuarto de hora en este indigno ejercicio
cuando de la venta salió un hombre pequeño, doblado, de mezquina
arquitectura, semejante a la de esos edificios bajos y sólidos que no
tienen por objeto la gallarda expresión de un ideal, sino simplemente
servir para cualquier objeto terrestre y positivo. Siendo posible la
comparación de las personas con las obras de arquitectura, y
habiendo quien se asemeja a una torre gótica, a un palacio señorial, a
un minarete árabe, puede decirse de aquel hombre que parecía una
cárcel. Con su musculatura de cal y canto se avenía maravillosamente
una como falta de luces, rasgo misterioso o inexplicable de su
semblante, que a pesar de tener cuanto corresponde al humano
frontispicio, parecía una fachada sin ventanas. Y no eran pequeños
sus ojos ciertamente, ni dejaban de ver con claridad cuanto enfrente
tenían; pero ello es que mirándole no se podía menos de decir: «¡Qué
cara tan oscura!».
Su fisonomía no expresaba cosa alguna, como no fuera una calma
torva, una especie de acecho pacienzudo. Y a pesar de esto no era
feo, ni sus correctas facciones habrían formado mal conjunto s
estuvieran de otra manera combinadas. Tales o cuales cejas, boca o
narices más o menos distantes de la perfección, pueden ser de
agradable visualidad o de horrible aspecto, según cual sea la
misteriosa conexión que forma con ellas una cara. La de aquel hombre
que allí se apareció era ferozmente antipática. Siempre que vemos po
primera vez a una persona, tratamos, sin darnos cuenta de nuestra
investigación, de escudriñar su espíritu y conocer por el mirar, por la
actitud, por la palabra, lo que piensa y desea. Rara vez dejamos de
enriquecer nuestro archivo psicológico con una averiguación preciosa
Pero enfrente de aquel sótano humano el observador se aturdía
diciendo: «Está tan lóbrego que no veo nada».
Vestía de paisano con cierto esmero, y todas cuantas armas
portátiles se conocen llevábalas él sobre sí, lo cual indicaba que era
voluntario realista. Fusil sostenido a la espalda con tirante, sable
machete, bayoneta, pistolas en el cinto, hacían de él una armería en
toda regla. Calzaba botas marciales con espuelas, a pesar de no se
de a caballo; mas este accesorio solían adoptarlo cariñosamente todos
los militares improvisados de uno y otro bando. Chupaba un cigarrillo
y a ratos se pasaba la mano por la cara, afeitada como la de un fraile
pero su habitual resabio nervioso (estos resabios son muy comunes en
el organismo humano) consistía en estar casi siempre moviendo las
mandíbulas como si rumiara o mascullase alguna cosa. Su nombre de
pila era Francisco Romo.
Don Patricio, luego que le vio, llegose a él y le dijo:
—¡Ah, señor Romo! ¡Cuánto me alegro de verlo! Aquí estoy po
sexta vez buscando noticias de mi hijo.
—¿Qué sabemos nosotros de tu hijo ni del hijo del Zancarrón?
Papá Sarmiento, tú estás en Babia... No tardarás mucho en ir a
Nuncio de Toledo... Ven acá, estafermo —al decir esto le tomaba po
un brazo y le llevaba al interior de la venta que servía de cuerpo de
guardia—, ven acá y sirve de algo.
—¿En qué puedo servir al señor Romo? Diga lo que quiera con ta
que no me pida nada de que resulte un bien al absolutismo.
—Es cosa mía —dijo Romo hablando en voz baja y retirándose con
Sarmiento a un rincón donde no pudieran ser oídos—. Tú, aunque
loco, eres hombre capaz de llevar un recado y ser discreto.
—Un recado... ¿a quién?
—A Elenita, la hija de don Benigno Cordero, que vive en tu misma
casa, ¿eh? Me parece que no te vendrán mal tres o cuatro reales..
Este saco de huesos está pidiendo carne. ¿Cuántas horas hace que
no has comido?
—Ya he perdido la cuenta —repuso el preceptor con afligidísimo
semblante, mientras un lagrimón como garbanzo corría por su mejilla.
—Pues bien, carcamal: aquí tienes una peseta. Es para ti si llevas a
la señorita doña Elena...
—¿Qué?
—Esta carta —dijo Romo mostrando una esquela doblada en pico.
—¡Una carta amorosa! —exclamó Sarmiento ruborizándose—
Señor Romo de mis pecados, ¿por quién me toma usted?
El tono de dignidad ofendida con que hablara Sarmiento, irritó de ta
modo al voluntario realista que, empujando brutalmente al anciano, le
vituperó de este modo:
—¡Dromedario! ¿Qué tienes que decir?... Sí, una carta amorosa. ¿Y
qué?
—Que usted es un simple si me toma por alcahuete —dijo don
Patricio con severo acento—. Guarde usted su peseta, y yo me
guardaré mi gana de comer. ¡Por vida de la chilindraina! No faltan
almas caritativas que hagan limosnas sin humillarnos...
Inflamado en vivísima cólera el voluntario, y sin hallar otras razones
para expresarla que un furibundo terno, descargó sobre el pobre
maestro aburrido uno de esos pescozones de catapulta que abaten de
un golpe las más poderosas naturalezas, y dejándole tendido en tierra
magullados y acardenalados el hocico y la frente, salió del cuerpo de
guardia.
A don Patricio le levantaron casi exánime, y su destartalado cuerpo
se fue estirando poco a poco en la postura vertical, restallándole las
coyunturas como clavijas mohosas. Se pasó la mano por la cara, y
dando un gran suspiro y elevando al cielo los ojos llorosos, exclamó
así con dolorido acento:
—¡Indigno abuso de la fuerza bruta, y de la impunidad que protege
a estos capigorrones!... Si otros fueran los tiempos, otras serían las
nueces... Pero los yunques se han vuelto martillos, y los martillos de
ayer son yunques ahora. ¡Rechilindrona! ¡Malditos sean los instantes
que he vivido después que murió aquella preciosa libertad!...
Y sucediendo la rabia al dolor, se aporreó la cabeza y se mordió los
puños. Habíanle abandonado los que antes le prestaran socorro
porque fuera se sentía gran ruido y salieron todos corriendo al camino
Don Patricio, coronándose dignamente con su sombrero, al cual se
empeñó en devolver su primitiva forma, salió también arrastrado por la
curiosidad.
II
Era que venían por el camino de Andalucía varias carretas

precedidas y seguidas de gente de armas a pie y a caballo, y aunque
no se veían sino confusos bultos a lo lejos, oíase un son a manera de
quejido, el cual, si al principió pareció lamentaciones de seres
humanos, luego se comprendió provenía del eje de un carro que
chillaba por falta de unto. Aquel áspero lamento, unido a la algazara
que hizo de súbito la mucha gente salida de los paradores y ventas
formaba lúgubre concierto, más lúgubre aún a causa de la tristeza de
la noche. Cuando los carros estuvieron cerca, una voz acatarrada y
becerril gritó: «¡Vivan las caenas! ¡Viva el rey absoluto y muera la
nación!». Respondiole un bramido infernal, como si a una rompieran a
gritar todas las cóleras del averno, y al mismo tiempo la luz de las
hachas, prontamente encendidas, permitió ver las terribles figuras que
formaban procesión tan espantosa. Don Patricio, quizás el único
espectador enemigo de semejante espectáculo, sintió los escalofríos
del terror y una angustia mortal que le retuvo inmóvil y casi sin
respiración por algún tiempo.
Los que custodiaban el convoy y los paisanos que le seguían po
entusiasmo absolutista, estaban manchados de fango hasta los ojos
Algunos traían pañizuelo en la cabeza, otros sombrero ancho; muchos
con el desgreñado cabello al aire, roncos, mojados de pies a cabeza
frenéticos, tocados de una borrachera singular que no se sabe si era
de vino o de venganza, brincaban sobre los baches, agitando un girón
con letras, una bota escuálida o un guitarrillo sin cuerdas. Era una
horrenda mezcla de bacanal, entierro y marcha de triunfo. Oíanse
bandurrias desacordes, carcajadas, panderetazos, votos, ternos
kirieleisones, vivas y mueras, todo mezclado con el lenguaje carreteril
con patadas de animales (no todos cuadrúpedos) y con el cascabeleo
de las colleras. Cuando la caravana se detuvo ante el cuerpo de
guardia, aumentó el ruido. La tropa formó al punto, y una nueva
aclamación al rey neto alborotó los caseríos. Salieron mujeres a las
ventanas, candil en mano, y la multitud se precipitó sobre los carros.
Eran estos galeras comunes con cobertizo de cañas y cama hecha
de pellejos y sacos vacíos. En el delantero venían tres hombres, dos
de ellos armados, sanos y alegres, el tercero enfermo y herido
reclinado doloridamente sobre el camastrón, con grillos en los pies y
una larga cadena que, prendida en la cintura y en una de las muñecas
se enroscaba junto al cuerpo como una culebra. Tenía vendada la
cabeza con un lienzo teñido de sangre, y era su rostro amarillo como
vela de entierro. Le temblaban las carnes, a pesar de disfrutar de
abrigo de una manta, y sus ojos extraviados, así como su anhelante
respiración, anunciaban un estado febril y congojoso. Cuando e
coronel Garrote se acercó al carro, y alzando la linterna que en la
mano traía, miró con vivísima curiosidad al preso, este dijo a media
voz:
—¿Estamos ya en Madrid?
Sin hacer caso de la pregunta, Garrote, cuyo semblante expresaba
el goce de una gran curiosidad satisfecha, dijo:
—¿Conque es usted...?
Uno de los hombres armados que custodiaban al preso en el carro
añadió:
—El héroe de las Cabezas.
Y junto al carro sonó este grito de horrible mofa:
—¡Viva Riego!
Garrote se empeñó en apartar a la gente que rodeaba el carro
apiñándose para ver mejor al preso e insultarle más de cerca.
Un hombre alargó el brazo negro, y tocando con su puño cerrado e
cuello del enfermo, gritó:
—¡Ladrón, ahora las pagarás!
El desgraciado general se recostó en su lecho de sacos, y callaba
aunque harto claramente imploraban compasión sus ojos.
—Fuera de aquí. Señores, a un lado —dijo Garrote, aclarando con
suavidad el grupo de curiosos—. Ya tendrán tiempo de verle a sus
anchas...
—Dicen que la horca será la más alta que se ha visto en Madrid —
indicó uno.
—Y que se venderán los asientos en la plaza, como en la de toros.
—Pero déjennoslo ver..., por amor de Dios. Si no nos lo comemos
señor coronel —gruñó una dama del parador cercano.
—¡Si no puede con su alma...! ¿Y ese hombre ha revuelto medio
mundo? Que me lo vengan a decir...
—¡Qué facha! ¿Y dicen que este es Riego?... ¡Qué bobería!... S
parece un sacristán que se ha caído de la torre cuando estaba tocando
a muerto...
—Este es tan Riego como yo.
—Os digo que es el mismo. Le vi yo en el teatro cantando el himno.
—El mismo es. Tiene el mismo parecido del retrato que paseaban
por Platerías.
Hasta aquí las mortificaciones fueron de palabra. Pero un grupo de
hombres que habían salido al encuentro de los carros, una gavilla
mitad armada, mitad desnuda, desarrapada, borracha, tan llena de
rabia y cieno que parecía creación espantosa del lodo de los caminos
de la hez de las tinajas y de la nauseabunda atmósfera de los
presidios, un pedazo de populacho, de esos que desgarrándose se
separan del cuerpo de la nación soberana para correr solo
manchando y envileciendo cuanto toca, empezó a gritar con el gruñido
de la cobardía que se finge valiente fiando en la impunidad:
—¡Que nos lo den; que nos entreguen a ese pillo, y nosotros le
ajustaremos la cuenta!
—Señores —dijo Garrote con energía—, atrás; atrás todo el mundo
El preso va a entrar en Madrid.
—Nosotros le llevaremos.
—Atrás todo el mundo.
Y los pocos soldados que allí había, auxiliados con tibieza por los
voluntarios realistas, apartaban a la gente.
Unos corrieron a curiosear en los carros que venían detrás, y otros
se metieron en la venta, donde sonaban seguidillas, castañuelas
desaforados gritos y chillidos. Un cuero de vino, roto por los golpes y
patadas que recibiera, dejaba salir el rojo líquido, y el suelo de la venta
parecía inundado de sangre. Algunos carreteros sedientos se habían
arrojado al suelo y bebían en el arroyo tinto; los que llegaron más tarde
apuraban lo que había en los huecos del empedrado, y los chicos
lamían las piedras fuera de la venta, a riesgo de ser atropellados po
las mulas desenganchadas que iban de la calle a la cuadra, o del tiro
al abrevadero. Poco después veíanse hombres que parecían
degollados con vida, carniceros o verdugos que se hubieran bañado
en la sangre de sus víctimas. El vino, mezclado al barro y tiñendo las
ropas que ya no tenían color, acababa de dar al cuadro en cada una
de sus figuras un tono crudo de matadero, horriblemente repulsivo a la
vista.
Y a la luz de las hachas de viento y de las linternas, las caras
aumentaban en ferocidad, dibujándose más claramente en ellas la risa
entre carnavalesca y fúnebre que formaba el sentido, digámoslo así
de tan extraño cuadro. Como no había cesado de llover, el piso
inundado era como un turbio espejo de lodo y basura, en cuyo crista
se reflejaban los hombres rojos, las rojas teas, las bayonetas bruñidas
las ruedas cubiertas de tierra, los carros, las flacas mulas, las
haraposas mujeres, el ir y venir, la oscilación de las linternas y hasta e
barullo, los relinchos de brutos y hombres, la embriaguez inmunda, y
por último, aquella atmósfera encendida, espesa, suciamente
brumosa, formada por los alientos de la venganza, de la rusticidad y
de la miseria.
En el segundo carro estaban presos también y heridos los
compañeros de Riego, a saber: el capitán don Mariano Bayo, e
teniente coronel piamontés Virginio Vicenti y el inglés Jorge Matías
Don Patricio Sarmiento, que no se atrevió a acercarse al primer carro
se detuvo breve rato junto al segundo, pasó indiferente por el tercero
donde solo venían sacos y un guerrillero con su mujer, y se dirigió a
cuarto, llamado por una voz débil que claramente dijo:
—Señor don Patricio de mi alma... ¡Bendito sea Dios que me
permite verle!
—¡Pujitos!... ¡Pujitos mío!... —exclamó Sarmiento extendiendo sus
brazos dentro del carro—. ¿Eres tú?... Sí, tú mismo... Dime, ¿estás
herido? Por lo visto, también vienes preso.
—Sí señor —repuso el maestro de obra prima—; herido y preso
estoy... Diga usted, ¿nos ahorcarán?
—¿Pues eso quién lo duda?
—¡Infeliz de mí!... Vea usted los lodos en que han venido a para
aquellos polvos. Bien me lo decía mi mujer... Señor don Patricio, al que
está como yo medio muerto de un bayonetazo en la barriga, deberían
dejarle en manos de Dios para que se lo llevase cuando a su Divina
Majestad le diese la gana, ¿no es verdad?

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Advances in Computational Toxicology

Methodologies and Applications in

Advances in Data Science: Methodologies and

Recent Advances in Applications of Computational and

Computational Toxicology Orazio Nicolotti

Computational systems pharmacology and toxicology

Advances in Computational Techniques for Biomedical

Seafood Science Advances in Chemistry Technology and

Computational Geomechanics and Hydraulic Structures

Advances in Neutron Optics Fundamentals and

Huixiao Hong Editor

More information about this series at http://www.springer.com/series/6918

ISSN 2542-4491 ISSN 2542-4483 (electronic)

Library of Congress Control Number: 2019935555

© Springer Nature Switzerland AG 2019

foster collaboration by providing inspiration for scientiﬁc discourse among readers

Jefferson, AR, USA William Slikker Jr. Ph.D.

course on computational toxicology, this book would provide excellent reading

Cambridge, MA, USA Rebecca Kusko, Ph.D.

1 Computational Toxicology Promotes Regulatory Science . . . . . . . . 1

Part I Methods in Computational Toxicology

8 An Overview of National Toxicology Program’s Toxicogenomic

Part II Applications in Regulatory Science

18 Integrating QSAR, Read-Across, and Screening Tools:

About the Editor

Huixiao Hong is Chief of Bioinformatics Branch, Division of Bioinformatics and

Tero Aittokallio Institute for Molecular Medicine Finland, University of Helsinki,

Scott S. Auerbach Division of the National Toxicology Program, National

Zhiqiang Fu Key Laboratory of Industrial Ecology and Environmental

Anna Lombardo Istituto di Ricerche Farmacologiche Mario Negri – IRCCS,

Xianhai Yang Jiangsu Key Laboratory of Chemical Pollution Control and

Rebecca Kusko and Huixiao Hong

Keywords Computational toxicology · Regulatory science · Risk assessment ·

CYP Cytochrome P450 enzyme

1.1 Computational Toxicology

a major approach of estimating human effects of substances, ethical, economic, and

1.2 Domain of Computational Toxicology

1.3 Need for Computational Toxicology

When using research to guide toxicology regulation, reproducible and rigorous

1.4 Methods in Computational Toxicology

1.5 Potential Applications of Computational Toxicology

Computational toxicology has been accepted in the regulation of products. One of

cussed the implementations of workflows for assessing trusted reproducible in silico

Huixiao Hong is Chief of Bioinformatics Branch, Division of Bioinformatics and Biostatistics,

Title: El terror de 1824

Author: Benito Pérez Galdós

Release date: October 12, 2023 [eBook #71861]

Original publication: Madrid: Obras de Pérez Galdós, 1904

*** START OF THE PROJECT GUTENBERG EBOOK EL TERROR DE

Los errores de imprenta han sido corregidos.

En la tarde del 2 de octubre de 1823 un anciano bajaba con paso

Era que venían por el camino de Andalucía varias carretas

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