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Computational Toxicology Volume I 1st Edition Brad
Reisfeld Digital Instant Download
Author(s): Brad Reisfeld, Arthur N. Mayeno (auth.), Brad Reisfeld, Arthur N.
Mayeno (eds.)
ISBN(s): 9781627030502, 1627030506
Edition: 1
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Year: 2013
Language: english
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.
Computational Toxicology

Volume I

Edited by

Brad Reisfeld
Chemical and Biological Engineering & School of Biomedical Engineering
Colorado State University, Colorado, USA

Arthur N. Mayeno
Chemical and Biological Engineering,
Colorado State University, Colorado, USA
Editors
Brad Reisfeld Arthur N. Mayeno
Chemical and Biological Engineering Chemical and Biological Engineering
& School of Biomedical Engineering Colorado State University
Colorado State University Colorado, USA
Colorado, USA

ISSN 1064-3745 ISSN 1940-6029 (electronic)

ISBN 978-1-62703-049-6 ISBN 978-1-62703-050-2 (eBook)
DOI 10.1007/978-1-62703-050-2
Springer New York Heidelberg Dordrecht London
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Preface

Rapid advances in computer science, biology, chemistry, and other disciplines are enabling
powerful new computational tools and models for toxicology and pharmacology. These
computational tools hold tremendous promise for advancing applied and basic science,
from streamlining drug efficacy and safety testing to increasing the efficiency and effective-
ness of risk assessment for environmental chemicals. These approaches also offer the
potential to improve experimental design, reduce the overall number of experimental trials
needed, and decrease the number of animals used in experimentation.
Computational approaches are ideally suited to organize, process, and analyze the vast
libraries and databases of scientific information and to simulate complex biological phe-
nomena. For instance, they allow researchers to (1) investigate toxicological and pharma-
cological phenomena across a wide range of scales of biological organization
(molecular $ cellular $ organism), (2) incorporate and analyze multiple biochemical
and biological interactions, (3) simulate biological processes and generate hypotheses
based on model predictions, which can be tested via targeted experimentation in vitro or
in vivo, (4) explore the consequences of inter- and intra-species differences and population
variability on the toxicology and pharmacology, and (5) extrapolate biological responses
across individuals, species, and a range of dose levels.
Despite the exceptional promise of computational approaches, there are presently very
few resources that focus on providing guidance on the development and practice of these
tools to solve problems and perform analyses in this area. This volume was conceived as
part of the Methods in Molecular Biology series to meet this need and to provide both
biomedical and quantitative scientists with essential background, context, examples, useful
tips, and an overview of current developments in the field. To this end, we present a
collection of practical techniques and software in computational toxicology, illustrated with
relevant examples drawn principally from the fields of environmental and pharmaceutical
sciences. These computational techniques can be used to analyze and simulate a myriad of
multi-scale biochemical and biological phenomena occurring in humans and other animals
following exposure to environmental toxicants or dosing with drugs.
This book (the first in a two-volume set) is organized into four parts each covering a
methodology or topic, subdivided into chapters that provide background, theory, and
illustrative examples. Each part is generally self-contained, allowing the reader to start with
any part, although some knowledge of concepts from other parts may be assumed. Part I
introduces the field of computational toxicology and its current or potential applications.
Part II outlines the principal elements of mathematical and computational modeling, and
accepted best practices and useful guidelines. Part III discusses the use of computational
techniques and databases to predict chemical properties and toxicity, as well as the use of
molecular dynamics. Part IV delineates the elements and approaches to pharmacokinetic
and pharmacodynamic modeling, including non-compartmental and compartmental mod-
eling, modeling of absorption, prediction of pharmacokinetic parameters, physiologically
based pharmacokinetic modeling, and mechanism-based pharmacodynamic modeling;
chemical mixture and population effects, as well as interspecies extrapolation, are also
described and illustrated.

v
vi Preface

Although a complete picture of toxicological risk often involves an analysis of environ-

mental transport, we believe that this expansive topic is beyond the scope of this volume,
and it will not be covered here; overviews of computational techniques in this area are
contained in a variety of excellent references [1–4].
Computational techniques are increasingly allowing scientists to gain new insights into
toxicological phenomena, integrate (and interpret) the results from a wide variety of
experiments, and develop more rigorous and quantitative means of assessing chemical
safety and toxicity. Moreover, these techniques can provide valuable insights before initiat-
ing expensive laboratory experiments and into phenomena not easily amenable to experi-
mental analysis, e.g., detection of highly reactive, transient, or trace-level species in
biological milieu. We believe that the unique collection of explanatory material, software,
and illustrative examples in Computational Toxicology will allow motivated readers to
participate in this exciting field and undertake a diversity of realistic problems of interest.
We would like to express our sincere thanks to our authors whose enthusiasm and
diverse contributions have made this project possible.

Colorado, USA Brad Reisfeld

Arthur N. Mayeno

References

1. Clark, M.M., Transport modeling for environmental engineers and scientists. 2nd ed. 2009, Hobo-
ken, N.J.: Wiley.
2. Hemond, H.F. and E.J. Fechner-Levy, Chemical fate and transport in the environment. 2nd ed.
2000, San Diego: Academic Press. xi, 433 p.
3. Logan, B.E., Environmental transport processes. 1999, New York: Wiley. xiii, 654 p.
4. Nirmalakhandan, N., Modeling tools for environmental engineers and scientists. 2002, Boca Raton,
Fla.: CRC Press. xi, 312 p.
Contents

Preface. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . v
Contributors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ix

PART I INTRODUCTION
1 What is Computational Toxicology? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3
Brad Reisfeld and Arthur N. Mayeno
2 Computational Toxicology: Application in Environmental Chemicals . . . . . . . . . . . 9
Yu-Mei Tan, Rory Conolly, Daniel T. Chang, Rogelio Tornero-Velez,
Michael R. Goldsmith, Shane D. Peterson, and Curtis C. Dary
3 Role of Computational Methods in Pharmaceutical Sciences . . . . . . . . . . . . . . . . . . 21
Sandhya Kortagere, Markus Lill, and John Kerrigan

PART II MATHEMATICAL AND COMPUTATIONAL MODELING

4 Best Practices in Mathematical Modeling. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 51

Lisette G. de Pillis and Ami E. Radunskaya
5 Tools and Techniques . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 75
Arthur N. Mayeno and Brad Reisfeld

PART III CHEMINFORMATICS AND CHEMICAL PROPERTY PREDICTION

6 Prediction of Physicochemical Properties. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 93

John C. Dearden
7 Informing Mechanistic Toxicology with Computational Molecular Models . . . . . . 139
Michael R. Goldsmith, Shane D. Peterson, Daniel T. Chang,
Thomas R. Transue, Rogelio Tornero-Velez,
Yu-Mei Tan, and Curtis C. Dary
8 Chemical Structure Representations and Applications
in Computational Toxicity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 167
Muthukumarasamy Karthikeyan and Renu Vyas
9 Accessing and Using Chemical Property Databases . . . . . . . . . . . . . . . . . . . . . . . . . . 193
Janna Hastings, Zara Josephs, and Christoph Steinbeck
10 Accessing, Using, and Creating Chemical Property Databases
for Computational Toxicology Modeling . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 221
Antony J. Williams, Sean Ekins, Ola Spjuth, and Egon L. Willighagen
11 Molecular Dynamics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 243
Xiaolin Cheng and Ivaylo Ivanov

vii
viii Contents

PART IV PHARMACOKINETIC AND PHARMACODYNAMIC MODELING

12 Introduction to Pharmacokinetics in Clinical Toxicology . . . . . . . . . . . . . . . . . . . . . 289
Pavan Vajjah, Geoffrey K. Isbister, and Stephen B. Duffull
13 Modeling of Absorption. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 313
Walter S. Woltosz, Michael B. Bolger, and Viera Lukacova
14 Prediction of Pharmacokinetic Parameters. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 337
A.K. Madan and Harish Dureja
15 Ligand- and Structure-Based Pregnane X Receptor Models . . . . . . . . . . . . . . . . . . . 359
Sandhya Kortagere, Matthew D. Krasowski, and Sean Ekins
16 Non-compartmental Analysis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 377
Johan Gabrielsson and Daniel Weiner
17 Compartmental Modeling in the Analysis of Biological Systems . . . . . . . . . . . . . . . 391
James B. Bassingthwaighte, Erik Butterworth,
Bartholomew Jardine, and Gary M. Raymond
18 Physiologically Based Pharmacokinetic/Toxicokinetic Modeling . . . . . . . . . . . . . . . 439
Jerry L. Campbell, Rebecca A. Clewell, P. Robinan Gentry,
Melvin E. Andersen, and Harvey J. Clewell III
19 Interspecies Extrapolation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 501
Elaina M. Kenyon
20 Population Effects and Variability . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 521
Jean Lou Dorne, Billy Amzal, Frédéric Bois, Amélie Crépet,
Jessica Tressou, and Philippe Verger
21 Mechanism-Based Pharmacodynamic Modeling . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 583
Melanie A. Felmlee, Marilyn E. Morris, and Donald E. Mager

Index . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 601
List of Contributors

HERVÉ ABDI  School of Behavioral and Brain Sciences, The University of Texas
at Dallas, Richardson, TX, USA
BILLY AMZAL  LA-SER Europe Ltd, London, UK
MELVIN E. ANDERSEN  The Hamner Institutes for Health Sciences,
Research Triangle Park, NC, USA
JAMES B. BASSINGTHWAIGHTE  Department of Bioengineering, University
of Washington, Seattle, WA, USA
FRÉDÉRIC Y. BOIS  Royallieu Research Center, Technological University
of Compiegne, Compiegne, France; INERIS, DRC/VIVA/METO,
Verneuil en Halatte, France
MICHAEL B. BOLGER  Simulations Plus, Inc., Lancaster, CA, USA
ERIK BUTTERWORTH  Department of Bioengineering, University of Washington, Seattle,
WA, USA
JERRY L. CAMPBELL JR.  The Hamner Institutes for Health Sciences,
Research Triangle Park, NC, USA
DANIEL T. CHANG  National Exposure Research Laboratory, US Environmental
Protection Agency, Research Triangle Park, NC, USA
XIAOLIN CHENG  Oak Ridge National Laboratory, UT/ORNL Center
for Molecular Biophysics, Oak Ridge, TN, USA; Department of Biochemistry
and Cellular and Molecular Biology, University of Tennessee, Knoxville,
TN, USA
HARVEY J. CLEWELL III  The Hamner Institutes for Health Sciences, Research Triangle
Park, NC, USA
REBECCA A. CLEWELL  The Hamner Institutes for Health Sciences,
Research Triangle Park, NC, USA
JEAN PAUL COMET  I3S laboratory, UMR 6070 CNRS, University of Nice-Sophia
Antipolis, Sophia Antipolis, France
RORY CONOLLY  National Health and Environmental Effects Research Laboratory,
U.S. Environmental Protection Agency, Research Triangle Park, NC, USA
AMÉLIE CRÉPET  French Agency for Food, Environment and Occupational Health Safety
(ANSES), Maisons-Alfort, France
CURTIS C. DARY  National Exposure Research laboratory, US Environmental Protection
Agency, Research Triangle Park, NC, USA
LISETTE G. DE PILLIS  Department of Mathematics, Harvey Mudd College,
Claremont, CA, USA
JEAN LOU DORNE  Emerging Risks Unit, European Food Safety Authority,
Parma, Italy
STEPHEN B. DUFFULL  School of Pharmacy, University of Otago, Otago,
New Zealand
HARISH DUREJA  M. D. University, Rohtak, India

ix
x List of Contributors

SEAN EKINS  Collaborations in Chemistry, Fuquay Varina, NC, USA; Department

of Pharmaceutical Sciences, University of Maryland, Baltimore, MD, USA; Department
of Pharmacology, University of Medicine & Dentistry
of New Jersey (UMDNJ)-Robert Wood Johnson Medical School, Piscataway,
NJ, USA
MELANIE A. FELMLEE  Department of Pharmaceutical Sciences,
University at Buffalo, State University of New York, Buffalo, NY, USA
JOHAN GABRIELSSON  Division of Pharmacology and Toxicology,
Department of Biomedical Sciences and Veterinary Public Health,
Swedish University of Agricultural Sciences, Uppsala, Sweden
P. ROBINAN GENTRY  Environ International Corporation, Monroe, LA, USA
MICHAEL R. GOLDSMITH  National Exposure Research Laboratory,
US Environmental Protection Agency, Research Triangle Park, NC, USA
JANNA HASTINGS  European Bioinformatics Institute, Hinxton, UK
GEOFFREY K. ISBISTER  Department of Clinical Toxicology and Pharmacology,
Calvary Mater Newcastle, University of Newcastle, Newcastle, NSW, Australia;
Discipline of Clinical Pharmacology, University of Newcastle,
Newcastle, NSW, Australia
IVAYLO IVANOV  Department of Chemistry, Georgia State University, Atlanta,
GA, USA
BARTHOLOMEW JARDINE  Department of Bioengineering, University of Washington,
Seattle, WA, USA
ZARA JOSEPHS  European Bioinformatics Institute, Hinxton, UK
MUTHUKUMARASAMY KARTHIKEYAN  National Chemical Laboratory,
Digital Information Resource Centre & Centre of Excellence in Scientific Computing,
Pune, India
ELAINA KENYON  Pharmacokinetics Branch, Integrated Systems Toxicology Division, MD
B105-03, National Health and Environmental Effects Research Laboratory, Office of
Research and Development, U.S. Environmental Protection Agency,
Research Triangle Park, NC, USA
JOHN KERRIGAN  Cancer Institute of New Jersey, Robert Wood Johnson
Medical School, New Brunswick, NJ, USA
SANDHYA KORTAGERE  Department of Microbiology and Immunology, Drexel University
College of Medicine, Philadelphia, PA, USA
MATTHEW D. KRASOWSKI  Department of Pathology, University of Iowa
Hospitals and Clinics, Iowa City, IA, USA
MARKUS LUKACOVA  Department of Medicinal Chemistry and Molecular Pharmacology,
Purdue University, West Lafaytte, IN, USA
VIERA LUKACOVA  Simulations Plus, Inc., Lancaster, CA, USA
A.K. MADAN  Pt. B.D. Sharma University of Health Sciences, Rohtak, India
DONALD E. MAGER  Department of Pharmaceutical Sciences, University
at Buffalo, State University of New York, Buffalo, NY, USA
ARTHUR N. MAYENO  Department of Chemical and Biological Engineering,
Colorado State University, Fort Collins, CO, USA
MARILYN E. MORRIS  Department of Pharmaceutical Sciences,
University at Buffalo, State University of New York, Buffalo, NY, USA
 List of Contributors xi

SHANE D. PETERSON  National Exposure Research Laboratory, US Environmental

Protection Agency, Research Triangle Park, NC, USA
AMI E. RADUNSKAYA  Department of Mathematics, Pomona College,
Claremont, CA, USA
GARY M. RAYMOND  Department of Bioengineering, University of Washington,
Seattle, WA, USA
BRAD REISFELD  Department of Chemical and Biological Engineering,
Colorado State University, Fort Collins, CO, USA
OLA SPJUTH  Department of Pharmaceutical Biosciences, Uppsala University, Uppsala,
Sweden; Swedish e-Science Research Center, Royal Institute of Technology, Stockholm,
Sweden
CHRISTOPH STEINBECK  European Bioinformatics Institute, Hinxton, UK
YU-MEI TAN  National Exposure Research Laboratory, U.S. Environmental
Protection Agency, Research Triangle Park, NC, USA
ROGELIO TORNERO-VELEZ  National Exposure Research Laboratory, U.S. Environmental
Protection Agency, Research Triangle Park, NC, USA
THOMAS R. TRANSUE  Lockheed Martin Information Technology,
Research Triangle Park, NC, USA
JESSICA TRESSOU  National Institute for Agronomic Research (INRA),
Paris, France
PAVAN VAJJAH  School of Pharmacy, University of Otago, Otago, New Zealand; Systems
Pharmacology Group, Simcyp Ltd, Sheffield, UK
PHILIPPE VERGER  Department of Food Safety and Zoonoses, World Health Organization,
Geneva, Switzerland
RENU VYAS  Department of Bioinformatics and Computer Science,
Dr. D.Y. Patil Biotechnology and Bioinformatics Institute, Pune, India
DANIEL WEINER  Division of Certara, Pharsight Corporation, Cary, NC, USA
ANTONY J. WILLIAMS  Royal Society of Chemistry, Wake Forest, NC, USA
EGON L. WILLIGHAGEN  Department of Pharmaceutical Biosciences, Uppsala University,
Uppsala, Sweden; Division of Molecular Toxicology, Institute of Environmental Medicine,
Karolinska Institutet, Stockholm, Sweden;
Department of Bioinformatics - BiGCaT, Maastricht University
Universiteitssingel 50, Maastricht, The Netherlands
WALTER S. WOLTOSZ  Simulations Plus, Inc., Lancaster, CA, USA
 Part I

Introduction
 Chapter 1

What is Computational Toxicology?

Brad Reisfeld and Arthur N. Mayeno

Abstract
Computational toxicology is a vibrant and rapidly developing discipline that integrates information and
data from a variety of sources to develop mathematical and computer-based models to better understand
and predict adverse health effects caused by chemicals, such as environmental pollutants and pharmaceu-
ticals. Encompassing medicine, biology, biochemistry, chemistry, mathematics, computer science, engi-
neering, and other fields, computational toxicology investigates the interactions of chemical agents and
biological organisms across many scales (e.g., population, individual, cellular, and molecular). This multi-
disciplinary field has applications ranging from hazard and risk prioritization of chemicals to safety screening
of drug metabolites, and has active participation and growth from many organizations, including govern-
ment agencies, not-for-profit organizations, private industry, and universities.

Key words: Computational toxicology, Computational chemistry, Computational biology, Systems

biology, Risk assessment, Safety assessment

1. Introduction

There are over 80,000 chemicals in common use worldwide, and

hundreds of new chemicals and chemical mixtures are introduced
into commerce each year. Because chemical safety has traditionally
been assessed using expensive and time-consuming animal-based
toxicity tests, only a small fraction of these chemicals have been
adequately assessed for potential risk.
Aside from these environmentally relevant chemicals, drugs are
another class of chemicals for which toxicity testing is crucial. For
new drugs, toxicity is still the cause of a significant number of
candidate failures during later development stages. In the pharma-
ceutical industry, toxicity assessment is hampered by the large
amounts of compound required for the in vivo studies, lack of
reliable high-throughput in vitro assays, and inability of in vitro
and animal models to correctly predict some human toxicities.

Brad Reisfeld and Arthur N. Mayeno (eds.), Computational Toxicology: Volume I, Methods in Molecular Biology, vol. 929,
DOI 10.1007/978-1-62703-050-2_1, # Springer Science+Business Media, LLC 2012

3
4 B. Reisfeld and A.N. Mayeno

For both environmental pollutants and drugs, there is a clear

need for alternative approaches to traditional toxicity testing to help
predict the potential for toxicity and prioritize testing in light of the
limited resources. One such approach is computational toxicology.

2. What is
Computational
Toxicology?
The US Environmental Protection Agency (EPA) defines Compu-
tational Toxicology as “the application of mathematical and com-
puter models to predict adverse effects and to better understand the
single or multiple mechanisms through which a given chemical
induces harm.”
In a larger context, computational toxicology is an emerging
multidisciplinary field that combines knowledge of toxicity path-
ways with relevant chemical and biological data to inform the
development, verification, and testing of multi-scale computer-
based models that are used to gain insights into the mechanisms
through which a given chemical induces harm. Computational
toxicology also seeks to manage and detect patterns and interac-
tions in large biological and chemical data sets by taking advantage
of high-information-content data, novel biostatistical methods, and
computational power to analyze these data.

3. What Are Some

Application Areas
for Computational
Toxicology? Some of the principal application areas for computational toxicology
are (1) hazard and risk prioritization of chemicals, (2) uncovering
mechanistic information that is valuable in tailoring testing pro-
grams for each chemical, (3) safety screenings of food additives and
food contact substances, (4) supporting more sophisticated
approaches to aggregate and cumulative risk assessment, (5) estimat-
ing the extent of variability in response in the human population, (6)
pharmaceutical lead selection in drug development, (7) safety
screening and qualification of pharmaceutical contaminants and
degradation products, and (8) safety screening of drug metabolites.

4. What Are
the Major Fields
Comprising
Computational Computational toxicology is highly interdisciplinary. Researchers in
Toxicology? the field have backgrounds and training in toxicology, biochemistry,
chemistry, environmental sciences, mathematics, statistics, medicine,
engineering, biology, computer science, and many other disciplines.
 1 What is Computational Toxicology? 5

In addition, the development of models in computational

toxicology has been supported by the development of numerous
“-omics” technologies, which have evolved into a number of scien-
tific disciplines, including genomics, proteomics, metabolomics,
transcriptomics, glycomics, and lipomics.

5. Who Uses
Computational
Toxicology?
A broad spectrum of international organizations are involved in the
development, application, and dissemination of knowledge, tools,
and data in computational toxicology. These include
l Government agencies in
 The USA (EPA, Centers for Disease Control, Food and
Drug Administration, National Institutes of Health,
Agency for Toxic Substances and Disease Registry).
 Europe (European Chemicals Agency, Institute for Health
and Consumer Protection).
 Canada (Health Canada, National Centre for Occupational
Health and Safety Information).
 Japan (National Institute of Health Sciences of Japan).
l The USA state agencies.
l Not-for-profit organizations.
l National laboratories.
l Nongovernment organizations.
l Military laboratories; private industry.
l Universities.

6. What Are Some

Current Areas
of Research
in Computational This volume covers a diverse range of applications for computa-
Toxicology? tional toxicology. This trend is also reflected by recent publications
in the scientific literature. Some of the topics of papers published
recently in the area of computational toxicology include
l Computational methods for evaluating genetic toxicology.
l Structure-based predictive toxicology.
l Informatics and machine learning in computational toxicology.
l Estimating toxicity-related biological pathways.
l Computational approaches to assessing human genetic
susceptibility.
6 B. Reisfeld and A.N. Mayeno

l Assessing activity profiles of chemicals evaluated across bio-

chemical targets.
l Pharmacokinetic modeling for nanoparticles.
l Quantitative structure–activity relationships in toxicity predic-
tion.
l In silico prediction of carcinogenic potency.
l Virtual tissues in toxicology.
l Public databases supporting computational toxicology.
l Regulatory use of computational toxicology tools and data-
bases.
l Computational approaches to assess the impact of environmen-
tal chemicals on key transcription regulators.
l Molecular modeling for screening environmental chemicals for
estrogenicity.
l Predicting inhibitors of acetylcholinesterase by machine
learning approaches.
l Predicting activation enthalpies of cytochrome-P450-mediated
reactions.

7. What Are Likely

Future Directions
in Computational
Toxicology? Progress in computational toxicology is expected to facilitate the
transformative shift in toxicology called for by the US National
Research Council in the recent report entitled “Toxicity Testing
in the 21st Century: A Vision and a Strategy.” Specifically, the
following directions are among those that will be critical in enabling
this shift:
l Broadening the usage of high-throughput screening methods
to evaluate the toxicity for the backlog of thousands of indus-
trial chemicals in the environment.
l Informing computational models through the continued and
expanded use of “-omics” technologies.
l Acquiring new biological data at therapeutic or physiologically
relevant exposure levels for more realistic computational
endpoints.
l Predicting adverse outcomes of environmental chemical and
drug exposure in specific human populations.
l Establishing curated and widely accessible databases that
include both chemical and biological information.
l Creating models for characterizing gene–environment
interactions.
 1 What is Computational Toxicology? 7

l Developing approaches to predict cellular responses and bio-

logically based dose–response.
l Utilizing toxicogenomics to illuminate mechanisms and bridge
genotoxicity and carcinogenicity.
l Incorporating rigorous uncertainty estimates in models and
simulations.
l Implementing strategies for utilizing animals more efficiently
and effectively in bioassays designed to answer specific
questions.
l Generating models to assess the effects of mixtures of chemicals
by employing system-level approaches that encompass the
underlying biological pathways.
l Developing virtual tissues for toxicological investigations.
 Chapter 2

Computational Toxicology: Application

in Environmental Chemicals
Yu-Mei Tan, Rory Conolly, Daniel T. Chang, Rogelio Tornero-Velez,
Michael R. Goldsmith, Shane D. Peterson, and Curtis C. Dary

Abstract
This chapter provides an overview of computational models that describe various aspects of the source-to-health
effect continuum. Fate and transport models describe the release, transportation, and transformation of
chemicals from sources of emission throughout the general environment. Exposure models integrate the
microenvironmental concentrations with the amount of time an individual spends in these microenviron-
ments to estimate the intensity, frequency, and duration of contact with environmental chemicals. Physio-
logically based pharmacokinetic (PBPK) models incorporate mechanistic biological information to predict
chemical-specific absorption, distribution, metabolism, and excretion. Values of parameters in PBPK models
can be measured in vitro, in vivo, or estimated using computational molecular modeling. Computational
modeling is also used to predict the respiratory tract dosimetry of inhaled gases and particulates [computa-
tional fluid dynamics (CFD) models], to describe the normal and xenobiotic-perturbed behaviors of
signaling pathways, and to analyze the growth kinetics of preneoplastic lesions and predict tumor incidence
(clonal growth models).

Key words: Computational toxicology, Source-to-effect continuum, Fate and transport, Dosimetry,
Signaling pathway, Physiologically based pharmacokinetic model, Biologically based dose response
model, Clonal growth model, Virtual tissue

1. Overview

Computational toxicology involves a variety of computational

tools including databases, statistical analysis packages, and predic-
tive models. In this chapter, we focus on computational models
that describe various aspects of the source-to-health effect contin-
uum (Fig. 1). Literature on the application of computational
models across the continuum has been expanding rapidly in recent
years. Using the Web of Science portal, we conducted a

Brad Reisfeld and Arthur N. Mayeno (eds.), Computational Toxicology: Volume I, Methods in Molecular Biology, vol. 929,
DOI 10.1007/978-1-62703-050-2_2, # Springer Science+Business Media, LLC 2012

9
10 Y.-M. Tan et al.

Fig. 1. Major components of the source-to-effect continuum.

bibliometric analysis of publications that appeared between 1970

and 2009. Using the search structure [TS ¼ (computational
OR “in silico” OR predictive OR model* OR virtual) AND TS
¼ (toxicology) AND TS ¼ (environment*)] (TS: Topic), a total
of 397 articles were found. Adding “NOT pharmaceutic*” to the
search structure above, found 371 articles, indicating only a
small fraction of the 397 deal with aspects of drug development.
A PubMed search (Feb 17, 2011) on “physiologically based phar-
macokinetic (PBPK) modeling” found 769 articles, indicating
that our search, which focused on computational modeling spe-
cifically in environmental toxicology, was quite restrictive.
Literature searches using specific terminology were performed to
understand the publication frequency of some of the most common
types of modeling used in computational toxicology, including fate
and transport, exposure, PBPK, computational fluid dynamic (CFD),
signaling pathway, biologically based dose–response (BBDR), and
clonal growth modeling. Searches were restricted to original scientific
publications only (i.e., reviews were excluded) and fields of science
were restricted (e.g., “NOT eco*”) in order to focus on applications
relevant to human health effects. A yearly breakdown showing publi-
cation frequency over time is presented in Fig. 2. The data show a
rapid increase in publication frequency for many of the modeling
types beginning in the early 1990s and that PBPK, fate and transport
and signaling pathways are the most common. BBDR and clonal
growth modeling have received considerably less attention.
 2 Computational Toxicology: Application in Environmental Chemicals 11

Fig. 2. Literature searches performed to understand publication frequency of common modeling types used in environ-
mental computational toxicology.

2. Computational
Models Along the
Source-to-Health
Effect Continuum Fate and transport models describe the release, transportation, and
transformation of chemicals from sources of emission throughout
2.1. Fate and Transport the general environment. Fate addresses persistence, dissipation,
and loss of chemical mass along the migration pathway; and trans-
port addresses mobility of a chemical along the migration pathway
(1). Based on their complexity, models of fate and transport can be
used for either “screening-level” or “higher-tiered” applications
(2). Screening-level models often use default input parameters
that tend to over-predict exposures (the preferred default approach
used in the absence of data). These models are suitable for obtain-
ing a first approximation or to screen out exposures that are not
likely to be of concern (3). Screening-level models have limited
spatial and temporal scope. Higher-tiered models are needed when
analyses require greater temporal and spatial resolution, but much
more information is required, such as site-specific data.
The processes that can be described in fate and transport models
include advection, dispersion, diffusion, equilibrium partitioning
between solid and fluid, biodegradation, and phase separation of
immiscible liquids (1). In general, fate and transport models require
information on physicochemical properties; mechanisms of release
Another Random Scribd Document
with Unrelated Content
 538 THE NORTHERX FORESTS. [Part IX. " Alpli, the sacred
river, ran Tlirougli caverns measureless to man Do'svn to a smiless
sea." There certainly are numerous springs in the sands along the
shore at the point referred to ^, whose o]^eiiings are covered by
the tide at high water ; but whether a connection exists between
any one of them and the well of Potoor is a problem still unsolved.
At Potoor, one of the fine old churches erected by the Portuguese
abuts on the high road, and has recently been restored, the
Wesleyan ]\Iission having a successful station in the vicinity. From
thence into Jaffna the road passes through a succession of fields so
cleanly cultivated and securely fenced, that a stranger might almost
fancy a resemblance between it and a scene in England, — an
illusion wliich is not dispeUed on arri\-ing at the residence of Mi\
Dyke, the Government agent of the province : a spacious mansion in
the midst of a park-hke demesne, studded with forest-trees, and
diversified with clumps of flowers and groups of the choicest and
rarest plants and shrubs of Ceylon. In the court-yard to the rear is a
spacious garden, in Avliich Mr. Dyke has succeeded in cultivating the
black grape of Madeira, trained over a trellis, — the want of winter
rest for the plants being supphed by baring the roots, and exposing
them to the sun. The vines give two crops in the year, — the
principal one in ^ This lefTond of a subten-anean river ill Ceylon was
earned westward by the Ai'abian maiiners in the middle ages ; and it
will be remembered that Sindbad of the Sea, in his sixth voyage,
wherein he nan-ates his arrival in Serendib, describes hia shipwreck
on the coast, " near a lofty moimtain,'" underneath which a stream
was flowing inland. Embarking on this, on a raft of aloes and
sa,ndalwood, together with heaps of the peai'ls, jacinths, and
ambergi-is which he collected on the beach, Sindbad " proceeded to
the place where the river entered," and in the midst of profoimd
darloiess, was carried luider ground by the cun-ent, through a
passage so naiTow and low, that " the raft rubbed against the sides,
and his head against the roof." Emerging at last into light, his " eyes
beheld an extensive tract, and a company of people like Abyssinians,
m-Iio had come to irrigate their fields and so\^^l lands," and wlio
forthwith conducted him to the presence of tlie King of Serendib.—
Lake's Arabian Xif/hfs, vol. iii.
 ClIAP. VI.] THE TAMILS. 539 March, and the second in
September, — but the operation of stripping the roots is only
resorted to once, about the time of pruning in July.^ The fruit fi'om
some cuttings of white Muscat vines, obtained from Pondiclierry by
Mr. Dyke in 1840, proved to be identical with the Jaffna grape, the
Dutch having probably brought the latter from Kegapatam, whence it
liad been carried from Muscat. Of late years, the Tamils at Jaffna
have begun to cultivate the \'ine ; so that grapes are now not only,
procurable in the public market, but are also occasionally sent for
sale to Colombo. Jaffna has been peopled by Tamils for at least two
thousand years, the original settlement being of date coeval with the
earliest Malabar invasion of the islanel, B.C. 204 ^, and their chiefs
continued to assume the rank 1 See Vol. I. Pt. I. cli. iii. p. 89. ^ Tlie
arrival of tlie Tamils and the expulsion of the Nagas is
coninieniorated in an ancient poem, called the Kylasa Mala, a
translation of which will he found in the- Asiat-. Journ. for 1827, vol.
xxiv. p. 58, and the substance of it has been embodied in a sketch of
the ancient history of JaiRia, by Casie Chittt, in the Journ. of the
Asiatic Society of Colombo, 1847, p. 09. The pui-jjoi-t of the legend
is, that a princess of Tani'ore, desirous of being freed fi'oni a lorse's
head with which she had the misfortune to be born, was directed in
a vision to batlie in the well of Keremale, on the northern shore of
Ceylon, near which a temple still exists that, commemorative of lier
cure, bears the name " ^lahavittepuram," and an annual fosti\al is
perfonned in lier honour. The legend runs, that one of her followers,
a minstrel or " Yalpanon," having made his way to the Singhalese
Court, the reigning sovereign, charmed by his powers, conferred on
him the territory of the peninsula, which tliereafter took tlie name of
Yalpannaii,ov Yaljxmna nadu, by whicli it is still known to the natives,
though corrupted \>y Europeans into ".Taffiia and Jaflhapatam. This
occurrence took place a century before the Cliristian era, and, in
succession to the lutanist, there arose a dpiasty of IJajalis of .Taflha,
who held their court at Xalloor, .and tlience extended their conquest
OA-er the Wanny and Manaai*. It is even possible that " Kachias,"
the ambassador who arrived at Rome in the reign of Claudius, may
have represented, not the Singhalese monarch, but the Rajah of
Jatlha. De Couto relates that about the year 1574, when Joao de
Melho de Sampaio was Captain of ]Manaar, there were discovered,
under the foundation of a building, an iron chain of curious
workmanship, and coins on which the letter 6' wsxs legible, and on
the reverse the letters R.M.N.R., which were imderstood to mean
Cl.VVDIUS IjirEK.VTOR RoMAXORrjf, and were supposed to \m\e
been brouglit to Ceylon by tlu' freedman of .Vnnius Rlocamus, who
was the first Roman that landed on the island, " e cousa he possivel,
quefossem e.«tcis moedas das que alii Icvou o Liberto do Anio." —
De Couto, dec. v. liv, i, ch. vii. vol. ii. pt. i. p. 71,
 540 THE XORTIIERX FORESTS. rPART IX. and title of
independent princes down to the seventeenth century. The Rajavali
recounts the occasions on wliich they carried on wars with the
Singhalese kings of the island ^ ; — and their authority and
influence in the fourteenth century are attested by the protection
which the Eaja (whose dominions then extended as far south as
Chilaw) afforded to Ibn Batuta, whom, Avith his companions, he
permitted to visit the sacred footstep on the summit of Adam's
Peak.Elsewhere, the story has been told of the persecution of the
native converts who had embraced Christianity under the preaching
of St. Francis Xavier, about the year 15-44, and of the wars
undertaken by the Portuguese to avenge them, which terminated,
a.d. 1617, in the conquest of their country and its final annexation to
the possessions of Portugal in Ceylon.^ In their turn, the Portuguese
were expelled by the Dutch m 1658 ; but although the tenure of
Jaffna by the former did not much exceed forty years, the exertions
which they made, during that brief period, to establish the Eoman
Catholic rehgion are attested by the number of churches they built.
These remain to the present day, having served in turn for the
missionaries of three nations, of Portugal, Holland, and England, and
successively "v\dtnessed the celebration of the rites of three
communions, the Eoman Catholic, the Eeformed, and the
Episcopahan.* The Portuguese divided the peninsula into parishes,
with schools and a mansion for the priests in each ; and within the
town they maintained a college of Jesuits, a convent of Franciscans,
and a monastery of Dominican Friars.'^ » Rajavali, p. 208. ^ Ibx
Batuta, Travels, S^c, Trans, by Lee, pp. I8.S-I80. ' 3 Faria y SorzA,
aoI. iii. ch. xii. p. 259. See the poi-tion of tlie present work relative
to tlie Portug-uese in Ceylon, Vol. II. Ft. vi. cli. i. p. 20. * Views of
the most important of these buildin For an account of the missionary
proceedings of the Portuguese at Jaffiia, see Sir .1. Emeesox
Tkxxext's Hidorifof ('hristianitii in Cci/h», ch. i. p. 10. ■ ■
 CUAP. VI.] JAFFNA. 541 On the occupation of Ceylon by the
Britisli, the principal European inhabitants emigrated to Bata\ia ; yet,
of all the settlements of HoUand in the island, none is still so
thoroughly Dutch in its architecture and aspect as the town of
Jaffna. The houses, hke those of Colombo, consist of a single story,
but they are large and commodious, with broad verandahs, lofty
ceihngs, and spacious apartments. Every building, inside and out, is
as clean and showy as whitewash, fresh paint, bright red tiles and
brick floors can make them. The majority of them are detached, and
situated in enclosed gardens filled with fruit-trees and flowering
shrubs ; and I am told, some years ago, the finest specimens of
antique carved furniture in ebony and calamander, cabinets, arm-
chairs, and ponderous sofas, ■were still to be seen in these ancient
dwellings of the former rulers of the island. The streets of the town
are broad and regular, and are planted, as usual, ^vitli fines of Suria
trees, for the sake of their asiireeable shade and yeUow flowers. The
fort, which was entirely reconstructed by the Dutch, is the most
perfect little mihtary work in Ceylon, — a pentagon, built of blocks of
white coral, and surrounded by a moat. It contains several excellent
buildings, a residence for the Commandant, and an old chui'ch in the
form of a Greek cross. This, by the capitulation of 1795, was
specially reserved for the Presbyterian Consistory, but by their
courtesy is at present used for the service of the Church of England.
^ The native town is almost exclusively occiq)ied by Tamils and
Moors, and the tradesmen and dealers exhibit in their several
pursmts no less inteUigence and industry than characterise the rural
population. They weave a substantial cotton cloth, which is dyed and
* y.VLEXTTN describes tlie fortress of Jcaftiiapatam -with great
particularity, its bastions, its ravelin, and "water pass ; and such was
the importance attached to it by the Dutch^ that he says the gain-
ison maintained there was much stronger tlian tliat of ]jatavia.- —
Oudcn Nicuic Oo»f-I/idicn, ch. ii. p. .'30.
 542 THE XOKTHERX FORESTS. [Part IX. ornamented by a
class of calico-painters, the descendants of a party avIio were invited
to settle here under the Dutch Government, nearly two hundred
years ago. The goldsmiths are ingenious and excellent workmen,
and produce bangles, chains, and rings, whose execution is as fine
as their designs are tasteful. Nothing is more interesting than to
watch one of these primitive artists at liis occupation, seated in the
open air, with no other apparatus that a few clumsy tools, a blow-
pipe, and a chatty full of sand on which to hght his charcoalfire. The
crushing of the coco-nut for the expression of the oil is another
flomishing branch of trade, and for this purpose the natives erect
their creaking miUs under the shade of the groves of palm-trees
near their houses. These consist of the trunk of a tree hollowed into
a mortar, in which a heavy upright pestle is worked round by a
bullock yoked to a transverse beam. A NATIVE OIL MILL. Jaffna is
almost the only place in Ceylon of wliich it might be said that no one
is idle or unprofitably employed. The bazaars are fuU of activity, and
stocked with a greater variety of fruits and vegetables than is to be
seen in any other town in the island. Every one appears to be more
or less busy ; and at tlie season of the year when labour is not in
demand at liome, numbers of the natives 2:0 off to trade in tlie
interior ;
 Chap. VI.] IXDUSTRIOUS HABITS OB^ THE TAMILS. 543
carrying adventures of curry stuffs, betel-leaves, and other produce,
to be sold in the villages of the Wanny. Large bodies of them also
resort annually to the south, where they find lucrative employment
in repaking the village tanks, — a species of labour in which they are
peculiarly expert, and which the Singhalese are too indolent or too
litigious to perform for themselves. If the deserted fields and
sohtudes of the Wanny are ever again to be re-peopled and re-tilled,
I am inchned to beheve that the movement for that purpose will
come from the Tamils of Jaffna ; for, looking to their increasing
intelhi2jence and wealth, their habits of industrv and adaptation to
an agricultural hfe, I can have little doubt that, as population
increases, and the arable lands of the peninsula become occupied,
emigration will gradually be directed towards the south, where, w'ith
the natural capabihties of the soil and the facilities for irrigation, one
half of the exertion and toil bestowed on the reluctant sands of
Jafiha would speedily convert the wilderness into a garden. Already
there is a satisfaction, experienced in no other portion of Ceylon, in
visiting their villao:es and farms, and in witnessinsj the industrious
habits and improved processes of the peasantry. The whole district is
covered with a net-work of roads, and at certain situations there
exist what are maintained in no other part of the island (except at
Matura in the south), regular markets, to which the peasantry resort
from a distance, and bring theu' fruit, vegetables, and other produce
for sale. These markets are generally held in the early morning,
before the sun pours down his fiercest rays ; and in driving along the
roads at such an hoiu-, tlie active and busy picture which they
present would have strongly reminded me of some rural scenes in
England, had it not been for the disproportionate share of the labour
borne by the women, who always seemed to carry the heaviest
burdens, and to take the most toilsome share in the business of the
day.
 544 THE NORTHERX FORESTS. [Part IX. Even amongst the
more civilised portion of the Tamils, there is no characteristic Avhicli
so forcibly as this demonstrates the barbarism of their customs, and
the degraded nature of their domestic relations. Thouoh the outward
demeanour of men of the higher castes and of ambitious
pretensions, and the nature of their pubhc pursuits, may draw off
attention from their homes and their personal habits ; still thek
social arrangements, and the economy of their private
estabhshments, when these can be examined, exhibit a picture of
demoraUsation truly deplorable. Notwithstanding all that has been
achieved by the successful labours of the Christian missions in the
peninsula \ the private hfe of such of the lowest classes of the
people as are still uninfluenced by moral instruction, and untouched
by civilisation, is, of course, still more depraved and disgusting. Their
households exhibit none of those endearments and comforts which
constitute the charms and attractions of a home. Sensuality and gain
are the two passions of their existence, and in the pursuit of these
they exhibit a hcentiousness so shocking, and practices so
inconceivably vile, as woidd scarcely obtain credence from those
who are famihar only with the aspect and usages of civihsed hfe,
even in its lowest and least attractive forms. Amongst the Tamils in
Ceylon, as amongst the natives on the coast of India, the behef in
sorcery is strongly and generally entertained, and its professors turn
the practice of witchcraft and charms to lucrative account, pandering
to the w^orst passions of degraded humanity by the secret exercise
of pretended arts, and the performance of revolting ceremonies. In
1849, an occurrence of this Idnd was brouglit officially imder my
notice, involving the disclosure of practices, the existence of which
amidst a dense popu^ For an accoimt of the missions I labours, see
Sir J. Emersox Tex Jafliia, and especially of the j nent's Hi at on/ of
Christ ianifi/ in erican missionaries and their j Ceylon, ch, iv. pp. 1-38
— 17(>; Sec. in American
 Chap. VI.J SUPERSTITIOUS CEREMOXIES. .:4.> latiou, and
in tlie vicinity of the chief town of tlie province, is in itself an
exemphiication of tlie mass of barbarism and superstition which still
exists amongst the natives of Jaffna, even after three hundred years
of European government, and despite the labours and acliievements
of so many Christian teachers and ministers. In December, 1848, the
police vidahn of Vannarpoonne, in the suburbs of Jaffna, came to
the magistrate in much mental agitation and distress, to complain
that the remains of his son, a boy of about eight years of age, which
had been buried the day before, had been disinterred during the
night, and that the head had been severed from the body to be used
for the purposes of witchcraft. Suspicion fell on a native doctor of
the village, who was extensively consulted as an adept in the occult
sciences ; but no evidence could be produced sufficient to connect
him with the transaction. The vidahn stated to the magistrate that a
general belief existed amongst the Tamils in the fatal effects of a
ceremony, performed with the skull of a child, with the design of
producing the death of an individual against whom the incantation
was directed. The skull of a male child, and particularly of a first-
born, is preferred, and the effects are regarded as more certain if it
be killed expressly for the occasion ; but for ordinary purposes, the
head of one who had died a natural deatli is presumed to be
sufficient. The form of the ceremony is to draw certahi figures and
cabahstic signs upon the skull, after it has been scraped and
denuded of the flesh ; adcUng the name of tliia*ndividual upon
whom the charm is to take effect. A paste is then prepared,
composed oi sand from the footprints of the intended victim, and a
portion of his hair moistened with his sahva, and this, being spread
u]^on a leaden plate, is taken, together with the skull to the
graveyard of the village, where for foi'ty nights the evil spirits are
invoked to destroy the person so denounced. The universal belief of
the natives VOL. II. NX
 54S THE XORTHEKX FORESTS. [Part IX. is, that as the
ceremony proceeds, and the paste dries up on tlie leaden plate, the
sufferer will waste away and decline, and that death, as an
inevitable consequence, must follow. In this instance a watch was
kept upon the proceedings of the suspected doctor, and it was
ascertained that he and liis family were engaged in the most
infamous practices. His sons were his assistants in operations sunilar
to that Avhich has been described, and in the preparation of philters
to facihtate seduction and medicines for producing abortion. His
house was an asylum for unmarried females in pregnancy, where
their accouchements were assisted by women retained for their
knowledge of midwifery ; and the skulls of the infants were apphed
as occasion required for the composition of love potions and the
performance of incantations. In the course of the folloAving moutli\
a second complaint against the same inchvidual was brought before
the magistrate at Jaffna, to the effect that on a stated morning, he
had mmxlered an infant in order to possess himself of its head, and
that at the moment of bringing the charge, a second child was
concealed in his dwelling, and destined for a similar fate. On
searching the house the body of one cliild was found as represented,
with the head recently severed ; and after considerable search, the
other httle creature was discovered, still ahve, under some baskets
near the roof of an inner apartment. The doctor and his sons had
been seen on pre\dous occasions to buiy something in the garden at
the rear of the building. On this being dug over, the remains of other
children were discovered, in sufficient numbers to attest the extent
of the practice. Unfortunately the criminal was himself permitted to
escape ; the character of his establishment, and the testimony of the
women in his service 1 8th Jaiiuarv, 1840.
 CiiAP. VT.J A TAMIL DOCTOR. 547 giving some colour to lii.s
assertion, that the infants whose remains were disinterred had died
a natiural death ; whilst he was able to offer a plausible explanation
for the mutilation of tlie body that liad been found, by declaring that
it was devoured by a Pariah dog. His papers were seized by the
magistrate, among which was a volume of receipts for compounding
nefarious preparations and poisons ; — and along with these a
manuscript book containing the necessary diagrams and forms of
invocation to " Siva the Destroyer," for every imaginable purpose — "
to seduce the affections of a female — to effect a separation
between a husband and wife — -to procure abortion — to possess
with a devil — to afflict witli sickness," — and innumerable directions
" for procuring the death of an enem3\" In this remarkable treatise
on domestic medicine, there was not one single receipt for the cure
of disease amongst the numerous formulas for its infliction ; nor one
instruction for effecting a harmless or benevolent purjiose amidst
diagrams and directions for gratifjdng the depraved passions, and
encouraging the fiendish designs of tlie author's dupes. Thus the
same energy of character in whicli tlie Tamils of Jaffna
constitutionally excel the Singhalese and Kandyans, and which is
strildngly exhibited in all their ordinary pursuits, is equally
perceptible in its vicious as in its moral developments. In both
particulars the two races that are most nearly assimilated in Ceylon
are the Hindus of the northern province, and the active-minded and
vigorous Moors of the south and east; — next to these are the
mountaineers of Kandy and Oovali ; whilst the weakest and the most
cunning are the natives of the lowlands and the maritime districts.
The statistics of crime as exlubited by the calendars of the Supreme
Court are demonstrative of these local peculiarities. Amongst the
Singhalese of the l(^w country, the majority of the crimes cognisable
by the higher tribunals are generally of a secondaiy N N 2
 548 THE NORTHERN FORESTS. [P.^ TX cliaracter, and tlie
instances in Avhicli violence to tlie person accompanies offences
against property are fewer than in other parts of the island. The
proportion of cases so aggravated increases in the southern and
Kandjan provinces ; and crime in the noith consists principally of
burglary, frequently accompanied by personal violence and
characterised by daring and combination.' ^ From a paper on the
state of crime in Ceylon, by the Hon. Mr. Justice STARKE,publishecl
in the Transactmif of the Ceylon Asiatic Socief I/, vol. i. p. 52.
 549 CHAP. \TI. THE ISLANDS. — ADAll'S BRIDGE AJsB THE
PEARL FLSIIERY, As, owing to tlie shallows, the Government
steamer, — the " Seaforth," on board which we were to be received
at Jaffna, — was unable to approach nearer than the group of
islands that he off the western point of the peninsida, we were
rowed in one of the great canoes called bedlams, or vallanis ^
through the channel of Kayts^ under the miniatm^e fort of
Hammaniel^, and embarked off the island of Analativoe or Donna
Clara.^ We brought to, an hour after starting, at the island of Delft.
" The portion of Ceylon," says Pliny, " which approaches nearest to
India is the promontory of Coliacum, and midway between it and the
mainland is the island of die Sun ; " ^ — assuming the Cohacum of
Pliny ^ The ballams are usually hollowed out of the ti'iuik of the
Atuielij or Atu/elica tree (artocarjytis Jn'rsida ?). These canoes are
genertilly brought from the coast of India, chiefly from Mangalore
and Calicut. ^ Kayts, or Cays, was so called from the Portuguese
temi for a wharf, cais or caes, this being the utmost point to which a
sea-going vessel could enter the shallows on approaching Jaffiia. ^
Yalexttn explains this term by saying, that as the outline of Ceylon
resembled that of a ham, this little island occupied the position of its
shank or h(H»l, wheace its name, " hamman-hk'l." — Oiid en Nieuw
Oost-Indien, ch. i. p. 18 ; elsewhere, ch. XV. p. 217, Valentyn calls
Ilammaniel tlie " Water Fort :" upon this, and upon the land fort at
KangesentoiTe, the Dutch relied as defences against the passage of
ships towards Jaffiia. — Ibid. ch. ii. p. 31. * Donna Clara, who
ajipeai-s to have been the chief owmer of this islet in the time of the
Portuguese, was renowned for her extraordinary size ; her chair,
according to IJiiiEYRo, was preserved in his time as the sole curiosity
of the island ; " et les deux plus gi'os hommes y peuvent tenir assis
tres a I'aise et tres au large." — Lib. i. ch. XXV. p. 190. ^ Plixy, X
 550 THE IS^ORTHERN FOEESTS. [Part IX. to be Bamancoil
or Eamiseram, Delft would appear to be " the island of the Sun." Its
length does not exceed seven or eight miles, and a tiny lake, formed
in a depression in its centre, so facihtates vegetation and the growth
of trees, that the Portuguese, wliilst in possession of Manaar,
occupied it as a breeding place for cattle and horses, and hence it
acquired from them its designations of the " Ilha das Vacas," and "
Illia dos Cavallos." * The breed of the latter, which had been
originallyimported from Arabia, was kept up b}^ the Dutch, and
afterwards for some time by the Enghsh, the horses behio- allowed
the free ranse of the island, and when reqiui'ed were caught by the
lasso, in the use of which the natives had probably been instructed
by the Portuguese.^ The stud was discontinued many years ago, the
buildings constructed for it have since gone to ruin, and the island is
now thickly inhabited and partially brouo-ht under cidtivation. As we
approached the Indian side of the channel at sum'ise on the
following morning, we landed on the island of Eamiseram, to visit
the Great Pagoda, the lofty towers of which were visible long before
we were able to discern the low sandy beach on which it is built.
This shrine, which, in the estimation of the Brahmans, has rendered
Eamiseram one of the most sacred spots in the luiiverse, is
dedicated to Eama, whose uivasion of Ceylon from this point is
commemorated by so many incidents 1 RiBEYRO says, it was also
called j Tliis tliey contrive to thro-w about by the Portuguese the '^
Ilha das j one of his hind legs whilst he is in Cabras," because of the
multitude of fidl gallop, and thus make sm'e of goats which it fed,
and he adds that him. One cannot see this manoeu\Te it supplied
the finest bezoar stones in practised without the gi-eatest asthe
world. (Lib. i. ch. xxv. p. 188.) tonishment, for these horse-catchers
2 " Tlie horses run wild on the ^ are so trained that they never fail,
island and are caught by driving them They teach their children this
art (Ijv into a korahJ, which is circidar and practising) oiyi man, and
I liave tried fenced with round stones — here, one j them on myself.
I had only to say in particular being pitched on, some on which arm
or foot I chose to have of the natives set after him witli ropes the
rope thrown while I was numing nuide into a noose, eight fatliom
long, as fa.st as I was able, and it was and the thickness of a nian"s
finger, done." — Memoirs of Wolf, p. ll>7.
 CuAP. VII.] THE GREAT PAGODA. 551 in the surrounding
region. The islet on wliich it stands is, and has been innneniorially,
exempted from cidtivation ; its inhabitants are interdicted from all
secular pursuits and callings, and the place consecrated to devotion,
solemnity, and repose. The temple or coil, with its majestic towers,
its vast and gloomy colonnades, and its walls encrusted with carved
work and statuary, exhibits a grand exam})le of the style of sucli
monuments in Southern India ; though inferior in dimensions to
those of Seringham, Madm-a, and Tanjore.^ We found the vicinity of
the Pagoda surrounded by thousands of pilgrims from all parts of
India ; mingled with whom were fakirs of the most hideous aspect,
exhibiting their hmbs in inconceivably repulsive attitudes. Gaudy
vehicles, covered with gilding and velvet, and drawn by cream-
colom-ed oxen, carried ladies of distinction, who had crossed in
pilgrimage from the opposite coast, and beside the grand porch
stood the lofty cars of the idol, structures of richly-carved wood
adorned with vermihon and gold. At the great entrance of the
temple, we were received by the officers, and conducted round the
immense quadrangle, supported by innumerable columns. Here we
were met by the band of nautcli girls, who presented us Avith
flowers, and performed before us one of their melancholy and
sj)U'itless movements, which is less a dance than a series of
postures, wherein the absence of grace is sought to be compensated
by abrupt gestures, stamping the feet and wringing the arms, to
extract an inharmonious accompaniment from the jingling of bangles
and anklets. On leaving the temple, we rounded the western point of
the island, and entered the gidf of Manaar, by the Paumbam
Passage, which here intersects Adam's Bridge. ^ Detailed
descriptions of the Temple of Raniiseram, and its establislnnent will
be fonnd in Lord Valioatia's TrairU, lijc, vol. i. p. o.SO, kv. ; and in
Cordinkk's Cei/loii, (Sr., vol. ii. ch. XV. p. 12 ; I'krcivai/s C'e;//o»,
cSV., vol. i. p. t<0.
 552 THE NOETIIERN FOEESTS. [Part IX. The advantages of
tliis narrow channel are so striking, and the facihties ah^eady
afforded by its enlargement are so highly appreciated, that surprise
is excited that a work of such imperial importance as the deepening
of this channel should have been so long deferred, and so
imperfectly accomphshed, when at last undertaken. Such is the
circuit that a vessel is obliged to make in saihng from Bombay to
Madi^as, in order to guard against calms on the hue, and to
weather the Maldives and Ceylon, that practically she " performs a
voyage of five thousand miles, although the real distance by sea
does not exceed fifteen hundred.'''' ' The barrier that here obstructs
the communication between Palk's Bay and the Gulf, — appropriately
called the " dam," — is about a mile and quarter in length. The
rocks, which are Hat upon the upper surface, have been so curiously
broken up and intersected by the action of the waves, that they
present the closest possible resemblance to iGE, AUAiil'd BRIDGE.
deliberate arrangement, and "bear e\'ery appearance of liaving been
placed there by art." ^ Formerly, the fissure, through which small
craft alone ' Minute of the GovERMorv OF | '• Cotton^ liejxtrt on the
Pdiinihtui) 31.viiK.\s, November, 1828. | Passor/e, Septonibcr, lX'22.
 Chap. VIT.] ADAM'S BKIDGE. 553 could pass, was but
thirty-five yards wide, witli a maximum depth of httle more than six
feet of water. ^ Lately, this passage has been so enlarged and
improved, that vessels di^awing ten feet may venture through it in
safety. On the east side, the white houses of the village of Paumbam
hue the beach, nestling beneath groves of coco-nut palms and
arboi'escent mimosas, and on the west the low hue of the Indian
coast approaches so close, that the passage of the steamer
disturbed the sea-birds which were feeding in the rij^ple of the
waves upon the shore. Turning eastward at Paumbam, on our Avay
towards Manaar and Aripo, Ave kept as close as the shallows
rendered prudent, to the long hne of sandy embankments, which
form the barrier of Adam's Bridge. The (composition of this singular
reef has been akeady alluded to^, and recent examinations have
sliown that, instead of being a remnant of the original rock, by
Avhich Ceylon is supposed to have been once connected with the
Indian continent, it is in realit}' a comparatively recent ridge of
conglomerate and sandstone^, covered with alluvial deposits,
carried by the currents and heaped up at this particular point, whilst
the gradual rising of the coast has contributed to give the reef its
present altitude.'* ^ BALD.T:rs relates the improbable story, tliat in
10."»7 tifteen Portuguese frigates, ehased by the Duteli cruisers,
escapeil through the passage of Paiuubaui ; a circumstance which he
accounts for by the still more unlikely conjecture, that the natives in
charge of tlie channel had the power of adjusting the depth of the
water which last has more the appearance of indurated gravel than
rock.*" — Major Sim's Repoti mi Adaiii'.t Ih-'uhje, 1828 ; see Capt.
Stewakt's llepoH to the Governor of C'ci/loti, 1887. * The Dutch,
although they adopted the popular themy that Ceylon had been
separated from by " either bmng in or removing India by a sudden
convulsion, enter certain stones from the entrance." — tained doubts
of the primary fm-ma 1'. 700. tiou of Adam's Bridge, and ^'AhEX-
See Vol. I. Pt. I. ch. i. p. 1.5, 20. ^ "It appears to be sandstone of a
soft description, and generally in an advanced stage of decav. It is
hardest at the surface, and lic'conies softer and coarser towards llie
Itodnni. 218 TYX suggests that its origin is referable to the deposit
of sand at the point where the currents meet at the change of the
monsoons. — 0ml Nleuw Oost-Indien, ch. xv. p.
 554 THE NORTHERN FORESTS. [Part IX. From its frequent
disruption by the sea, and the deposit of sand-drift on its smface,
the formation to the east, between Eamiseram and Manaar, presents
less of tlie artificial appearance Avhich is exhibited in the vicinity of
Paunibam, and which uo doubt sufficed in ancient times to establish
the behef that it was in reahty a causeway constructed by
superhiunan power. The Hindus ascribed its origin to Eania^, and
amongst the Mahometans, the behef that Adam had found a retreat
in Ceylon on his expulsion from Paradise, led to the conjectures that
he must either have ahghted from the sky, or passed by this singular
causeway. ^ The legend of tlie building of the bridge by llama for tlie
passage of his army to the conquest of Lanka, fonus one of the
episodes in the Rumai/ana. In the Culcidta Reriew, No. X. p. 299, a
translation of this passage has been given, and the mischievous
character of Hanuman, the monkey-god, has been preserved in the
tale which is related, to the effect that his jealousy of Nala, who was
associated with him in forming tlie Bridge, led him to obstruct rather
than to further the work. The legend is told as follows : Eama having
solicited Nala (one of the monkey chiefs) to throw a bridge across
the Strait, the latter reh-ing on the power imparted to him by
Brahma " of causing stones, trees, and rocks to float," imdertoolc to
complete the task witliin a month, although the distance from Lanka
to the mainland was tlieu eight hundred miles. "He first caused one
of the liuge forests which gi-ew along the shore to be transplanted
and placed upon the waters. LIpon this bedding of trees he placed
several strata of rocks, and made the breadth of the bridge eighty
miles. Tlie first day he completed the work to a length of eight miles,
beginning from the north and proceeding s
 Chap. VII.] CORAL IXSECT. — PEARL FISHERY. 555
Valentyn says, that the iiaiiic of Adam's Bridge was first conferred on
it hy the Portuguese ^ ; but tliere is existing evidence to show that
centuries before the appearance of the Portuguese in the East, the
Arabs believed that Adam had passed by this way into Ceylon.^ In
coasting along this remarkable shore, the extreme purity of the
water enabled us to see, with astonishing distinctness, the coral
groves which rise in the clear blue depths, and conceal the surface
of the sand and rocks. Tliek branches, when severed, are exquisitely
beautiful, so long as they retain the faint purple halo that plays
around their ivory tips, but which disappears after a very short
exposure to the au'^ ; so rapidly does atmospheric exposure affect
them, that immediately after withdrawing them from the water, we
almost fail to recognise the lovely objects which a moment before
Avere o-lowino; in the still recesses below. The cilia and bright
tentacula of the pol}^3i are withdrawn and concealed the instant
the coral is disturbed, but these, when expanded in the water, cover
the suiface with brilliant tints, intense crimson and emerald green.
Feeding amongst them, are to be seen nuchbranchiate moUusca and
ajdi/sia of strange forms ; and through tlie branches dart small
fishes, with scales that ghsten like enamelled silver. Manaar appears
to be the island of Epiodorus, which, according to the Periplus^ was
the seat of the pearl fishery.'* At the present day, its importance has
greatly decHned. The Portuguese, who wrested it from the Eaja of
Jaffna, in 1560^, fortified the town ' Valentyit, Oitd en Kietiw
OostIndien, ch. xv. p. 235. ^ See a pa8.^aiie in Kaswixi's Ajaih el
Makhlouhat, written in the tliirtceutli century, and quoted by Sir W.
OuSELKY. — Traveh, ^-c, vol. i. p. 37. 3 Pliny says that the soldiers
of Alexander noticed the purple halo which plays about the coral in
the \ ii. cb. xv. vol. ii. p. 20G. Indian seas when first \\itlidra\vn from
tlie water, " in alto quasdam arbusculas colore bubuli conins raniosas
et cacuminihui^ rubenfes." — Pliny, Xaf. Hid., lib. xiii. ch. Ii. *
Peripliis, ch. lix. See Vincent, vol. ii. p. 489. ^ De Couto, dec. vii. lib.
iii. ch. V. voL iv. pt. i. p. 210; Valextyn, ch. xii. p. 147 ; Fari v Y
Souza, pt.
 556 THE NORTHERN FORESTS. [Part IX. for the protection
of their own trade, and the Dutch, Avdio seized it in 1658, were so
conscious of its value, strategetical as well as commercial, that they
designated it " the key of Jaffnapatam," and maintained in it at all
times an effective garrison, mider the apprehension that the
Portuguese, if they ever attempted a re-conquest of Ceylon, would
direct their first efTorts to the recovery of Manaar.^ During the early
ages, a considerable portion of the trade between the east and
w^est of India was carried through the narrow channel wliich
separates Manaar from Ceylon, and active estabhshments w^ere
formed, not only at Mantotte on the mainland, but in the httle island
itself, to be used for unlading and reloading such craft as it was
necessary to hghten, in order to assist them over tlie shoals.^ N^o
other than commercial motives could have led to the formation of
populous towns in the midst of arid wastes, around which fertile
lands extended on every side, and hence the peophng of Manaar,
whose barren sand-drifts, though mcapable of producing a sufficient
quantity of grain for the w^ants of its inhabitants, were adapted to
the growth of the palmjTa and the coco-nut palm. Manaar also pelds
in abundance the ch(n"a-root^, which was once exported to Europe
for the sake of its brilhant red dye ; and its shores, besides
producing salt, afford favourable positions for the fishery of clianks^,
1 ^'De sleutel van 't Eyk van Jaffnapatam." — YALEyxTiir, Oucl en
Nievxo Oost-Indien, ch. xii. p. 150. ^ See a paper by Sir Alexandeh
Johnston, containiii
 CllAP. VII.] THE DUGOXG. 557 and the preparation of the
holothuria, which feed on the coral polypi, and are captured to be
dried in the snn, and ex])orted to China under the name of '*
tripang" and bicho de mar} One of the most remarkable animals on
the coast is the dugong^, a phytophagous cetacean, numbers of
which are attracted to the inlets, from the bay of Calpentyn to
Adam's Bridge, by the still water and the abundance of marine algie
in these parts of the gulf. The rude approach to the human outline,
observed in the shape of the head of this creature, and the attitude
FEMALE DDGONG OF CEYLON. fislierinen in the natiu'al hi.stoiy of
the chank. "All sliells found to the northward ot a line drawai from a
point about niidwaj- from jNIanaar to the opposite coast (of India)
are of the kind called pattji, and are disting'uished by a short flat
head ; and all those found to the southward of that line are of the
kind called pnjcl, and are known from having- a lf)nnce for 1000,
and "this quantity," he says, " can be easily collected by two men
during one ebb tide." ^ HnUcorc Diif/ioi;/.
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