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 Toxicology
of the Lung
Fourth Edition

© 2006 by Taylor & Francis Group, LLC

 TARGET ORGAN TOXICOLOGY SERIES
Series Editors
A. Wallace Hayes, John A. Thomas, and Donald E. Gardner

TOXICOLOGY OF THE LUNG, FOURTH EDITION

Donald E. Gardner, editor, 696 pp., 2006

TOXICOLOGY OF THE PANCREAS

Parviz M. Pour, editor, 720 pp., 2005

TOXICOLOGY OF THE KIDNEY, THIRD EDITION

Joan B. Tarloff and Lawrence H. Lash, editors, 1200 pp., 2004

OVARIAN TOXICOLOGY
Patricia B. Hoyer, editor, 248 pp., 2004

CARDIOVASCULAR TOXICOLOGY, THIRD EDITION

Daniel Acosta, Jr., editor, 616 pp., 2001

NUTRITIONAL TOXICOLOGY, SECOND EDITION

Frank N. Kotsonis and Maureen A. Mackey, editors, 480 pp., 2001

TOXICOLOGY OF SKIN
Howard I. Maibach, editor, 558 pp., 2000

TOXICOLOGY OF THE LUNG, THIRD EDITION

Donald E. Gardner, James D. Crapo, and Roger O. McClellan, editors,
668 pp., 1999

NEUROTOXICOLOGY, SECOND EDITION

Hugh A. Tilson and G. Jean Harry, editors, 386 pp., 1999

TOXICANT–RECEPTOR INTERACTIONS: MODULATION OF SIGNAL

TRANSDUCTIONS AND GENE EXPRESSION
Michael S. Denison and William G. Helferich, editors, 256 pp., 1998

TOXICOLOGY OF THE LIVER, SECOND EDITION

Gabriel L. Plaa and William R. Hewitt, editors, 444 pp., 1997

FREE RADICAL TOXICOLOGY

Kendall B. Wallace, editor, 454 pp., 1997

(Continued)

© 2006 by Taylor & Francis Group, LLC

 ENDOCRINE TOXICOLOGY, SECOND EDITION
Raphael J. Witorsch, editor, 336 pp., 1995

CARCINOGENESIS
Michael P. Waalkes and Jerrold M. Ward, editors, 496 pp., 1994

DEVELOPMENTAL TOXICOLOGY, SECOND EDITION

Carole A. Kimmel and Judy Buelke-Sam, editors, 496 pp., 1994

IMMUNOTOXICOLOGY AND IMMUNOPHARMACOLOGY,

SECOND EDITION
Jack H. Dean, Michael I. Luster, Albert E. Munson, and Ian Kimber,
editors, 784 pp., 1994

NUTRITIONAL TOXICOLOGY
Frank N. Kotsonis, Maureen A. Mackey, and Jerry J. Hjelle,
editors, 336 pp., 1994

OPHTHALMIC TOXICOLOGY
George C. Y. Chiou, editor, 352 pp., 1992

TOXICOLOGY OF THE BLOOD AND BONE MARROW

Richard D. Irons, editor, 192 pp., 1985

TOXICOLOGY OF THE EYE, EAR, AND OTHER SPECIAL SENSES

A. Wallace Hayes, editor, 264 pp., 1985

CUTANEOUS TOXICITY
Victor A. Drill and Paul Lazar, editors, 288 pp., 1984

© 2006 by Taylor & Francis Group, LLC

 Target Organ Toxicology Series

Toxicology
of the Lung
Fourth Edition

Edited by
Donald E. Gardner

Boca Raton London New York

A CRC title, part of the Taylor & Francis imprint, a member of the
Taylor & Francis Group, the academic division of T&F Informa plc.

© 2006 by Taylor & Francis Group, LLC

Published in 2006 by
CRC Press
Taylor & Francis Group
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Boca Raton, FL 33487-2742

© 2006 by Taylor & Francis Group, LLC

CRC Press is an imprint of Taylor & Francis Group

No claim to original U.S. Government works

Printed in the United States of America on acid-free paper
10 9 8 7 6 5 4 3 2 1
International Standard Book Number-10: 0-8493-2835-7 (Hardcover)
International Standard Book Number-13: 978-0-8493-2835-0 (Hardcover)
Library of Congress Card Number 2005047214
This book contains information obtained from authentic and highly regarded sources. Reprinted material is
quoted with permission, and sources are indicated. A wide variety of references are listed. Reasonable efforts
have been made to publish reliable data and information, but the author and the publisher cannot assume
responsibility for the validity of all materials or for the consequences of their use.
No part of this book may be reprinted, reproduced, transmitted, or utilized in any form by any electronic,
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Library of Congress Cataloging-in-Publication Data

Toxicology of the lung / [edited by] Donald E. Gardner.-- 4th ed.

p. cm.
Third ed. published: Philadelphia, Pa. : Taylor and Francis, 1999.
Includes bibliographical references and index.
ISBN 0-8493-2835-7 (alk. paper)
I. Gardner, Donald E., 1931-

RC720.T695 2005
616.2'407--dc22 2005047214

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© 2006 by Taylor & Francis Group, LLC

 PREFACE

A strong response to the third edition of Toxicology of the Lung inspired

this substantially updated and revised fourth edition. This fourth edition
provides an excellent forum for addressing the recent growth in informa-
tion in both basic and applied research in pulmonary toxicology since
the third edition. It presents a comprehensive and critical synthesis of the
latest advances, leading to a better understanding of how the body
responds to airborne contaminants.
A number of new topic areas have been added to this edition,
providing an insight into the most important current thinking regarding
the (1) critical need for understanding the kinetics and dynamic inter-
actions associated with toxic effects, (2) appropriateness of recent
advances being made across disciplines to address human clinical testing
and new emerging technology for using animal and in vitro models to
detect adverse effects, (3) identification of how airborne substances can
alter physiological, biochemical and morphological functioning of bio-
logical systems, and (4) the latest modeling approaches for predicting
deposition and fate of inhaled particles. These 16 chapters address the
important areas in toxicology as well as illustrate ongoing research efforts
for better understanding the association between airborne substances
and systemic effects.
All of the chapters in this new edition are written by a multidisciplinary
team of authors, who are internationally recognized experts in their
selected area and all except one are new contributors for this edition.
Special attention is devoted to providing the reader with an up-to-date
reference section for each topic area, a useful repository of comprehensive
information that will direct the reader to additional resources.

vii

© 2006 by Taylor & Francis Group, LLC

viii  Toxicology of the Lung

This text is unique in that it presents the information from a target

organ perspective, addresses critical issues and recent advances in toxi-
cology research, and focuses on assessment of human effects through
clinical human, animal, cellular toxicology, and modeling studies.

Donald E. Gardner

© 2006 by Taylor & Francis Group, LLC

 CONTRIBUTORS

Corrie B. Allen John Doull

Lone Wolf Bioscience Consulting University of Kansas Medical Center
La Conner, Washington Department of Pharmacology Toxicology
and Therapeutics
Kansas City, Kansas
Bahman Asgharian
CIIT
Centers for Health Research David J. Doolittle
Research Triangle Park, North Carolina R.J. Reynolds Tobacco Company
Science & Regulatory Affairs Division
Bowman Gray Technical Center
Paul H. Ayres Winston-Salem, North Carolina
R.J. Reynolds Tobacco Company
Science & Regulatory Affairs Division
Bowman Gray Technical Center Mark Frampton
Winston-Salem, North Carolina University of Rochester
School of Medicine
Rochester, New York
David M. Bernstein
Consultant in Toxicology
Chemin de la Petite-Boissière Shayne C. Gad
Geneva, Switzerland Gad Consulting Services
Cary, North Carolina
Mitchell D. Cohen
New York University Werner Hofmann
School of Medicine Institute of Physics and Biophysics
Tuxedo, New York University of Salzburg
Salzburg, Austria
Geoffrey M. Curtin
R.J. Reynolds Tobacco Company Ilona Jaspers
Science and Regulatory Affairs Division University of North Carolina at Chapel Hill
Bowman Gray Technical Center CEMALB
Winston-Salem, North Carolina Chapel Hill, North Carolina

ix

© 2006 by Taylor & Francis Group, LLC

x  Toxicology of the Lung

Frederick J. Miller Karl K. Rozman

Fred J. Miller and Associates, LLC University of Kansas Medical Center
Cary, North Carolina Department of Pharmacology Toxicology
and Therapeutics
Paul Morrow Kansas City, Kansas
University of Rochester
School of Medicine
James E. Swauger
Rochester, New York R.J. Reynolds Tobacco Company
Science & Regulatory Affairs Division
Bowman Gray Technical Center
Jürgen Pauluhn Winston-Salem, North Carolina
Bayer AG
Institut für Toxikologie Mark Utell
Wuppertal, Germany
University of Rochester
School of Medicine
Anthony P. Pietropaoli Rochester, New York
University of Rochester
School of Medicine Bellina Veronesi
Rochester, New York U.S. Environmental Protection Agency
NHEERL
Ryan J. Potts Research Triangle Park, North Carolina
R.J. Reynolds Tobacco Company
Science & Regulatory Affairs Division André Viau
Bowman Gray Technical Center CTR
Winston-Salem, North Carolina BioResearch Inc.
Senneville, Quebec, Canada
Christopher A. Reilly
University of Utah Jim C. Walker
Department of Pharmacology and Florida State University
Toxicology Sensory Research Institute
Salt Lake City, Utah Tallahassee, Florida

David B. Warheit
Stephen I. Rennard
E.I. duPont de Nemours
University of Nebraska Medical Center
Haskell Laboratory
Department of Internal Medicine
Newark, Delaware
Nebraska Medical Center
Omaha, Nebraska
Hanspeter Witchii
University of California at Davis
Keith Robinson ITEH
CTR Davis, California
BioResearch Inc.
Senneville, Quebec, Canada Gerold S. Yost
University of Utah
William L. Roth Department of Pharmacology
Office of Food Additive Safety and Toxicology
College Park, Maryland Salt Lake City, Utah

© 2006 by Taylor & Francis Group, LLC

 CONTENTS

1. Methods for Evaluating the Lung in Human Subjects ..............1

Stephen I. Rennard and John R. Spurzen
2. Human Clinical Studies of Airborne Pollutants ......................29
Mark W. Frampton, Anthony P. Pietropaoli,
Paul E. Morrow, and Mark J. Utell
3. Nasal Irritation—Current Understanding and Future
Research Needs...........................................................................83
James C. Walker
4. In Vitro Models for Lung Toxicology .....................................107
Corrie B. Allen
5. Dosimetry of Particles in Humans: from
Children to Adults ....................................................................151
Bahman Asgharian, Werner Hofmann,
and Frederick J. Miller
6. Influences of Dynamics, Kinetics, and Exposure
on Toxicity in the Lung ...........................................................195
Karl K. Rozman, William L. Roth, and John Doull
7. Safety Assessment of Therapeutic Agents
Administered by the Respiratory Route ................................231
Shayne C. Gad
8. Vanilloid Receptors in the Respiratory Tract ........................297
Christopher A. Reilly, John M. Veranth,
Bellina Veronesi, and Garold S. Yost

xi

© 2006 by Taylor & Francis Group, LLC

xii  Toxicology of the Lung

9. Pulmonary Immunotoxicology...............................................351
Mitchell D. Cohen
10. Animal Models of Respiratory Allergy ...................................419
Jürgen Pauluhn

11. Fiber Toxicology.......................................................................461

David M. Bernstein
12. Reproductive Toxicology Testing of Inhaled
Pharmaceuticals and Biotechnology Products ......................501
André Viau and Keith Robinson
13. Effects of Engineered Nanoscale Particulates
on the Lung...............................................................................537
David B. Warheit
14. Diesel Exhaust and Viral Infections .......................................559
Ilona Jaspers
15. Adaptation to Toxicant Exposure during
Rodent Lung Tumorigenesis ...................................................587
Geoffrey M. Curtin, Ryan J. Potts, Paul H. Ayres,
David J. Doolittle, and James E. Swauger
16. Tobacco Smoking .....................................................................623
Hanspeter Witschi

Index .................................................................................................649

© 2006 by Taylor & Francis Group, LLC

 EDITOR

Donald E. Gardner, Ph.D., Fellow, ATS, has over 40 years of experience

in the field of toxicology. He earned B.S. and M.S. degrees from Creighton
University, Omaha, Nebraska and a Ph.D. in environmental health from
the University of Cincinnati.

Past employment has included the U.S. Environmental Protection Agency/

U.S. Public Health Service, where he was director of the Toxicology Division
that was responsible for both the animal and human toxicology program
that addressed the potential health risks associated with exposure to envi-
ronmental chemicals. Following retirement from the EPA, he joined the staff
of Northrop/ManTech Corp. as vice president and chief scientist. He has had
adjunct professor appointments at Duke University, North Carolina State
University and University of Massachusetts, Amherst.

Since 1995 he has been president of Inhalation Toxicology Associates, a

consulting company that provides consulting services to governmental
agencies including U.S. EPA, NIEHS, NASA, DOD and NIH and to private
industry and law firms. He is active on numerous international advisory
panels in the area of environmental health and toxicology.

He is a board certified Fellow in Toxicology and has chaired numerous

expert panels for the National Academy of Science, National Research
Council, Committee on Toxicology and has been vice chairman of the
Committee on Toxicology. He is currently an associate editor of the Journal
of Immunotoxicology and on the Editorial Board of Toxicology Mechanisms
and Methods. He is coeditor of Target Organ Toxicology Series, editor of

xiii

© 2006 by Taylor & Francis Group, LLC

xiv  Toxicology of the Lung

Toxicology of the Lung and coeditor of New Perspectives: Toxicology and

the Environment.

Throughout his career he has published over 250 research manuscripts

and book chapters. He is the editor of the Journal of Inhalation Toxicology
(1988-present).

© 2006 by Taylor & Francis Group, LLC

 1
METHODS FOR EVALUATING
THE LUNG IN HUMAN
SUBJECTS

Stephen I. Rennard and John R. Spurzen

CONTENTS
1.1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .2
1.2 Physiology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .2
1.2.1 Airflows . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .2
1.2.2 Lung Volumes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .3
1.2.3 Challenge Tests . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .4
1.2.4 Other Tests . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .6
1.3 Imaging . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .6
1.4 Sampling the Lungs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .9
1.4.1 Exhaled-Breath Analysis . . . . . . . . . . . . . . . . . . . . . . . . . . .9
1.4.2 Exhaled-Breath Condensate . . . . . . . . . . . . . . . . . . . . . . . .9
1.4.3 Sputum Analysis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10
1.4.4 Bronchoscopy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12
1.4.4.1 Rigid Bronchoscopy . . . . . . . . . . . . . . . . . . . . . . 12
1.4.4.2 Flexible Bronchoscopy (55) . . . . . . . . . . . . . . . . 12
1.4.4.3 Performance of Bronchoscopy (55,56,66) . . . . . . 14
1.4.4.4 Sampling the Lungs Using Bronchoscopes . . . . . 15
1.4.4.5 Bronchoalveolar Lavage . . . . . . . . . . . . . . . . . . . 15
1.4.4.6 Biopsy Procedures . . . . . . . . . . . . . . . . . . . . . . . 18
1.5 Summary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 21
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 22

© 2006 by Taylor & Francis Group, LLC

2  Toxicology of the Lung

1.1 INTRODUCTION
The lung is frequently the target of environmental and systemic toxic
exposures. A normal adult at rest takes in more than 7000 l of air daily (1).
Gas exchange requires exposure of a surface area of approximately 80 m2
of the lung to this inhaled air (2). This makes the lung uniquely exposed
to airborne toxins. In addition, the lung receives the entire cardiac output
from the right side of the heart, which places it at risk for systemic toxins.
Finally, specific metabolic reactions in the lung can lead to the uptake
and concentration of a variety of toxins in the lung. As a result, toxic
exposures are a frequent cause of lung disease. Evaluation of the lung,
therefore, is highly relevant in toxicological studies.
Of the parenchymal organs, the lung is relatively easy to evaluate,
making the assessment of toxic exposures feasible in human subjects. The
current chapter will provide an overview of the methods by which the
lung can be evaluated, including physiological, imaging, and sampling
techniques. The methods available include well-established ones that are
widely available as well as developing technologies.

1.2 PHYSIOLOGY
1.2.1 Airflows
The most widely used assessment of lung functions are measures of
airflow, particularly expiratory airflow (3). The most widely used method,
spirometry, requires that a subject inhale to total lung capacity (TLC) and
then exhale as rapidly and completely as possible (Figure 1.1). Expired-
air volume is then measured as a function of time, which provides airflow
as a function of time. The most important parameters obtained by this
maneuver are the forced expiratory volume in 1 sec (FEV1) and the forced
vital capacity (FVC). Consensus standards for the performance and inter-
pretation of spirometry are available from both the American Thoracic
Society (4,5) and the European Respiratory Society (6).
Vital capacity (VC), which is the volume of air that can be voluntarily
moved in and out of the lungs, would, in theory, require an infinitely
prolonged exhalation. In most individuals, the lungs are almost completely
emptied after 6 sec, and FEV6 (forced expiratory volume after 6 sec) is
often accepted as a surrogate for FVC. The maximal flow rate obtained
during a forced maneuver occurs shortly after beginning the maneuver,
and flow rates then decrease as lung volumes decrease. The peak expi-
ratory flow (PEF) is fairly easily measured and is often used in monitoring
subjects with asthma and in epidemiological studies.
It has been proved useful to plot the data generated by a spirometer as
flow vs. volume rather than as volume vs. time. The resulting flow-volume

© 2006 by Taylor & Francis Group, LLC

 Methods for Evaluating the Lung in Human Subjects  3

Volume (liters)

5
FVC
4
FEV1
3

1 2 3 4 5 6
Time (seconds)

Figure 1.1 Spirogram. After inhaling as deeply as possible, a subject exhales as

rapidly as possible. The volume of air (vertical axis) is plotted against time
(horizontal axis). Airflow, as a function of time, is given by the slope at any point.
Forced expiratory volume in 1 sec (FEV1) is the volume of air exhaled in 1 sec.
It would be reduced in case of airway obstruction and airway restriction. Forced
vital capacity (FVC) is the maximal volume of air exhaled. In obstruction, the
FVC may be normal, but the subject may not be able to exhale long enough to
make an accurate measure. In restriction, the FVC will be reduced. Peak expiratory
flow rate (PEFR) is the steepest slope on the curve, and this occurs very near the
beginning of the maneuver. FVC and FEV1 are indicated for a normal subject.
(See the color version of this figure after page 18.)

curve has a characteristic shape and is often used in the diagnosis of

pulmonary disease. Plotting data from inspiration, together with expiration
data, results in a flow-volume loop (Figure 1.2). Data contained in the flow-
volume loop is the same as that in the spirogram.
The increase in intrathoracic pressure generated in a forced maneuver
can cause airways to collapse in some individuals, particularly those with
lung disease. This can reduce the rate and volume of the exhaled air. As
a result, FVC may differ from slow vital capacity (SVC), which is measured
in a similar way except that after a subject inhales fully, he or she is allowed
to exhale as completely as possible in a manner that is most comfortable.

1.2.2 Lung Volumes

In addition to airflow, measurement of lung volumes (3) provides infor-
mation that can help distinguish the presence of air trapping or restrictive
ventilatory defects (Figure 1.3). The first is common in obstructive disease,

© 2006 by Taylor & Francis Group, LLC

4  Toxicology of the Lung

Peak
Expiratory
Flow FEV1

Out

Flow
FVC Volume

In

Peak
Inspiratory
Flow

Figure 1.2 Flow-volume loop. Data from a spirogram is often plotted as flow
vs. volume. This can be plotted for both expiration and inspiration, resulting in
a loop. Peak inspiratory and expiratory flows, FEV1, and FVC can be read directly
from the plot. The characteristically shaped triangular expiratory and semicircular
inspiratory limbs of the curve are altered in disease.

and the latter is common with interstitial fibrosis. Although VC can be

measured easily by spirometry, measurement of TLC is complicated by
the fact that some air remains in the lung following maximal forced
expiratory efforts. This volume, the residual volume (RV), can be estimated
using Boyle’s law. This requires the subject to sit inside a body plethys-
mograph. Although straightforward, this is a relatively expensive test that
is not easily standardized across many centers.
RV can also be measured using a dilution tracer. Helium is most
commonly used for this purpose. This method, unfortunately, is relatively
inaccurate and becomes progressively more so in the presence of irreg-
ularities in ventilation, which are common in individuals with lung disease.

1.2.3 Challenge Tests

Smooth muscles surrounding the airways will constrict in response to a
variety of stimuli, and this can be used in challenge tests. As the airways

© 2006 by Taylor & Francis Group, LLC

 Methods for Evaluating the Lung in Human Subjects  5

Vital
Capacity
Rest

Total
Lung
Capacity

Functional
Residual
Capacity

Residual
Volume

Figure 1.3 Lung volumes. Total lung capacity (TLC) is the total volume of air in
the lungs at maximal inhalation. Vital capacity (VC) is the volume of air that can
be exhaled from TLC. Residual volume (RV) is the volume of air that remains in
the lung after a maximal exhalation. In the absence of any muscular activity, the
lungs are partly expanded. This is the point at which normal inhalation begins
and is termed Functional Residual Capacity (FRC). VC can be determined by
spirometry. Measurements of TLC, RV, and FRC require other methodologies (see
subsection titled “Lung Volumes”).

in asthma are characteristically hyperresponsive, challenge tests have been

used to diagnose and gauge the severity of asthma. Challenge tests using
methacholine, histamine, cold dry air, nebulized distilled water, and specific
allergens have been widely used (3,7). Other challenge tests have also been
described. Although individuals with hyperreactive airways will generally
respond to most stimuli, differences in response have been seen, and these
may characterize different subsets of individuals with hyperreactive airways.
Airway reactivity, although a feature of asthma, is not uniformly present in
asthmatics (8). Moreover, airway reactivity may be present in individuals
who appear to have no other features of asthma. Measurement of airway
reactivity has been used in challenge studies of normal and asthmatic
subjects exposed to a number of toxins.

© 2006 by Taylor & Francis Group, LLC

6  Toxicology of the Lung

Exercise challenge tests also provide means of assessing lung function

in further detail (3). With increasing cardiac output, blood flow in the
lung uses additional alveolar capillary units. In the presence of poorly
ventilated areas of the lung, this can result in worsening ventilation
perfusion matching and a drop in arterial PO2. In addition, exercise is
associated with an increase in minute volume occurring as a result of
increased tidal volume and respiratory rate. This has been used in challenge
studies to increase the exposure to potential toxins such as ozone (9).
In the presence of airflow limitation, there may be insufficient time for
complete emptying of the lungs because with exercise the increased
respiratory rate results in a decreased expiratory time. As a result, exercise
may be associated with dynamic hyperinflation (10). Recent physiological
studies suggest that this is a significant mechanism for dyspnea, particularly
in patients with chronic obstructive pulmonary disease (11). Dynamic
hyperinflation reduces the amount of air that can be inhaled, i.e., the
inspiratory capacity (IC). Because IC can be estimated quite easily using
spirometry, it has been suggested as a potentially useful surrogate for
dynamic hyperinflation, and it may be amenable to large-scale studies.

1.2.4 Other Tests

A number of other physiological parameters can be assessed. Airway
conductance and resistance can be determined with a body plethysmo-
graph. Measurement of lung compliance requires placement of an esoph-
ageal balloon. Measurement of blood gases (PO2, PCO2, and pH) provides
an estimate of gas exchange and can also be regarded as a lung function
test. Pulmonary hypertension often results from acute and chronic lung
disease, and measurement of pressures in the pulmonary circulation is
often performed. The most precise measures require right heart and
pulmonary artery catheterization. Echocardiographic techniques, which
estimate pulmonary pressures from the Doppler effect generated by the
acceleration of blood in the pulmonary artery, have been developed, and
they provide noninvasive estimates of peak pulmonary pressure (12). This
method has also been applied to animal studies (13).

1.3 IMAGING
A variety of methods are available for imaging the lungs, the most widely
used one being routine roentgenography. Posterior, anterior, and lateral
views of the chest have been the mainstays of clinical diagnosis for a
century. Compared to computed tomography, routine x-rays are relatively
less sensitive to subtle changes. Such studies, however, have been widely

© 2006 by Taylor & Francis Group, LLC

 Methods for Evaluating the Lung in Human Subjects  7

Extrinsic Allergic Alveolitis

Figure 1.4 Computed tomography of the chest. Two axial sections of the right
lung at the level of the carina (right) and more proximally in a subject with
extrinsic allergic alveolitis are shown. The peribronchial location of the infiltrative
lesions is readily recognizable. This could not have been ascertained by conven-
tional radiographs. (Images courtesy of Prof. J. Gurney, University of Nebraska
Medical Center, Omaha.)

used in the diagnosis of toxic exposures in both clinical and epidemio-

logical studies.
Computed tomography of the chest provides much greater anatomic
resolution than does routine roentgenography (Figure 1.4). In addition,
algorithms for the quantitative assessment of the lungs using computed
tomography have been developed. These can provide a measure of the
severity and extent of emphysema (14–16) and airway disease (17). The
development of high-speed scanners that use relatively low radiation
exposures has made this test incr easingly appropriate for research
applications.
Magnetic resonance imaging has not been widely applied to the
assessment of the lungs, primarily because conventional scanners image
the protons present in water, and the large air content of the lungs makes
them invisible by this method. It is possible, however, to utilize tracer
gases that can be hyperpolarized to provide a magnetic signal (18,19).
Both 3He and 129Xe have been used for this purpose. These methods
can image air spaces of the lung at a level that permits investigation of
abnormalities that cannot be detected by other means (Figure 1.5). Because
attenuation of the magnetic signal depends upon its interactions with the

© 2006 by Taylor & Francis Group, LLC

8  Toxicology of the Lung

Hyperpolarized Helium Imaging

Normal Asthma
FEV1
132%

Asthma Asthma
FEV1 FEV1
83% 34%

Samee et al. JACI 111: 1205, 2003

Figure 1.5 Hyperpolarized gas imaging of the lungs. Images were obtained
following inhalation of 3He in asthmatic subjects with varying lung function. The
ability to image ventilation with a high degree of resolution makes possible the
detection of abnormal areas even when lung function, as a whole, is normal. See
Reference 99 for details. (From Samee, S., T. Altes, P. Powers, E.E. de Lange,
J. Knight-Scott, G. Rakes, J.P. Mugler, 3rd, J.M. Ciambotti, B.A. Alford, J.R. Brookeman,
and T.A. Platts-Mills: Imaging the Lungs in Asthmatic Patients by Using Hyperpo-
larized Helium-3 Magnetic Resonance: Assessment of Response to Methacholine
and Exercise Challenge. J Allergy Clin Immunol 2003, 111: 1205–1211. With
permission.)

surrounding space, it is possible to utilize magnetic methods to estimate

the apparent diffusion coefficient within the lung, which provides an
indirect measure of alveolar size (20) and can also be used in the
assessment of small airway diameter (21). In addition to being a research
tool, such studies may provide a noninvasive tool to assess the progression
of emphysema.

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 Methods for Evaluating the Lung in Human Subjects  9

1.4 SAMPLING THE LUNGS

Of the parenchymal organs, the lungs are among the most easily sampled.
This is true for several reasons: First, the large volume of air that is inhaled
is also exhaled. Contents in the exhaled gas that derive from the lungs
can be collected and analyzed. Second, material present in the lungs may
be expectorated in sputum, either spontaneously or in response to specific
induction. Finally, it is fairly straightforward to introduce a flexible fiberop-
tic bronchoscope into the lower respiratory tract in order to collect samples
by using a variety of techniques. Because samples of material from the
lungs permit a variety of biochemical and cellular analyses, these methods
have great potential in the evaluation of toxic exposures.

1.4.1 Exhaled-Breath Analysis

Exhaled breath contains a number of volatile components that derive from
the lower respiratory tract, and their assessment has provided a means
for evaluating the lung (22,23). The most widely studied component is
nitric oxide (NO)(24). NO is produced endogenously by several enzyme
systems, and it serves as an important mediator in most tissues. Inflammatory
reactions are often associated with the induction of iNOS, an enzyme that
generates large amounts of NO. Inflammatory lung diseases are associated
with an induction of iNOS and a measurable increase in exhaled NO.
Elevated NO production has been assessed in a large number of lung
diseases. In asthma, measurement of NO has been suggested as a gauge
of clinical severity and therapeutic effect (25). NO is produced throughout
the respiratory tract. By analyzing NO concentrations at different flow
rates, it is potentially possible to separate upper airway production from
the distal lung production of nitric oxide (26).
Other gases present in exhaled air have also been measured. Carbon
monoxide can be readily measured, and increased levels are exhaled by
smokers and by individuals exposed to environmental CO (27–29). CO is
also produced endogenously by two heme oxygenases, one of which,
HOX-1, is associated with inflammation (30). Increased levels of CO in
the exhaled air have been reported in some inflammatory lung diseases
(22,23). Pentane is generated as a result of oxidation of cellular lipids. It
has been quantified in exhaled air and has been suggested to be a marker
of oxidative stress (31,32). Ethane and other alkanes may have similar
significance (33,34).

1.4.2 Exhaled-Breath Condensate

By chilling exhaled breath, water vapor, together with other components
present in the exhaled air, will condense and can be collected. Collection

© 2006 by Taylor & Francis Group, LLC

10  Toxicology of the Lung

of exhaled breath condensate samples is fairly simple. A subject at rest

breathes into a mouthpiece while tight seal is maintained with the mouth
and a nose clip is in place. In a 15-min time frame, approximately 2 ml
of material can be collected. Most studies have been performed with
normal tidal breathing at rest. Although relatively few studies have
addressed methods of sample collection, alterations in ventilation may
affect the results (35). A major problem with this technique has been
contamination of the exhaled breath with saliva and other oral contents.
Several devices, however, have been developed that appear to address
this problem (36,37).
A larger number of moieties have been found in exhaled br eath
condensate. Low-molecular-weight substances such as hydrogen peroxide
are likely to be present as gases in the exhaled breath and may condense
in chilled air. In addition, ions and macromolecules, including proteins,
have been found, although the results are not uniformly reproducible and
are controversial. Data using this method are, as yet, limited. Cigarette
smokers have been described as having alterations of a number of param-
eters (Table 1.1).
Some controversy also exists regarding the mechanism by which non-
volatile substances reach the exhaled breath condensate. Aerosolization
of microdroplets as a consequence of turbulent flow within the lungs has
been suggested (38,39). Increases in various markers in the exhaled breath
condensate, therefore, could represent alterations in lung anatomy or in
the composition of the fluid or gaseous compartments of the lower
respiratory tract. Although the significance of most of the markers present
in the lower respiratory tract is still incompletely defined, several have
been evaluated in considerable detail. Hydrogen peroxide, for example,
has been reported to be increased in various lung conditions (22,23).
Alterations in the pH of exhaled breath condensate have also been
reported (40,41). Because of the ease with which samples are obtained
and the noninvasive nature of the test, analysis of exhaled breath con-
densates holds great promise for the assessment of biomarkers in the
lower respiratory tract.

1.4.3 Sputum Analysis

Both spontaneously expectorated (42) and induced sputum (43) have been
used to analyze components present in the lower respiratory tract. Sputum
contains mucus produced by goblet cells that line the airways and by
mucous glands. Both are much more common in the proximal airways (2),
although goblet cell metaplasia in the distal airways is a common feature
of many lung diseases. In addition to mucus, sputum also contains other
components present within the airway lumen and within the lumen of
the distal airways that frequently move proximally as a result of the

© 2006 by Taylor & Francis Group, LLC

 Methods for Evaluating the Lung in Human Subjects  11

Table 1.1 Measures Reported to be

Abnormal in the Exhaled Breath of
Smokers as Compared to that of
Nonsmokers
Analyte Reference

4-HHE 100
4-HNE 100
Acrolein 100
H2O2 (µ M) 101
Heptanal (nM) 100,102
Hexanal (nM) 102
IL-1 (pg/ml) 103
IL-6 (pg/ml) 104, 105
Isoprostane (pg/ml) 104
LTB4 105
Malondialdehyde (nM) 100, 102
NCA 103
Nitrite (µ M) 103, 106
Nitrotyrosine 106
NO2 + NO3 106
NO3 ( µ M) 107
Nonanal (nM) 100, 102
S-Nitrosothiols 106
TBARs (µ M) 101
TNFα 103
Total protein (µ g/ml) 103

mucociliary escalator. Sputum samples, therefore, contain both cellular

and molecular components present within the lower respiratory tract.
Analysis of sputum generally requires processing, and a consensus
panel has provided recommendations (44). A variety of techniques have
been utilized to separate “true” sputum from saliva. Rinsing the specimens
is less widely used than removing specimens of sputum manually with a
forceps. The gel-like nature of sputum complicates its analysis. Ultracen-
trifugation can separate the “gel” phase from the “sol” phase. Alternatively,
the structure of the gel is dependent on disulfide bonds within mucin
molecules, and the samples can be solubilized by reduction. Dithiothriatol
is most commonly used, but this, as with any form of processing, can
potentially alter analytes of interest (45). Spontaneously produced sputum
samples have the advantage of representing what is spontaneously present
in the lower respiratory tract. Sputum induction, which likely serves as

© 2006 by Taylor & Francis Group, LLC

12  Toxicology of the Lung

an irritant and, therefore, has the possibility of altering the composition

of the contents of the lower respiratory tract, is more widely used for
several reasons. First, 60 to 70% of normal individuals who do not
spontaneously produce sputum will produce adequate samples following
induction with hypertonic saline. Second, sputum induction permits col-
lection of samples in a controlled laboratory setting where salivary con-
tamination, recent food ingestion or smoking, and subject clinical state
can be controlled. Finally, sputum induction permits evaluation of samples
during collection, ensuring that adequate material is obtained.
Cells present in sputum can be readily evaluated. Alteration in cellular
composition has been described in a number of clinical settings (46,47)
as well as following challenge studies (48,49). Although the majority of
these studies have evaluated asthma, exposure to toxins such as ozone
has been performed, and the response assesed by induced sputum (50,51).
Moreover, cells recovered in sputum may be viable, and they have been
assessed functionally (52). Finally, recovery of cells in sputum permits
their analysis using molecular methods (53).

1.4.4 Bronchoscopy
This is a method by which the lungs can be directly inspected and sampled.
There are two basic techniques: rigid (54) and flexible bronchoscopy (55,56).

1.4.4.1 Rigid Bronchoscopy

This method was developed more than 100 yr ago. It utilizes a straight,
hollow tube, which is inserted through the mouth, between the vocal
cords, and into the trachea. Insertion of the instrument requires hyperex-
tension of the neck. Rigid bronchoscopy is most commonly performed
under general anesthesia. By means of a light and optical system, the
carina, the proximal portions of the left mainstem bronchus, and the right
middle and lower lobes may be inspected. Because the instrument is rigid,
it is not easily manipulated around bends in the airways, and the ability
to visualize the more-distal airways is limited. Rigid bronchoscopy has
largely been supplanted by flexible bronchoscopy, which is more easily
performed and which permits inspection of the more-distal airways. How-
ever, because the intraluminal diameter of the rigid bronchoscope is much
larger than that of the flexible bronchoscope, the rigid instrument remains
the procedure of choice in selected settings (57).

1.4.4.2 Flexible Bronchoscopy (55)

Fiber-optic elements are frequently included in the optical systems of the rigid
bronchoscope and are sometimes termed flexible fiberoptic bronchoscopy.

© 2006 by Taylor & Francis Group, LLC

 Methods for Evaluating the Lung in Human Subjects  13

The application of fiber optics has made the flexible bronchoscope possible.
The most commonly used instrument for adult bronchoscopy is approximately
0.5 cm in diameter and is flexible. By means of a wire, the bronchoscopist
can bend the bronchoscope tip up to 180°. By bending the tip and rotating
the instrument, it is possible to insert the bronchoscope into all the major
lobar and segmental airways in a normal adult lung. The limit of airways
that may be inspected with the flexible bronchoscope is determined not by
the flexibility of the instrument, but by its size: the instrument cannot be
advanced beyond airways that have the same caliber as the external diameter
of the bronchoscope.
The original flexible fiber optic bronchoscopes contained three fiber
optic bundles. Two provided illumination without shadows. The third was
used for inspection of the airways. Resolution of the image in the original
bronchoscopes was determined by the number of fibers in the bundle.
Current bronchoscopes have generally replaced the fiber optic inspection
bundle with a wire connected to a high-resolution television camera small
enough to be incorporated into the bronchoscope tip. The camera provides
far superior resolution. In addition, the camera provides the possibility of
digitally processing the recovered information. In fact, color images are
generated from a black-and-white camera by using a series of images and
filters. The application of similar methods to explore the biology and
biochemistry of the airways is under investigation.
A number of modifications of the bronchoscope allow various types
of inspection. A bronchoscope with a side-viewing camera has been
developed (58). This provides relatively clear imaging of airway mucosa
and a remarkable view of the airway vasculature, in contrast to the
foreshortened images obtained with an end-viewing bronchoscope, in
which the regions close to the bronchoscope tip are foreshortened. Bron-
choscopes have been modified for florescence imaging and have been
used to identify neoplastic cells with either florescent dyes (59) or endog-
enous florescence (60,61). Finally, bronchoscopes have been equipped
with ultrasound probes (62,63). These permit imaging of bronchial wall
thickness and of structures such as lymph nodes that are adjacent to
airways.
Bronchoscopes are available in a variety of sizes (55). The most
commonly used instruments for bronchoscopy in adults are approximately
5 mm in external diameter. The biopsy channel of such instruments is
generally about 2 to 2.2 mm in diameter. Such an instrument can be
routinely inserted into all the lobar segmental and subsegmental airways
in normal adults. A pediatric instrument with an external diameter of about
3.5 mm and a sample channel diameter of 1.2 mm is routinely used.
Obviously, the distance to which it can be inserted depends on the size
of the child being bronchoscoped. An ultrathin bronchoscope 1.8 mm in

© 2006 by Taylor & Francis Group, LLC

14  Toxicology of the Lung

diameter has been developed. This can be inserted through the lumen of
a conventional bronchoscope and can be advanced into the peripheral
airways (64). Although it does not have a sample channel, the ultrathin
bronchoscope can be used to guide the collection of samples with a brush
under direct visualization (65).

1.4.4.3 Performance of Bronchoscopy (55,56,66)

Prebronchoscopy evaluation should include electrocardiography, assess-
ment of blood electrolytes, and coagulation studies, especially if biopsy
procedures are planned. Subjects should refrain from using aspirin for
one week prior to the procedure in order not to compromise platelet
function. To minimize the risk of gastric aspiration, the stomach should
be empty. This is routinely accomplished by keeping subjects NPO over-
night prior to the procedure. The procedure may be performed either
transnasally or transorally. Transoral procedures permit the use of an
endotracheal tube. Once in place, this minimizes subject gagging, makes
it possible to remove and reinsert the bronchoscope readily, and offers
an additional measure of safety should bleeding occur. The transoral route
also avoids contamination of airway samples with ciliated cells from the
nasopharynx. The transnasal route, however, may be technically easier.
Anesthesia of the nose (if necessary) is generally achieved with topical
viscous lidocaine. Anesthesia of the posterior pharynx, hypopharynx, and
larynx is also achieved with lidocaine administered via nebulization under
direct vision. It is also common practice to administer lidocaine together
with a beta agonist bronchodilator via nebulization prior to performing
topical anesthesia as described in the preceding text (67). This may
contribute to topical anesthesia in the upper airways, may reduce cough
later in the procedure, and is believed to prevent bronchospasm. Subjects
are routinely monitored with continuous oximetry. It is common practice
to administer supplemental oxygen via a nasal cannula during and fol-
lowing the procedure. An intravenous line should be inserted in the event
of emergency medications being required. An intravenous line can also
facilitate administration of narcotics or sedatives as needed.
After insertion through the mouth or nose, the bronchoscope is inserted
under direct vision between the vocal cords. The bronchoscope can then
be advanced into the trachea. If desired, an endotracheal tube can be
placed over the bronchoscope and the remainder of the procedure be
performed through the in-place endotracheal tube. After inserting the
bronchoscope, most bronchoscopists perform a full inspection of all
airways prior to any other procedure. In addition to describing any lesions
present, it is possible to evaluate airway inflammation. The Thompson
Bronchitis Index is a scoring system that assesses erythema, edema,

© 2006 by Taylor & Francis Group, LLC

 Methods for Evaluating the Lung in Human Subjects  15

secretions, and friability systemically in the lobes of the lung (68). This
scoring system has been utilized in research studies as it quantifies visible
inflammation. Visible inflammation is sensitive to change, and reductions
in this parameter have been reported in a variety of interventions (69–71).
Interobserver agreement among trained bronchoscopists is very high (69).
In addition, the bronchitis index can be scored on videotaped images,
permitting independent and blinded assessment of visible airways inflam-
mation, although color rendering of taped images and, in particular, of
erythema may be somewhat problematic.

1.4.4.4 Sampling the Lungs Using Bronchoscopes

There are several methods for sampling the lungs using a bronchoscope.
These include aspiration procedures in which intraluminal contents are
aspirated through the sample channel and biopsy methods that use a
cutting forceps, a brush, or a needle.

1.4.4.5 Bronchoalveolar Lavage

The simplest technique is simple aspiration, in which intraluminal contents
are recovered by vacuum aspiration and collected in an in-line suction
trap. This method is commonly used to remove secretions and has many
clinical applications. A modification of this procedure involves the instal-
lation of 5 to 10 ml of sterile isotonic saline followed by the aspiration
of the saline together with intraluminal airway contents. This is sometimes
termed a bronchial wash, but it should not be confused with bronchoal-
veolar lavage (66,72), which represents a further modification of the
aspiration procedure and allows routine sampling of both airway and
alveolar spaces under controlled conditions. Bronchoalveolar lavage is
most commonly performed by first “wedging” the bronchoscope. This is
accomplished by advancing the bronchoscope gently into an airway that
is approximately the same size as the outer diameter of the bronchoscope
(Figure 1.6). Once in position, application of suction to the bronchoscope
channel causes the airway to collapse. Instillation of saline through the
bronchoscope can then be performed in a controlled manner such that
only the portion of the lung in the airway distal to the bronchoscope is
sampled. Because the volume of lung accessed by the bronchoscope is
generally about 1% of the total lung volume, lavage can be performed
with little physiological compromise. A decline in FEV1 of about 5 to 10%
has been reported, and a similar decline occurs in mild asthmatics (73).
Thus, bronchoalveolar lavage is generally well tolerated in individuals
with relatively normal lung function. Patients with compromised lung
function will be at increased risk for complications.

© 2006 by Taylor & Francis Group, LLC

16  Toxicology of the Lung

Bronchoscope

Saline

Airway

Cells Alveoli
Soluble Components

Figure 1.6 Schematic diagram of bronchoalveolar lavage. The bronchoscope is

advanced to the “wedged” position, where the caliber of the airway is the same
as that of the bronchoscope. An instilled fluid samples the intraluminal space in
the airways and the alveoli distal to the bronchoscope. Samples of the cells and
the fluid lining the alveoli and the airways are recovered by aspiration.

There are a number of “standardized” procedures for performing

bronchoalveolar lavage (66,74). These vary, most prominently, in the
volume of fluid infused per aliquot, the number of aliquots infused, the
length of time the fluid is allowed to remain in the lung before aspiration
(the “dwell” time), and the total volume of fluid infused. It is generally
recommended that lavages of at least 100 ml be used in order to effectively
assess the alveolar space. The most commonly used procedures are to
infuse and sequentially aspirate four 60-ml aliquots at a single site or
repeat five 20-ml aliquots at two or three different sites within the lung.
Most commonly, a “zero dwell time” procedure is used in which the fluid
is aspirated immediately following instillation.
The first fluid instilled reaches the proximal airways, but samples the
alveolar spaces less efficiently (75). When sequential 20-ml aliquots are
infused, the first aliquot is relatively enriched in “bronchial” contents as
evidenced by a relatively high percentage of ciliated epithelial cells (76).
Subsequent lavages are progressively enriched in alveolar contents as
evidenced by an increase in alveolar macrophages as compared to colum-
nar epithelial cells. Return from an initial 20-ml aliquot, which generally
approaches 5 ml, may be processed separately in order to provide a

© 2006 by Taylor & Francis Group, LLC

 Methods for Evaluating the Lung in Human Subjects  17

somewhat selective evaluation of airways. Return from subsequent lavages

progressively increases in volume, perhaps because of a “pump priming”
effect. As a result, the four subsequent 20-ml lavages will yield 50 to 60 ml
of return of the 80 ml infused. Some investigators pool all lavages, whereas
others process the initial aliquot separately from the subsequent aliquots.
Differences in methodologies may account for some differences in reported
results. Use of larger-volume lavages does not permit separate analysis of
the “bronchial” component (77).
Bronchoalveolar lavage fluid contains the molecular and cellular com-
ponents present within the intraluminal space of the lung (66,72). A number
of biochemical measures have been made and demonstrated to be abnormal
in disease or following exposures (72,74,78). Several methods have been
used to express the results of measures made on bronchoalveolar lavage
fluid. The simplest is to express results as concentrations in the recovered
lavage. However, because the fluid used to perform the lavage dilutes the
intraluminal contents, there has been much interest in utilizing other denom-
inators. Albumin is present in the epithelial-lining fluid of the lower respi-
ratory tract at a concentration estimated to be about 10% that of plasma.
BAL measures for a number of proteins, therefore, have been normalized
to albumin concentrations (74,79). The concentration of albumin in the
lower respiratory tract, however, can vary with disease, particularly inflam-
matory diseases that alter lung permeability. An alternative approach
involves the measurement of urea. Because it is freely diffusible, urea
concentrations in the epithelial-lining fluid of the lung are equal to those
in plasma, which can be measured. Measurement of urea in recovered
bronchoalveolar lavage fluid, therefore, permits estimation of the dilution
engendered by the lavage procedure (80). Urea, however, diffuses quite
rapidly. Therefore, the longer it takes to perform the lavage, the higher will
be the amount of urea recovered and the less accurate the estimate of
dilution (81,82). Nevertheless, this method has proved useful to estimate
concentration of lower respiratory tract parameters, for example, to dem-
onstrate that prostaglandin E and prostaglandin D are present in the lower
respiratory tract at concentrations that are physiologically relevant (83,84).
Cellular components are also obtained by bronchoalveolar lavage
(Figure 1.7) (66,74). These can be evaluated by a variety of histological
and immunohistological methods. In addition, viable cells are routinely
recovered, which permits their functional evaluation ex vivo (85). Finally,
it is possible to use molecular methods, for example, to assess gene
expression of recovered cells using microarray or other analytical methods.
Alterations in cellular populations of the lower respiratory tract are
characteristic of a variety of disease states (66,74). In addition, exposures
are often associated with acute recruitment into the lung of specific popu-
lations of cells. The ability to apply a variety of biochemical, histological,
and molecular methods to samples recovered by bronchoalveolar lavage

© 2006 by Taylor & Francis Group, LLC

18  Toxicology of the Lung

Figure 1.7 Bronchoalveolar lavage cells. A bronchoalveolar lavage sample from

a normal subject was used to prepare a cytocentrifuge specimen that was stained
by a modified Wright–Giemsa stain. The majority of the cells are alveolar mac-
rophages. A ciliated epithelial cell, a neutrophil, and several lymphocytes are also
present.

has permitted a great variety of studies, both in disease and following

defined exposures (86), including environmental pollutants such as diesel
exhaust (87) and ozone (88–90). It is also possible to administer exposure
through the bronchoscope, and endobronchial challenge studies have been
widely used in asthma (91). As noted earlier, bronchoalveolar lavage is
easily performed, and there are a variety of acceptable variations on the
procedure. These variations as well as variations in sample processing can
contribute to differences in measurements. Although not generally a problem
for the evaluation of clinical samples, such variations may be problematic
in research studies and may account for variations in published results.
Standardization of lavage procedures at a single site has proved easier than
standardization of the procedure across several sites in multicenter studies.

1.4.4.6 Biopsy Procedures

The lower respiratory tract can also be sampled by several biopsy proce-
dures. These include endobronchial biopsy, transbronchial biopsy, endo-
bronchial brush biopsy, and transbronchial needle aspiration biopsy.

© 2006 by Taylor & Francis Group, LLC

 Volume (liters)

5
FVC
4

FEV1 3

1 2 3 4 5 6
Time (seconds)

Color Figure 1.1 Spirogram. After inhaling as deeply as possible, a subject

exhales as rapidly as possible. The volume of air (vertical axis) is plotted against
time (horizontal axis). Airflow, as a function of time, is given by the slope at any
point. Forced expiratory volume in 1 sec (FEV1) is the volume of air exhaled in
1 sec. It would be reduced in case of airway obstruction and airway restriction.
Forced vital capacity (FVC) is the maximal volume of air exhaled. In obstruction,
the FVC may be normal, but the subject may not be able to exhale long enough
to make an accurate measure. In restriction, the FVC will be reduced. Peak
expiratory flow rate (PEFR) is the steepest slope on the curve, and this occurs
very near the beginning of the maneuver. FVC and FEV1 are indicated for a normal
subject.

© 2006 by Taylor & Francis Group, LLC

 A.

B.

Color Figure 1.8 Endobronchial biopsy. Panel A: An endobronchial biopsy from a

normal volunteer stained with hematoxylin-eosin. Note the pseudostratified colum-
nar cells and the ciliated border. Panel B: an endobronchial biopsy from a “normal”
smoker Stained with PAS. Note the hypercellularity, the partial loss of cilia, and
the marked increase in mucin containing goblet cells.

© 2006 by Taylor & Francis Group, LLC

 Methods for Evaluating the Lung in Human Subjects  19

1.4.4.6.1 Endobronchial Biopsy

In this procedure, a biopsy forceps is advanced through the sampling
channel of the bronchoscope and, under direct vision, a biopsy is obtained
of the bronchial wall, usually a branch point that fits nicely between the
biopsy cups of the forceps. Cancers, which protrude into the airway lumen,
can often be readily biopsied with this method. Biopsies of branch points
of 1 to 2 mm in diameter can be routinely obtained from normal subjects
and subjects with disease (Figure 1.8). Biopsy of the airway wall away
from branch points is difficult as it is not easy to grasp the airway with
forceps.
The biopsies are small, and the forceps can compress the tissue,
possibly damaging the airway epithelium. Nevertheless, specimens
obtained using this method by a skilled bronchoscopist usually yield
readily available airway mucosa as well as submucosal tissue. Because
the depth of the biopsy is much less than the thickness of the normal
airway, there is little risk of pneumothorax. Bleeding may be a significant
complication, although it is usually minimal in the absence of coagulation
defects, such as renal failure or in the presence of abnormal blood
vessels as may occur with cancer. Endobronchial biopsy, because of the
relative ease of the procedure, has been easier to standardize in multi-
center studies.

1.4.4.6.2 Transbronchial Biopsy

In this procedure, the biopsy forceps is advanced into distal regions of
the lung. The biopsy forceps is used to cut through the small airway
wall, and a biopsy of alveolar structures is obtained. The Zavala method
has been suggested to minimize the risk of pneumothorax (92). With
this technique, the subject is instructed to take a deep breath, and the
biopsy forceps, in the closed position, is advanced under fluoroscopic
control. The forceps is then retracted 2 to 3 cm and opened. The subject
is then instructed to exhale, and the forceps is advanced approximately
1 cm. With the subject in forced exhalation, the forceps is closed and
then retracted. The concept behind this procedure is that lung tissue is
pressed into the biopsy forceps in a manner that prevents the forceps
from reaching the pleural space, thus minimizing the risk of pneumotho-
rax. The incidence of pneumothorax and significant bleeding following
transbronchial biopsy is conventionally stated to be 3 to 5%, but better
results have been reported (93,94). With transbronchial biopsy, both
small airway and alveolar structure biopsies can be obtained. The tech-
nique is routinely used in selected clinical settings and has been applied
to research studies in patients with asthma (95). The risk of pneumothorax

© 2006 by Taylor & Francis Group, LLC

20  Toxicology of the Lung

Figure 1.8 Endobronchial biopsy. Panel A: An endobronchial biopsy from a nor-

mal volunteer stained with hematoxylin-eosin. Note the pseudostratified columnar
cells and the ciliated border. Panel B: an endobronchial biopsy from a “normal”
smoker Stained with PAS. Note the hypercellularity, the partial loss of cilia, and
the marked increase in mucin containing goblet cells. (See the color version of
this figure after page 18.)

© 2006 by Taylor & Francis Group, LLC

 Methods for Evaluating the Lung in Human Subjects  21

is believed to be greater in the presence of chronic obstructive pulmonary

disease.

1.4.4.6.3 Endobronchial Brush Biopsy

With this method, an endobronchial brush is inserted through the bron-
choscope. The brush, which has a distal tip approximately 1-cm long
with bristles approximately 2 to 3 ml in length, is contained within a
sheath. The sheath containing the brush is then advanced through the
sampling channel of the bronchoscope, after which the brush is advanced
out of the sheath. Under direct vision, the proximal airways can then
be “brushed,” i.e., superficial cells are scarped from the airway epithelium
and are retained in the brush. The brush is then retracted into the sheath,
and cells within the brush are removed either in a saline solution or by
smearing on a slide. A variety of histochemical and molecular methods have
been applied to the analysis of samples obtained by endobronchial brush-
ings (96,97). The brush may also be advanced to more-distal regions in the
lung in order to sample small airways. Peripheral airways are thus sampled,
and the ultrathin bronchoscope permits sampling under direct vision (65).
Fluoroscopic guidance may help minimize the risk for pneumothorax.

1.4.4.6.4 Transbronchial Needle Aspiration Biopsy

This method, developed by K.P. Wang, permits sampling of tissues outside
the airways (98). A needle equipped with a stylette is inserted through
the sampling channel of the bronchoscope. The needle is then used to
penetrate the airway wall in the region of interest. The stylette is then
withdrawn, and an aspiration sample can be obtained through the needle.
This method has been utilized successfully to diagnose both neoplastic
and infectious conditions in peribronchial tissues.

1.5 SUMMARY
The lung is frequently the target of toxic exposures. The lung, however,
is also readily amenable to investigation. A number of well-established
methods permit physiological assessment, imaging, and sampling of the
lung. New methods are currently under investigation. Because of the ability
to assess the lung, toxicologists have many options for the study of lung
disease in humans. A variety of studies ranging from epidemiology to
natural history and mechanisms of disease are possible with these methods.
The application of these methods is likely to play an increasingly important
role in toxicological studies.

© 2006 by Taylor & Francis Group, LLC

22  Toxicology of the Lung

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Exploring the Variety of Random
Documents with Different Content
 XX HISTORY OP MONMOUTH AND OCEAN COUNTIES. John
Corlies in. Naomi, dau. of Abiah Edwards, and had two children
James and John, named 1714 in mil of Edwards. In 1739 Benjamin
Corlies was deceased. Hannah Corlies m. Henry AUen 17(J2, she d.
1712. Elizabeth Corlies m. WiUiam Brinley 1704. Wilham Corhes m.
Sarah Winj^ 1731. Deborah Corlies m. Walter Herbert, Jr., 12th of
10th mo., 172S. In 1801 Sanniel Corlies, mariner, and w. Catharine,
sold half an acre of land on north side of Toms River to Dr. William E.
Imlay. CoTTEELL — Eliezar Cottrell of Middletown received a wan-ant
for GO acres of land 1676 ; in 1677 another for 120 acres and in
1687 for 100 acres. In Middletown, 1761, among i^ersons taxed
were John, Nicholas, Eobert and Samuel Cottrell. CouKTNEY -In
1796, Luke Courtney and Silas Crane bought land jointly in Stafford.
Luke Courtnej' was a soldier in the Revolution in Capt. Reuben F.
Randolph's company of militia and also in the Continental army. The
Courtneys were an ancient family of Devon.shire, England, and earls
of the shire. CovENHOVEN, CoNOVEE— In 1695, Cornelius
Covenhoven, Peter Wikoff, Garret Schenck and Stephen Courte
Voorhuy (Voorhees) all of Flatlands, bought of John Bound, 500
acres as described March 10, 1685, on a i^atent to Bowne fi'oui
Proprietors, land adjoining Richard Stout Derick Tunison and
Jonathan Holmes. In 1696, the cattle marks of Corneliirs
Cowenhoven, Garate Schenck and Peter Wikoff were recorded in
Middletown Town Book. Among members of Brick Church,
Marlborough were, 1709, Peter Kowenhoven and Patience Daws his
wife. The first named Peter Kowenhoven was an elder in the church,
1709. The common ancestor of the greater part of Conover family
was AVolphert Garretson van Couwenhoven who immigrated from
Holland 1630, with the colonists who settled Rensselaerwick, near
Albany. In South Jersey a branch of the Cowenhoven family descend
from Peter Van Covenhoven, son of Wolphert, who came from
HoUand when a boy in 1630, and was for many years a leading
citizen of New York. Joseph Covenhoven or Conover, who settled at
Forked River, was in 1824 a member of the Legislature from old
Monmouth. His brother. Esquire Daniel Conover, was a well-known
hotel keeper at Forked River. Peter lost his w. in 1633; she M^as
buried in New Y'ork. Many descendants of this familj' of Van
Cowenhoven are now li\-ing in New I'ork. The late Col. E. F.
Applegate , the well remembered editor of the Monmouth Inquirer,
was positive that traditions in his time stated that his ancestors were
of French origin, and the ancient names given above seem to
confirm this tradition. Another famiUar New Jersey surname of
l^ard, we find as we trace it back becomes DeYasse, also denoting
Norman origin. The will of John Conover, Jr., 1804, named father
John, and mother, property to be equally divided between his
brothers and sisters. The wiU of John P. Covenhoven, dated 1810,
named sons William, John and Robert, and dau. Elizabeth Robinson
and Sarah Ten Eyck. In 1796, Jan. 31, Garret Covenhoven was m. to
Sarah Stout, by Esquire John Covenhoven. The following
Covenhovens or Conovers have been members of the N. J.
Legislature, viz: 1776 John; 1792 John; 1821-2-3-4 William L ; 1824-
5-6 Joseph; 1841-2 John R, ; 1851-2 William H.; 1858-9 John V.;
1869 WiUiam H., Jr.; 1875-6 William V. In the State Senate WiUiam
H , Jr., served 1872. The following were Sheriffs: Holmes Conover,
1844-7; Samuel, 1847-50; Holmes 1853-6; Samuel 1856-9.
Surrogates, Arthur V. 1848; John R. 1858. Prosecutor of Pleas,
WiUiam H., Jr., 1872. CovEET — Abraham Covert bought land of
John Powel 1716. In 1721 Abraham Covert and Echte, his w. , sold
land to Frances Hoffmire, widow of Samuel. Among persons taxed in
Freehold township 1776 were John, William, Daniel and Isaac
Covert. The Covert family descend fi-om Teunis Janse Covert, who
came from North Holland 1651; settled in New Amsterdam,
belonged to Dutch church until 1660, then went to Bedford or
Brooklyn, L. I. He had ten children. The son Abraham probably was
the one subsequently named in Monmouth; he m. Egbert] e Eldertre
Voorhees . CowAED — Hugh Coward, a sea captain, who, it is said
came from Lon 
 GENEALOGICAL RECORD. XXI don hiid license to marry
Patience, dan. of John Throckmorton in New York, July B, 1703. In
1705 Hugh Coward and \v. Patience, I'homas Stilwell and Alse his w.,
Moses Lipet and Sarah his \v. Deliverance Throckmorton, sign deeds
as heirs of John Throckmorton, 2nd. Miss ( 'ooley in her work on
First Settlers of Trenton and vicinity, says Capt. Hugh Coward had a
son Kev. Jos. Coward, who had a son Joseph who died 17tiO, aged
50 yrs. who married Lucretia dau. of Jacob Scudder ; they had a son
(Japt. Joseph Coward, a hero of the Revolution, whose dau. Sarah
m. Hon. Chai'les Parker, formerly State treasiirer 'of New Jersey. In
1731, John Coward was taxed in upper Freehold In same township,
1758, John, Jr., and Joseph were taxed. John Coward, probably son
of John whose will was dated 1760, was an extensive owner of
timber land in what is now Ocean county ; about 1760, he united
with James F. Randolph in buying land around Toms River. Randolph
was the leading business man of Toms River before and during the
early part of the Revolt;tion. David Coward m. to Betsey Rouse Oct.
10, 1799, by Rev. Joshua Dunham of the M. E. church. CowDKicK—
Jesse Cowdrick, the favorably remembered hotel keeper of Toms
River, once kept a hotel and store at Cedar ( 'reek and at one time a
tan yard at lilue Ball. He once ran for Sheriff in old Monmoiith but
was defeated. He kept the jail there once. He d. May 21, 1857, a.
over 57 yrs. He bought the Toms River hotel, it is said, of Israel and
Anthony Ivins. This hotel was originally built by Ivins Davis.
CowpERTHWAiTE — Hugh ( 'owperthwaitc of Springheld, Burlington
county, bought land in Upper Freehold, Monmouth county, Mar. 29,
1749. This family came from Burlington county where a John
Cowperthwaite was named, 1698. In Little Egg Harbor there was a
Thomas Cowperthwaite, settled about middle of last century who m.
Margaret dau. of Reuben Tucker, Sr. Their descendants are named in
the History of Little Egg Harbor. Cox — The first of this family in Old
Monmouth was Thomas Cox who was among those who bought the
land of the Indians 1667. He settled at Middletown and in the first
division of town lots, recorded Dec, 1667, he was allotted lot number
eight; subsequently he was awarded other tracts. In 1668 he was
appointed with three others to muke "prudential laws." John Cox,
who may have been a brother or son of the first Thomas, was one of
the founders of the noted Baptist Church at Middletown. Gen. James
Cox, a hero of the Revohition, was of this family and was a member
of Congress from Ohio and d. in 1810 before his term expired. Hon.
Sam'l S. Cox, the late distinguished member of Congress, formerly of
Ohio, subseqiaently of New York, is a descendant of Gen. James
Cox, who was b. at Cox's Corners, Upper Freehold. In 1790 Wm.
Cox, Jr., gentleman, of the City of Burlington, and w. Abigail, made
deed of partition with John Bloomfield. Ckaft— Joseph Craft was m.
to Esther, daii. of Job Ridgway, of Barnegat, 1786. Their son. Job
Craft, was m. to Ann Cox June 15, 1810. There was a James Craft
who was m. to Susannah Moore about 1797. Job Craft and w., Ann,
had son Eli and dau. Esther. It is said that they emigrated West.
Ceane— Members of this faniilj' settled at Manahawken, in Ocean
Co., previous to the Revolution. In the State Militia during that war
were Nathan Crane who was a lieutenant, and Seth Crane, a private,
in ( 'ajjt. Reuben F. Randolph's company. Silas Crane was a member
of the State Legislative Council in 1811 and again in 1814. Atwater's
History of New Haven says that the first Jasper Crane probably came
from London. Jasper Crane in 1651 removed to Branf ord and thence
to Newark, N. J. Jasper, second, was a representative in the
Legislature from the town of Newark in 1699. Cranmee — The
Cranmer family of New Jersey, descend from William Cranmer, an
early settler of South old. Long Island; he is named in the History of
Southold by Rev. Epher Whitaker, among oiiginal settlers of that
place 1640-72. He m. Elizabeth, dau. of David Carwithy, who had
formerly lived at Salem, Mass., where he is named as freeman,
1644. The
 XXll HISTOEY OF MONMOUTH AND OCEAN COUNTIES.
tradition hauiled down in the Cranmer family states that they
descend from the family of the noted Archbishop Thomas Cranmer,
b. 1489, who was burned at the stake looB. The father of the .Ai-
ehbishop was also named Thomas and he had another son named
Edward, who was Archdeacon of t!anterbtiry, while his brother was
Archbishop, and it is possible the Uranmers of New Jersey may be
descendants of Archdeacon Edward, who had five sons and eight
daus., and d. 1604 aged &■) years. Around Forked Eiver and Cedar
Creek, William Cranmer took up land 1748-9 and thereabouts. Craig
—John Craig ajDpears to have been first of this family in Monmouth.
In December, 1705, "At ye request of Mr. John Craig, Walter Ker,
Wm. Eennel, Patrick Imlay, in behalf of themselves and their
brethren, Protestants, desenters of Freehold, called Presbiterians,
that their Public Meetinghouse may be recorded." It was so ordered
by court. The Craigs were well represented during the Revolution in
the ranks of the patriots. John Craig was a lieut. , James Craig, an
ensign, Da"vid Craig, a sergeant, and John, a private, all in Capt.
Epher Walton's company of dragoons. Others served in other military
organizations. Most of them resided in Old Freehold township as
may be seen b_y tax list of 1776. John Craig, first of the name, was
probably the one who came fi-om Scotland 1685. Crome —Richard
Hartshorn sold to Edward Crome, Dec. 26, 1670, the town lot No.
25, in MidtUetown, which Hartshorne had bought of William
Goulding. Crome is an unusual name, but it occurs once in Bartlett's
Rhode Island Records. Craven —Thomas Craven of Forked River,
moved to Highland county, Ohio, where he d. Nov. 29, 1880, a. over
64 yrs. Elizabeth, his w. , d. Jan. 11, 1868, a. over 52 yrs. Both were
buried in the Methodist grave yard at New Lexington. Crawford —
John Crawford, the ancestor of most of this name, in ancient deeds
was described as "of Ayrshire, Scotland, gentleman," and came to
this country it is said about 1672. Dec. 11, 1678, he purchased a
"house lott" in Middletown, and also outlands of Richard Gibbius and
w. Elizabeth. Gideon Crawford was High Sheriff of Monmouth 1714-
15-16 and again 1720-21. He m. a dau. of William and Margaret
Redford; who came from North Britain 1682. Joshua, supposed to
have been father of Joel Crawford, ^^•as of Scotch descent and a
Virginia frontier farmer. Following the tide of emigration he settled in
1779 in Edgefield District, South Carolina. His son, the noted William
Harris Crawford, was b. Feb. 24, 1772, in Amherst county, Virginia.
He finally settled in Georgia, from which State he was elected to the
U. S. Senate; was a candidate for the Presidency in 1824, etc. He
was engaged in two duels, in one of which he killed his adversary
(Van Allen) at the first fire. He d. in Elbert county, Georgia, on the
way to court of which he was judge, Sept. 15, 1834. He left five
sons and three daughters. Crowell — Two brothers, John Crowell
and Edward Crowell, came to North Carohna and settled in Halifax.
They emigrated from Woodbridge, N. J. The}' were originally from
England, and they or their ancestors were originally called Cromwell.
In the year 1674, says the Annalist of Phila. (John F. Watson) two
brothers of Oliver CromweU left Englnnd for America and settled in
New Jersey. Thej' fled f) om England from the political storms that
impended over the name and house of the late Protector. Bolton's
Histor}^ of West Chester county, says: " It is presumed that the
ancestry of the American line was Col. John Cromwell, third son of
Sir Oliver Cromwell, and a brother of the Protector." From what has
been stated, it is evident that the tradition carried to other States by
descendants of the Crowells and Cromwells of Woodbritlge, that they
descended from the noted Cromwell family of England, is probably
the fact. Davis — Nicholas Davis of Rhode Island was one of the
twelve men to whom was granted the Monmouth patent in 1665,
and he is also named among those who paid for a share of land in
1667. He had 480 acres.
 GENEALOGICAL RECORD. XXlll Nicholas Davis, the
patentee, was a freemen of Barnstable, in Plyuionth Colony 1643.
About 1656-7 he joined the Qitakers, and July 14, 1659, he was
arrested at Boston, where he had gone to trade and kept in prison
until September, \^'hen he was banished, with Mary Dyer, under
^oain of death if they returned. Mary Dyer subsequently returned
and was hanged on Boston Common. Thomas and James Davis were
taxed in Middletown 1761, and William Davis in Shrewsbury 1764.
Davison — ^\ illiam Davison is named in deeds, 1691, and
suV)sequently ; he was a carpenter and his will was dated Freehold,
April 6,1723. James Davison lived in Freehold, 1776. De Boogh, De
Bogh, Debow — Frederick De Bogh, innholder of Monmoiith. bought
land 1715-22 of John Eomine and w. Gertie. William De Bowe,
Monmouth, and w. Elizabeth sold land to William Cox, 1802.
Lawrence Debow was taxed in Upper Freehold, 1758 De Hakt —
Elias, or Elyas De Hart, an early settler of Old Shrewsbury, was a son
of Simon Aertsen De Hart who came to this country in 1664. Morris
De Hart was a tax payer in Shrewsbury, 1764. Denise — Jacques
Denise (spelled Denys) and Hendrick Hendrickson of New Utrecht, L.
I., bought land, 1719. Tunis Denise of Utrecht, L. L, bought land in
Freehold, 1720. The common ancestor of the Denise family was
Tennis Nyssen or De Nyse, who emigrated as early as 1638, from
Holland. He resided then in New Amsterdam, now New York. In
theEevolutionarj" war Dennis Denice was Major in 3rd Kegiment of
Monmouth. Daniel Denise was a private in Captain Waddell's
companj^ Fourth Regiment. In a list of jiatriots of Moniiiouth who
signed a pledge regarding retaliation for Refugee depredations
during the Revolution, are the names of Daniel Denise and Jacpaes
Denise. Dennis — Samuel Denrn's was born about 1650, in Great
Britain, settled in Shrewsbuiy 1675 ; he had w. Increase, two sons
and three daus. He was foreman of grand jury 1690, and a justice of
the court from 1700 to his death in 1723. His only w. was Increase,
who departed this life twentyeight yrs. before him. The name Dennis
occurs among original settlers of Woodbridge, where Robert, John
and Samuel Dennis were among the iirst. Denyke — Conraed
Denyke bought land of Samuel Warneand Margaret his w. in 1727.
Probably the name was meant for Conraed Tenyke or Ten Eyck as
the name is now generally given. Devill, Deuell — William Deuell of
Newport, R. I., bought Mark Lucas' share of land in Monmouth. In
1672, father, William, was an early settler in Plymouth Colony,
named there 1640. Deveeeaux — John Devereaux, during the last
century came to this country from Ireland, but his ancestor came
from Evieaux in Normandy, and hence received the name of
D'Evreaux. De Wildey — The will of John De Wildey of Monmouth
county, dated March 30th, 1708, proved Aug. 20th, 1708, named
dau. Dinah. Executors, Anthony Woodward and Richard Salter. Dey,
Dye — Isaac Dye bought 51 acres of land of John Antonides in
Monmouth county in 1737. In the Revolutionary war, John Dey,
Josiah Dey and (_!yrus Dey were soldiers in the patriot army, the
latter in ( 'aptain Kenneth Hankinson's company. DiKEMAN,
DYCEMAN—Hugh Dyckman was appointed "Schepen," or magistrate,
in Monmouth by the Dutch during their brief supremacy in 1673.
Dj'ckmau, who came to America was Joannes who came in 1652;
The Hugh Dikeman of Monmouth seems to have been of another
line. Dillon— James Dillon had land at Toms River in 1762. It is said
he owned, in 1763, Dillon's Island, now Island Heights, which, in
1774, was referred to in a deed of John Coward, who bought land
on the opposite side of Toms River. He had a dau. who m. Aaron
Buck and she and her husband had two daus., one of whom m.
Judge Ebenczer Tucker, from whom Tuckerton derives its name, and
the other dau. m. John Rogers, ancestor of families of that name in
Berkeley. James Dillon was a soldier in the Continental army. William
Dillon, brother of James, was an un 
 XXIV HISTORY OF MONMOUTH AND OCEAN COUNTIES.
principled Refugee, who is noticed in account of Refugee raids; it
was probably he that instigated the burning of Toms River. In 1783
he went to St. John, N. B., where he was given a town lot. The lands
of John Dillon, north side Toms River, are referred to in 1787 in a
deed to James Parker. DoESETT— James Dorsett is named as a juror
1076-8. In 1677 he took up 2U2 acres of land from proprietors. His
cattle mark is given in the old Middlftown Town Hook. His will was
dated Sept. 26, 1741. The will of Samiiel Dorset of Middletown, was
dated Sep. 10,, 1741. In 1741 John Dorset was an administrator on
estate of John Carman of Middletown. Among the soldiers from
Monmcmth in the Revolutionary armj' were : Benjamin, John,
Samuel, James and Josej^h Dorset, the latter in Capt. Dennis'
company. A dau. of John Dorsett m. James Wall, who was father of
General Garret Dorsett AVall, once Senator from New Jersey. Thos. I.
Bedle, father of Ex-Gov. Joseph Dorsett Bedle, m. Hannah Dorsett.
Four or live generations of the Dorsett family lie biiried in the Dorsett
burjing gi-ound, on the Dorsett farm (lately owned by John Stilwell,
deceased) about three miles from Matawan. The tradition in the
family says that the founder of the Dorsett family came from
Bermtida. DouciLASs — Thomas Douglass is named in a bond of
John Salter 171G. This bond is in possession of James G. Crawford,
near Freehold. Richard Douglass, of Monmoi^th, was m. to Lydia
Salter, March 10, 1740. AVilHam Douglass, of Monmouth, had license
to m. Rebecca Lawrence, Jan. 9, 1734. Thomas Douglass, of
Monmoiith, had license to m. Rachel De Bow Aug. 20, 1773. Dove—
Alexander Dove d. Oct. 7, 1736, and was buried in Tojianemus
burying groiand; will was dated Sept. 20, 1736. It is probable that
he came from Shropshire, England, about the year 1700. He took up
niimerous tracts of land in what is now called Ocean county, and had
a mill near the line of Ocean and Monmouth. He was assessed in
Freehold in 1776. Deummond -Gawen Drummond of Loch Harbor or
Lochaber, gent, deeded land to John Tucker of Deale, May 21, 1695.
He was jclerk of the court of Monmoiith 1700-1. He received a
i^atent for 265 acres, which is now the site of Key East on the north
side of Shark River. He had five children. A brother James, lived at
Prestonpanns, in Scotland, and one account says his father was
Peter Knott, who took up land in Monmouth as ea^iy as 1720. In
1819 Robert, son of Gawen Drummond, and Mary, his w. of
Shrewsbury, gave deed to Britten White. DunctAN -Thomas Dungan
was awarded a share of land 1667-70; 1674, Dec. 21, he transferred
it to Sarah Reape. He was a noted Baptist minister of Rhode Island.
In 1684 he left Newport and settled at Cold Springs, near Bristol,
Pa., where he established a Baptist church. He d. there in 1688.
EaelE" Ralph Earle was one of the original settlers in 1826 at
"Worcester, Mass. He had son Ralph who had sons Ralph and James
The third Ralph Earle was a member of the Royal Academy of
Science, and died at Lansingburg, N Y., and his brother James went
to Charleston, S. SN. John Eaton, the son, m. Joanna Wardell, dau.
of Joseph NN'ardell, and grandson of Eliakim Wardell. He was a
leading man in his time in business and pi;blic matters. He owned
mills on the stream in the village which derives its name chiefly from
him. He was Justice of the Peace for manv vears
 GENEALOGICAL RECORD. XXV and member of the
Provincial Assembly from 1723 to 1749, almost to his death, which
occurred Oct. 25, 1750. Joseph Eaton, son of John and Joanna, was
a physician. He d. 1761 in the 4:4th year of his age. He was buried
in Shrewsbury church yard. Thomas, another son of John, settled at
Elizabeth. Joanna, dau. of the last named Thomas, m. in 1750 Eev.
Elihu Spencer, who at that time was supplying the jjuljiits of the
Presbyterian churches in Middletown and Shrewsbury, and from
them descended Rev. Dr. Samuel Miller and John Sargent, the noted
Philadelphia lawyer. EccLES — Charles Eccles is named as a grand
juror, 1677. Probably the first of this name in the country was
Richard Eccles, who was at Cambridge, Mass., 1642. Some fifteen or
twenty years later, Solomon Eccles, a noted Quaker preacher who
had traveled extensively, was banished from New England for his
zeal, by Grovernor Bellingham. Edge— Gerard Edge of Freehold, late
innholder, appointed Gabriel Stelle his attorney, aboiit 1721. In 1723,
Thomas Foreman in his will names Rebecca Edge, w. of Gerard
Edge, and his grandchildren Mary and Rebecca Edge. Edwards —
Abiah Edwards of Shrewsbury is named in Freehold court records,
1683. He was a grand juror, 1691 and 1700. In 1714, he and w.
Ehzabeth conveyed land to John West. In this deed it is stated that
Edwards was a shipwright. The will of Aliiah Edwards was dated
January, 1714, and names w. Elizabeth and children and
grandchildren. Thomas Edwards and James Edwards were also
named in Freehold and Perth Amb'oy records at an early date. In
Middletown, 1761, Samuel Edwards was taxed. In Shrewsbiiry, 1764,
Philip and Webley EdAvards were taxed. The name Edwards
indicates Welsh origin. Among the first who bore the name in this
country were Robert Edwards who came fi-om London to New
England, 1635. The distingiiished divine. Rev. Jonathan Edwards,
who was President of Princeton College, 1703, was b. in Connecticut.
In the Revolutionary war, Thomas Edwards was 2nd Lieutenant in
the Monmouth militia. Ellis — Roger Elhs and son are named as
paying for shares of land, 1667. They were awarded two shares of
land. The father was probably the Roger Ellis of Yarmouth, Mass., an
ancient settler of Plymouth colony, named as able to bear arms m
1643. John Ellis is named as a witness to a deed in 1701, from John
West, Manascpian, to Joseph Lawrence. The will of Thomas Boell,
2nd, 1735, names brother-in-law Robert Ellis and grandson Robert
Ellis. The Ellis family early settled in West Jersey and are noticed in
Judge Clement's First Settlers of Newton, among them Thomas Ellis
in Burlington, 1677. It is said he came from BurUngton in Yorkshire,
England. William Ellis came to Burlington, 1683, and located in
SpringHeld. Simeon Ellis purchased land in Burlington, 1691. He left
wife Sarah and seven children. Daniel H. Ellis, the well remembered
county clerk of Monmouth, it is stated, descended fi'om Rowland
Ellis who came to Burlington, N. J., in 1714, being sent from England
as a teacher by the Society for the Propagation of the Gospel in
Foreign Parts. Ellison — John Ellison is named as witness in court
proceedings, 1 705. The will of Richard Ellison was dated March 5th,
1719, and proved Dec. 23d, 1732. Daniel Ellison was taxed, 1776, in
Freehold for 86 acres of land and other property. Empson— Captain
Christian D. Empson was b. in Sleseburg, Denmark, in Sept. 1794.
When a boy he was in Napoleon's navy. He followed the sea for
thirtj^ years. For a time he lived in Highland county, Ohio, where a
son and a dau. died. His dau. m. Orrin Pharo, former proprietor of
the Monmouth Inquirer. Both herself and husband died. His son,
Hon. Ephraim Potter Empson has long been identified with public
affairs in Ocean county. ENCiLisH— David English of Freehold,
wheelwright, bought land, 1737. Englishtown, in Monmouth county,
it is said, derives its name from James English, the original
jarojarietor of the land on which the village is situated. Dr. James
English, Jr., was b. 1792, and succeeded to his father's practice. He
died May 7th, 1834, at Enghshtown and was buried near his parents.
 XXVI HISTOEY OF MONMOUTH AND OCEAN COUNTIES. Dr.
David C. English, another son of Dr. David English, Sr. , was born at
Englishtown and died at Springfield, N. J., in 1860. Dr. Jeremiah
Smith English was born at Englishtown, Nov. 2 1st, 1798. He was
son of James E.. and Alice English and was the fourth in a family of
nine children, six sons and three dans. He died Oct. 9th, 1879. He
had two daus., one of whom m. Thomas E. Moriis. He was treasurer
of the New Jersey Medical Society from 1833 to 1865 continuously.
In 1750, among taxable inhabitants of Upper Freehold were Eobert
English and Robert English, Jr., and David English. James English
was a soldier fi'om Monmouth in the Revolution. EsTELL— Daniel
Estell was an original settler of MiddletoxsTi, and in the division of
town lots, 1667, he was given lot number thirty-two. Under
Proprietors' Concessions he was granted 271 acres in 1671. He came
from Gravesend, L. I. Ereiceson — Michael Errickson, in 1754, was a
pew owner in old Tennent church, for which he paid £12. In 1776,
he was taxed for 166 acres of land and other property in Freehold.
He was a soldier in the Revolution and was buried in the Tennent
churchyard. The will of John Eirickson was dated 1806, and proved
Jan. 1807. This family is of Sweedish descent and members wt-re
among the earlj^ settlers on the Delaware River. Among heads of
families were Joran Ericson and one child. Mats, (changed to
Mattheas) Ericson and three children, Erie Ericson and one child. All
three of these heads of families were born in this countiy. Thomas
Errickson m. Hester Patterson, April 26, 1795. John Errickson was m.
to Nellv Schenck, dau. of William, Aug. 24, 1797, by Rev. John
WoodhaH, D. Y. M. Among the soldiers of the Revolution were
ilichael, John and Thomas Errickson. EvEEiNGHAM — Thomas
Everingham and Henry Everingham were among tax joayers in
Upper Freehold, 1731, and William and Joseph Everingham in 1758.
In what is now Ocean count}', Evenngham's saw miU on North
bi'anch of Toms River or Pine Brook is frequently referred to. In the
Revolutionary war among soldiers from Monmouth were John,
Nathaniel and Thomas Everingham. EviLMAN, EviLLMAN— William
Evillman was a tax payer in Upper Freehold in 1731. In 1774, John
Evelman bought land in Upper Freehold of Moses Robbins. Robert
Evilman and w. Elizabeth are named in a record, 1818, among heirs
of Gowen Drummond. Emanuel, — Isaac Emanuel, late of Freehold,
merchant, appointed Solomon Isaacs, late of the same place, his
attornej', about 1720-3. Emley, Emblby — Peter Embley is named as
grand juror, 1700, and Peter Emlies is named, 1707. In old
Shrewsbury township, John Emley was assessed, 1764. In Freehold,
1776, Robert Embly and Ezekiel Embley were among taxable
inhabitants. It is probable that the names Emley and Imlay were
sometimes confounded in ancient records. This family descends from
Andries Emmons, an Englishman who emigi-ated from Leiden in the
Netherlands, in the ship Saint Jean Baptist, May 9, 1661, and settled
at Gravesend, L. I. A.ug. 21, 1661, he, with twelve others, petitioned
for land on Staten Island. He had children, John of Gravesend,
Hendrick and Abraham who came to New Jersej'. Abraham, son of
John and Sara, m. Abigail Stilwell and settled in Freehold. His will
was dated 1734, proven 1742. Falkinbuect — This family descends
from Henry Jacobs Falkinburg, who came from Holstein, a little
province adjoining Denmark on the south. His name in old records is
variously given. In what is now Ocean county, Caleb Falkinburg lived
at the beginning of the present century, between Forked River and
Goodluck, and at one time on the place subsequently owned by the
late Capt. Jos. Holmes. He wash. Feb. 28. 1768, andd. Jan. 8, 1815,
a. about 47 yrs., and was biiried in the old graveyard on the lane to
Benjamin B. Stout's, Goodluck. He married j\Iary Woodmansee,
daiighter of Samuel, born 1799. After Caleb Falkiuburg's decease, his
widow married Sylvester Tilton, and she moved to Highland county,
Ohio. Caleb Falkinburg's wiU was dated 1817. He named w. Mary, to
whom he
 GENEALOGICAL RECORD. XXVH left pliintatiou bought of
Cliaiiea Falkinburg until bis son Samuel comes of age. Eldest son
John, sons Auios and Job; daughters Phebe, Alice and Hannah.
Executors, Silas Crane, Daniel Stout, and w. Mary. Daniel Stout
declined to act. Charles Falkinbiarg, brother of Caleb, m. Sarah
Brindley, Nov. 3, 1795. He bought land near Goodluck, July 1, ISUfs,
of Joseph Miller and \v. Rachel. He had sons Caleb and others and
moved West about 1818. At Barnegat, Captain Timothy W.
Falkinburg, long a respected citizen of that place, d. July 5, 1878. He
descended from John Falkinburg. This John Falkinbiirg m. Mary
Somers of Great Egg Harbor, and had children Samtiel, John, Joseph,
Somers, Hannah, Tabitha, Judith, and Susanna. The son Samuel,
generally known as Captain Samuel Falkinburg, m. Jan. 1807, Marj',
dan. of Josiah Cranmer, of Cranmertown, Ocean county, and had
eleven children. All of the old stock Falkinburgs left Egg Harbor
except some of the descendants of Captain Samuel. Sarah
Falkinburg bought a tract of land at Forked River in 1812, of Anthony
Parker and Chai-les Parker for ninety doUars. In New Lexington
graveyard. Highland county, Ohio, is a tombstone to memorj' of
Rhoda, wife of Caleb Falkinburg who died Feb. 10th, 1849, aged 21
yrs. Faedon -In tracing this name back we find it given as Ferdon,
Vardon and originally Verdon. The name is of French origin. Jacob
Verdon appears to have been the first of this family in this country.
His farm was between twentieth and twenty-fifth streets, Brooklyn.
In Long Island records the name was sometimes given as Fferdon
and Ferdon; the latter is the orthography retained by some
descendants in New York state and elsewhere. Thomas Fardon who
died about 1877, in the Sith year of his age, was one of the first
Superintendents of the Sunday School of the old Holmdel Baptist
church. Fenton —John Fenton of Freehold, bought land of Edward
Worth and Mary his wife, of Freehold, 1713. Thomas Fenton's lands
bought of Thomas Parker, Jr., are referred to, 1716. Among soldiers
in the patriot army in the Revolution were George and Thomas
Fenton. Lewis Fenton, a blacksmith of Freehold, joined the Tories
and was killed by a party in pursuit of him in 1779. Flinn — Edward
Fiinn bought land of the proprietors in 1797, on the north side of
Cedar Creek. His will was dated 1810 and proved Jan. 7, 1811. It is
said that he was b. on the passage of his parents to this country and
was buried in an old graveyard on the Gifliord j^iace at Toms River.
FiTHiAN — The founder of this family was William Fithian. Tradition
says he was a native of Wales and a soldier in Cromwell's army, and
was present at the execution of Charles i; after Charles II was
restored he had to fly for his life; he came to Boston, thence to
Lynn, thence to East Hampton, L. I. Some account of his
descendants is given in Howell's History of Southampton, L. I. Fish
— Charles Fish hved in Freehold, 1733. It is probable he came from
Long Island. FoRMAN, FoEEMAN, FuEMAN— The flrst of this name,
probably, in New Jersej^, was George Foreman, who, in 1681,
bought with John Inians and others, 640 acres near, or at what is
now New Brunswick and west of the Raritan river adjoining
Matthews' Inchan purchase. In Monmouth county the first of this
family appear to have been Samuel Forman and Aaron Forman who
are named as early as 1688, and Thomas 1691. May 24th, 1695,
Thomas Foreman and Mary Allen, both of Monmouth, were licensed
to marry by Governor Andrew Hamilton. The license is now
preserved in the hbrary of the New Jersey Historical Societj^ The
first Foremans in America were John and Giles Firmin, who came
over with the Pilgrim Fathers in Governor Wiuthrop's fleet, 1630.
They came from Sudbury, Sufliolk county, England. The first named
Jonathan Foreman of Monmouth, who was an early member of the
Brick Church at Marlborough, married Margaret Wykott", dau. of
Cornelius Wykoff who was son of Peter and founder of the Wykoff
family. In Monmouth county, some have expressed the of)inion that
the Formans of Monmouth descend fro m John Foreman, the Scotch
refugee from persecution, whose name is given in
 XXVlll HISTORY OP MONMOUTH AKD OCEAN COUNTIES.
Whitehead's History of Perth Amboy, and who came over in 1685;
but the writer can tind nothing to sustain this theory. The
commission of Da\-id Forman as High Sheriff of Monmouth county,
1780, is filed in the Ubraiy of the New Jersey Historical Society.
General David Forman, the well remembered hero of Monmouth, is
said to have been the fourth son of Joseph and Elizabeth Lee
Forman. He was b. Nov. 3, 1745. His father was a wealthy shipping
merchant of New York and afterwards retired from business and
settled on a farm in New Jersey. Gen. Forman m. Feb. 28, 1767, Ann
Mar.sh, dau. of Wm. Marsh, of Maryland. He d. Sept. 12, 1797, aged
52 years. His children (as givea by Miss Anna M. WoodhuU) were: 1.
Sarah Marsh Forman, b. Feb. 1, 1773, d. Jan. 18, 1799; m. her
cousin, Major Wm. Gordon Forman (son of Joseph, of Shrewsbury,),
who was a graduate of Princeton, and died at Lexington, Ky., 1812.
2. Rivine Forman m. James, son of Ool. John Neilson, of New
Brunswick, leading an only dau., who m. Eev. George Grifiin. 3. Ann
Forman, who m. Dr. Jonathan Longstreet, of Monmouth. 4. Emma
Forman m. Eobert, son of General Oirmmings, of Newark, N. J. 5.
Malvina Forman, living in Fauquier county, Va., 1873, aged 85, who
owned the jiortraits of her parents, jjainted by Rembrandt Peale. The
will of David Forman of Freehold, dated Feb. 24th, 1802, proved
1813, speaks of him as "being anshant" ; it names w. NeUe's sons
Jonathan, Tunis and Samuel; daus. Anna Lloyd. Jonathan's son Da\id
; Samuel's son David. FoxALL — In 1677, the i^roprietors, under
concessions, granted to John Hance 240 acres of land in right of
John Foxall. Fkeeborn — Gideon Freeborn was awarded a share of
land 1667. He was of Portsmouth, near Newport, R. I., and was
probably related to William Freeborn, who is named among the
freemen at that place 1655. The proprietors' Records at Perth
Amboy, show that in 1677 a warrant for land was issued to Gideon
Freeborn and wife, and again in 1681. Feench — Philip French in
1736 bought 100 acres of John Antonides. This is an ancient West
Jersej' name. In 1670 John French, mason, had 15 acres of land at
Woodbridge. In 1689 Thomas French had 621 acres from West
Jersey proprietors, and other tracts at different dates. In 1694
Thomas French, Jr., had land from them. In 1737 Thomas French
had 96 acres in Mansfield and Richard French had 140 acres in
Mansfield. Mrs. Blackman says that the ancestor of the Little Egg
Harbor family of the name was Francis French, who settled at Bass
River before the Revolution. Fkeneau — Philip Freneau was a
resident of Mt. Pleasant, near JMatawan. He was b. in Frankfort
street. New I'ork, Jan. 2, 1752. The family was of Huguenot descent.
Pierre Freneau, the father of Philip, was at one time of South
Carolina. He bought a large tract of land near Mount Pleasant where
his son Philip removed to in 1794. The father and grandfather of
Philip are buried in Trinity chirrch yard. New I'ork. Philip Freneau,
when about 30 yrs. old, m. Eleanor Forman, dau. of Samuel. Gen.
Jonathan Forman and Denise Forman were her brothers. They had
four daughters. He graduated at Princeton in same class as did Jas.
Machson. He died from ex^josure Dec. 18. 1833. An account of his
life and literary labors is published in "Old Times in Old Monmouth."
Fkythowaet — Aaron Frythowart, weaver, bought land 1721 of Major
James Hubbard, Middletown. FuLLEKTON — Jamcd FuUerton is
named as a juror 1692. He may have been the James Fullerton who
at Woodbridge, March, 1684, was bj' a resolution in town meeting
"to be entertained as schoolmaster." Thomas and JHobert Fullerton
were among Scotch refugees from persecution who came to Perth
Amboy; the first-named with his w. and ten servants, and Robert
Avith nine servants, arrived in October, 1684. They were brothers of
the Laird of Kennaber and located themselves with Thomas Gordon
and others on Cedar Brook, about eight miles west of Amboy.
Gaediner — Richard Gardiner of Tintern Manor is named about 1680.
 GENEALOGICAL RECORD. XXIX In 1683 he bought land of
Morgan Brj'an; 1685, Feb. 17, he had conveyed to him by proprietors
100 acres of land at "Old Woman's Hill" in Middletown township. He
was appointed clerk of Monmouth county 1683 and continued until
1687. Joseph and Richard Gardiner are called sons-in-law by William
Winter, in his will 1722. A family of Gardiners of Rhode Island and
said to have descended from Sir Thomas Gardiner, whose son,
Joseph Gardiner, came to this country mth first settlers; was b. 1601
and d. in King's county, Rhode Island, 1679. He left six sons; the
fourth, George, d. a. 94; some of the family settled on Long Island.
Gaontt — Zachary Gauntt of Sandwich, Mass , was among the
original purchasers of land, 1667, but he seems to have settled at
Newport, R. 1. He had brothers Annanias and Israel who came to
Monmouth and Annanias' son removed to Burlington county. In
Bishop's "New England Judged" an ancient Quaker work published in
London, 1703, it is said that Peter Gaunt, Ralph Allen, AVilliam Allen
and Daniel Wing were fined twenty shillings each for not taking oft'
their hats in court, and distress to the value of five pounds taken to
satisfy the fine. This was about 1658. The same work adds that from
Peter Gaunt was taken five kine, two heifers £30; one mare, two
three-year-old steers, £12, eight bushels peas, £l-4s; four bushels
Indian corn and one-half bushel wheat 10s 6d — £43 lis 6d, and
other laws made to rob them of their goods. Zachary Gaunt of
Sandwich sold his share of land in Monmouth to his brother
Annanias, Jan. 30, 1668. GtBESON, Gdiberson — In 1693, John
Gibbonson and Daniel Hendrick of Fiatbush, L. I., sold land to
William Whitlock. John Gabeson was jtiror, 1699. In 1701, John
Gysbertson of Middletown, sold 104 acres of land to Peter Wyckott'of
Kings county. Long Island. Sep. 21, 1717, "John Gysbertse of
Neversink, in the township of Orosswicks in the Jersies," conveyed to
his brother Harman of Fiatbush, a house, barn, orchard and garden
in Fiatbush. After the Revolution, among land owners in what is now
Ocean county, were Hezekiah Giberson and B. Giberson. About 1820
to '30 John Guiberson's saw mill, in what is now Ocean countj', was
on Tice Van Horn's brook. Gibbons — Richard Gibbons, one of the
twelve men to whom was granted the Monmouth Patent, was an
early settler of Gravesend, L. I., where he was held in such good
estimation as to be chosen arbitrator in disputes. 1688, May 10,
Mordecai Gibbons had 540 acres confirmed to him in right of his
father. In 1693, he was named as ensign in the militia, Richard
Gibbons, the founder of this family, while on Long Island, signed his
name Richard Gibbine, as stated by "Tunis G. Bergen. In Monmouth
he signed it Richard Gibbings. Glffoed — William Gifford is named as
being assigned a share of land in Monmouth among the original
purchasers in 1667-70. He was probably the William Gift'ord who
about that time lived at Sandwich, Mass. In 1658-9 he was fined £57
19s. for refusing to swear allegiance and he, Geo. Allen and Richard
Kirby and other Quakers were quite prominent at Sandwich previous
to and about the time the first settlers came to Monmouth. The will
of William Gifford, founder of the family in this country, was
probated March 2, 1687. It is said by Bristol county descendants that
the Gifford family trace their origin back to the Conquest. At the
battle of Hastings, A. D. 1066, Sire Randolph de Gift'ord was a
standard bearer of William, the Conqueror; a descendant named Sir
Ambrose Gifford had a son, VValter, who came to America in 1630
and was founder of the American Branch. GooDBODT — William
Goodbody is named in court proceedings 1693 as juror and also in
the suit. In 1698 he bought land of Joseph Lawrence and in 1701 of
John Stewart and Elizabeth, his w. His will was dated April 6, 1703.
GoKDON — Thomas Gordon is occasionally mentioned in Freehold
records as King's Attornej^ and in connection with other business.
He was a native of Pitlochie, Scotland, and arrived in the Province of
New Jersey in Oct., 1684, with his w. Ellen, and four children. A
sketch of his life is
 XXX HISTORY OF MONMOUTH AND OCEAN COUNTIES.
given in Whitehead's History of Perth Amboy. In 1715 John Salter, ot
Freehold, deeded 120 acres to Peter Gordon, of same town. In 1753
Hon. Kichard Halter had this deed recorded. In 1774 Elizabeth
Gordon, dan. of Thomas, m. John Salter, son of the Hon. Richard
above named. Hon. John B. Gordon, U. S. Senator from Georgia,
probably descended from a native of Monmouth county. Judge Gyrus
Bruen, now in the 89th year of his age, thinks that he is a
descendant of a brother of Ezekiel Gordon, who formerly resided on
the Battle Ground, and well known in Freehold. The brother
preferred to remove to Georgia, and was at one time a merchant in
Savannah. In Freehold, 1776, David Gordon and William Goi-don
were named in list of inhabitants taxed In Christ Church gi-aveyard,
Middletown, are tombstones to the memory of Jos. Gordon, who d.
1841 in his 69th year; to his w., Euth, in her 42d year, 1811, and to
other members of the family. GotiLD — Daniel Gould of Newport, E.
I., with Joshua CoggshaU, paid for a share of land 1667. He did not
settle, however, here. He was a deputy to the Ehode Island Colonial
Legislature 1673, and Governor's assistant 1674. In 1677 he had a
warrant for 120 acres of land in Monmouth under proprietors'
concessions.. GoDLDiNG, GoLDiNG — W^ilUam Goulding was one of
the twelve men to whom was granted the Monmouth patent 1665. It
is supjjosed that he tirst settled in New Amsterdam, now New York,
as he owned land there in 1643. In the original di\asion of town lots
in Middletown, 1667, he was given lot 25 and also outlands. He sold
his town lot and meadows to Kichard Hartshorne, the deed for which
was acknowledged Nov. 25, 1672. In Freehold records his name is
signed Will. Golding. Joseph Golden or Goulding is next named in
Freehold records. He bought 13U acres of land near Schenck's Hill,
Middletown, of James Hubbard, Dec. 4, 1704; in 1709 himself and
w. Anneke Da-\ds were members of the Old Brick Church,
Marlborough; he was grand juror 1713, etc. It is supposed that
WilUam Goulding, the Monmouth patentee, was one of Lady
Deborah Moody s friends, who left Massachtisetts on account of
Puritan persecutions. The name is an ancient one in Massachusetts.
Geandin— In 1720 Daniel Grandin bought land of Eichard Salter. In
1728 Daniel Grandin of Freehold, " Practitioner of Law," deeded land
to Sarah Powell, who he calls sister-in-law. Among tombstones in old
Topanemus graveyard are some erected to the memorj' of members
of the Grandin family. In sirrveys about 1755, recorded in
proprietor's office, Perth Amboy, of land in what is now Brick
township, " Grandin's Folly is occasionally referred to as a landmark,
but no explanation is given of the origin of the term. - In the
Revolution, Daniel Grandin was a Loyalist officer in the New Jersey
Royal Brigade. Grant — J ohn Grant settled in Avhat is now Ocean
county, between Toms River and (.Jedar Creek before 1764, as in
that year he was named among taxable inhabitants of old
Shrewsbury township. He is frequently' named in old records of
deeds. John Grant of Monmouth had license to marry Sarah Irons,
Nov. 3, 1750. Gkeen — In 1684, Sarah Reape sold to i\.biah Edwards
all her claim to land of Henry Green. "Widow Green is named in a
suit in court, 1705. John Green bought land of Stej^hen Colver,
1716. Elizabeth Green of Squan, was deceased in 1730, in which yeir
letters of administration were granted on her estate to her son and
heir Joseph Gilford. In 1764, Henry Green and Henry Green, Jr. ,
were taxed in Shrewsbury township. Grover — James Grover was
one of the twelve men to whom was granted the Monmouth Patent,
1665, and he came to the county with the tirst settlers who are
named, 1667. He was granted home lot number sixteen, in
Middletown and outlet number fifteen. He was among the first
settlers of Gravesend, L. I., in 1646. He was collector for the poor,
1650. About 1654-5, James Grover, George Baxter and James
Hulibard, prefering English to Dutch rule, hoisted the Enghsh fiag at
Gravesend, declaring themselves subjects of the Eeijublic of
England. Baxter and Hubbard sent Grover to England bj'^ way of
Boston, in 1656, to take a memorial to
 GENEALOGICAL EECORD. XXXI Oliver Cromwell. Baxter and
Hubbard were arrested as traitors by the Diiteh and sent to Fort
Amsterdam and where they were liberated by Gov. Stuyvesant at the
earnest solicitation of Lady Deborah M oody. Under ihe Proprietors'
Concessions, Grover received in 1676, a warrant for 500 acres of
land as one of the twelve men named in the Monmouth Patent.
James Grover, Sr., died aboiit the beginning cf the year 1686. He had
three sons and two dans. Safety Grover, a son, and wife had a
warrant for 120 acres of land in 1679, from the Proprietors finder the
Concessions. 1684, July 26, Safety Grover and Richard Hartshorne
were the only ones in Middletown who voted against swine rnnning
at large on the commons. Among inhabitants taxed in Middletown,
1761, were James Grover, Esq., James Grover and Silvenns Grover.
In Upper Freehold, 1758, Joseph Grover was taxed for 420 acres of
land. GuLicK — Hendrick Gtilick bonght land in Middletown of Wm.
Mernll May 22, 1704, being probably the same tract which Merrill
bonght of Richard Stout, Jr., and Frances, his w., in 1687. The first of
the Gitlick family in this countrj' were Jochem and Hendrick. Jochem
came in 1653. Hendiick's name appears the same year as a witness
to a bajitism in the old Dxitch Reformed Church of New York.
Jochem Gulick bought land at Six Mile Run, in Middlesex county,
previous to 1717, where he owned 330 acres, situated on both sides
of Ten Mile Brook. Peter lived in Middlesex county and had four sons
and four daus. and d. near Franklin Park. Samuel Gulick, a brother of
Abram, had four sons, Hiram, Joachim, Isaac and John. The Ocean
county Giihcks, it is said, descend from Jacobus, who at one time
lived at Pleasant Plains and then removed to Rhode Hall, where he
kept the main hotel and stage house between New York and
Philadelphia. He had children : Joachim, Cofneliiis, Abram (or
"Brom," as the Dutch called him,'), John, Jacobus and Isaac. Isaac
settled at Toms River about 1794, and m. Abigail Hatfield, a widow
with one child. Isaac Gulick and w., Abigail, had five sons, viz :
James, Stephen, Abner and William. Abner and William m., removed
to Ohio and d. there, leaving issue. Nimrod moved to Tuckahoe, N.
J., where he d., leaving issue Stephen (from whom some of these
items are derived) lived at Toms River and then in Berkeley
township, and outlived all of the rest. James, who was the first judge
appointed in Ocean county, was b. at Cranbury, in Middlesex countj',
Jan. 9, 1793, the j^ear before his father removed to Toms River, and
he d. July 5th, 1855. He had sons : John Hatfield (at one time
Svirrogate), Sidney, Henry Clay, Horatio and «another. Horatio was
County Collector. Stephen, above named, was brother of Judge Jas.
Gulick. In 1797 Isaac Gulick sold Dillon's Island to Abraham and
George Parker, and in deed says he bought it 1794 of John Imlay.
Members of the Gulick family became noted as missionaries and
some settled in the Sandwich Islands, where, about 1870, Chas. T.
Gulick held an official position in the Custom House. Hall — John Hall
was awarded a share of land 1670. He was probably from
Portsmouth, R. I., as a John Hall is named there among original
settlers. In 1702 Benjamin Hall, of Freehold, bought land of John
Boude. In 1722 John Hall was a witness to Avill of Richard
Hartshorne. HaictHT— About the first of this name mentioned in
New Jersey records were Nicholas, Jonathan, David and John
Haight, sons of Samuel Haight of Flushing, L. I., who in 1717, sold
land at Amboy to George VN'illicks. The father, Samuel Haight of
Fhashing, was a prominent Quaker; he d. in 1712. William Haight
bought land in Monmouth in 1795 of Michael Parker and Sarah, his
w., and widow Abigail Bowman of New York. This William Haight had
brothers Joseph, Charles and John. Charles settled at Long Branch.
William Haight had son Thomas G. , who was father of Gen. Charles
Haight of Freehold. Haines, Haynes — Charles Hayres is named in
1671, in an agreement with Randall Huet about a sloop. In 1676 he
had patent for 200 acres of land and meadow. The same year, 1676,
Charles Haynes of Sussex, Delaware, formerly of Middletown,
deeded land granted by Carteret 1676 to WiUiam Clark.
 XXXll HISTORY OF MONMOUTH AND OCEAN COUNTIES,
Halsey — Jesse Halsey of Stafford bought land 1779 from Joseph
Emley. He was at one time Jiistice of the Peace in Stafford. The
Halsey family were early settlers in Essex county, and Joseph was
perhaps the first named. Members of the family early settled on
Long Island. In the tax list of Southampton, L. I., 1683, among
taxjjayers were Thomas Halsey, Isaac Halsey and Josiah Ealsey. A
large amount of genealogical information of blanches of the Halsey
family is to be foi;nd in the published records of the Presbytt-rian
church of Morristown. Hamilton — Robert Hamilton is named as
juror 1678. In 1679 he is named as living in New York. In 1682 he
bought land in Middletown of Jacob Truax. "At the ( ourt of Sessions
at Middletown, March 22, 1687, the commission of Robert Hamilton
as Clerk of the Peace was read. He is called Mnjor at this time.
Andrew Hamilton was Governor of East and \\ est Jersey, and also
Lieut. -Governor of Pennsylvania from 1701 to 17U3, and d. April 26
of the latter year. Hampton— John Hampton came to this country,
probably in 1683, as it is stated in Perth Amboy records that his
children Jane, Elizabeth, Lideah, John and David were "imported"
that year. His plantation in Monmouth is referred to in 1687. The will
of David Hampton of Freehold dated Sept. 16, 1710, was proved
Feb. 27, 1711. lu 1764, John Hampton and James Hampton were
assessed in old Shrewsbury township. Wilham Hampton was
assessed in Freehold, 1776. John Hampton was licensed to marry
Lidy Hankinson, March 9, 1761. Hance — John Hance was amtmg
original settlers of Monmouth 1667. He was Deputy and overseer at
a coiirt held at Portland Point, Dec. 28, 1669. Sept. 1 670, he
covenanted to make a pair of stocks for the town, for which he was
to receive twelve shilhngs and sixpence. During the brief sway of the
Dutch in 1673, he was appointed " schepen " or magistrate by them.
In 1676, he received a warrant for 330 acres of land. The will of
John Hance was dated March 24, 1707, proved Jan. 27, 1710. It
states that he was of Shrewsbury. Tradition says that John Hance
came originally from Wales. But it is evident that he had lived many
years in Dover, New Hampshire, before he came to Monmouth. After
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