Table Of ContentAdvances in Ocular Toxicology
Advances in Ocular Toxicology
Edited by
Keith Green
Medical College of Georgia
Augusta, Georgia
Henry F. Edelhauser
Emory University
Atlanta, Georgia
Robert B. Hackett
Alcon Laboratories, Inc.
Fort Worth, Texas
David S. Hull
Medical College oj"Georgia
Augusta, Georgia
David E. Potter
Morehouse School of Medicine
Atlanta, Georgia
and
Ramesh C. Tripathi
University of South Carolina School ofM edicine
Columbia, South Carolina
Springer Science+Business Media, LLC
Llbrary of Congress Catalog1ng-ln-Publ1catlon Data
Advances in ocular toxicology I edited by Keith Green ... [et al.].
p. cm.
·Proceedings of the Fifth Congress of the International Society of
Ocular Toxicology. held October 13-17, 1996, in Asheville. North
Carollna"--T.p. verso.
Includes bibliographical references and index.
ISBN 978-1-4613-7720-7 ISBN 978-1-4615-5937-5 (eBook)
DOI 10.1007/978-1-4615-5937-5
1. Ocular toxicology--Congresses. 1. Green. Keith.
II. International Society of Ocular Toxicology. Congress (5th
1996 Asheville. N.C.)
[DNLM, 1. Eye--drug effects--congresses. 2. Toxicology--methods-
-congresses. 3. Eye Injuries--congresses. 4. Eye--metabolism
-congresses. 5. Toxic;ty Tests--congresses. WW 525 A244 1997]
RE901 . T67A38 1997
617.7' l--dc21
DNLM/DLC
for Library of Congress 97-16694
CIP
Proceedings of the Fifth Congress of the International Society of Ocular Toxicology,
held October 13 - 17, 1996, in Asheville, North Caro lina
ISBN 978-1-4613 -7720-7
© 1997 Springer Science+Business Media New York
Originally published by Plenum Press in 1997
Softcover reprinl of Ihe hardcover 1s i edilion 1997
http://www.plenum.com
AII rights reserved
\0987654321
No part of this book may be reproduced, slored in a retrieval system, or transmitted in any form or by any
means, electronic, mechanical, photocopying, microfilming, recording, or otherwise, without written
permission from the Publisher
To Myra
for all the years of love, care,
encouragement and support,
and without whom the Congress
and this resulting text would
not have been possible
-Keith
PREFACE
This volume represents the proceedings of the Fifth Congress of the International
Society of Ocular Toxicology (ISOT), which was held at the Grove Park Inn and Resort in
Asheville, North Carolina, October 13-17, 1996. We are delighted to present this volume
to the ophthalmic community, especially those with a significant interest in ocular toxicol
ogy. The Fifth Congress was developed around themes relating to ocular drug metabolism,
the ocular pathophysiological effects of nitric oxide, government issues relating to the use
of alternative methods for toxicity testing, and a workshop that encompassed comparisons
of both in vitro versus in vivo models as well as different animal models.
The outcome of this congress, embodied in this volume, is a contribution to the
methodologies currently employed or under development and to various drug or physical
effects on different ocular tissues. While the focus of this proceedings is on ocular effects
of drugs or other materials, many of the contributions deal with topics that have a much
broader interest. The workshop concerning the use of different model systems and the
choice of the best animal model for drug testing covers a wide range of interests that ex
tends far beyond specific ocular effects. This is especially true in the area of alternative
methods and in the choice of the best animal model for examination of different disease
entities. This information will prove of value in the performance and assessment of studies
designed to determine drug, or other chemical, effects on the eye that will be used to pro
vide data pertinent to the protection of human health.
The editors of this volume, who are members of the Congress Organizing Commit
tee, thank the presenters, who gave their time, experience, and knowledge that made this
gathering a success. The discussions in this volume contain the essence of the presenta
tions and provide the material given orally or in poster format in an excellent manner.
Our thanks go to all participants, who offer a broad range of backgrounds, varying
from regulatory, industrial, and academic interests, for their attention to detail and their
contemporary contributions. This is one of the unique aspects of our society, where the in
termingling of individuals with such varied backgrounds can exchange information, ideas,
and concepts. These exchanges enable each of us from different environments to remain
fully conversant with the advances in other areas and to maintain an overview of the field
of ocular toxicology. We are particularly grateful to all of the workshop presenters and
discussants for their frank and open interactions that added so much to the outcome of this
session. All of the contributing authors require a special expression of gratitude for meet
ing deadlines imposed by the volume's editors so that the text could be as contemporary
as conceivably possible. Their rapid responses to requests for any component related to
the chapters not only kept the courier mail services in business, but also facilitated pro
gress in finalizing the present text.
vii
viii Preface
Once the workshop was recorded and transcribed and editorial changes were made
(many through the process of one of us [Keith Green] listening to all of the tapes while
reading the transcript), further editorial revision and rewriting of certain portions for clar
ity followed. Each presenter and/or discussant then performed his or her own readjust
ments of the already twice-editorialized remarks. These changes were again retyped and
reread by the workshop editors to arrive at the present chapters. We hope that this contri
bution, which contains the information in a relatively informal style, will be of interest
and value to many readers. We retained the style of oral presentation rather than that of
formal manuscripts because this reflected the tone of the workshop and the interaction be
tween the participants. Each participant, if contacted, will gladly provide references to any
quotes or citations of results.
A glance at the List of Participants will show the almost equal geographic distribu
tion between Europe and North America, as well as a similar distribution pattern between
academic and industrial representation. This same ratio applies to the membership of the
society, indicating a broad range of interests. Our meetings, held every two years, offer an
excellent forum for informational exchange on various aspects of ocular toxicology. This
year was no exception, as there was almost universal participation of the attendees in pa
per and poster discussions.
We also thank the generous corporate sponsors whose contributions helped make the
congress run successfully. Without their assistance and support, the congress would have
not had many of the scientific contributions that made the meeting such a setting for the
exchange of information. These funds are an essential part of the meeting, since they al
low the organizers latitude in providing an atmosphere where the interchange of ideas is
foremost.
Finally, many thanks are due to Ms. Brenda Sheppard, who was responsible for tran
scribing the entire workshop (over 100 pages) retyping the participants' amended remarks.
She was also responsible for typing many other parts of this text, including at least two
chapters, the index, and other components. Her dedication to this enormous task, as well
as her efforts before, during, and after the meeting, is appreciated by us all.
The next congress of the society will be held during the summer of 1998 (sometime
in the period of mid-September to mid-October) in Riom, France. Dr. Pierre Duprat, ISOT
president, will act as the host for this meeting. Announcements will be made as decisions
concerning the specific dates for the congress precipitate.
K. Green
H. F. Edelhauser
R. B. Hackett
D. S. Hull
D. E. Potter
R. C. Tripathi
BOARD OF DIRECTORS, INTERNATIONAL
SOCIETY OF TOXICOLOGY, 1995/1996
President Professor Keith Green, Augusta, Georgia
President-Elect Dr. Pierre Duprat, Riom, France
Past-President Dr. Ingo Weisse, Ingelheim/Rh, Germany
Secretary-Treasurer Professor Ramesh C. Tripathi, Columbia, South Carolina
Directors Dr. Hiroshi Suda, Osaka, Japan
Dr. Nobuo Takahashi, Ishikawa, Japan
Professor Eberhart Zrenner, Tiibingen, Germany
BOARD OF DIRECTORS, INTERNATIONAL SOCIETY OF
TOXICOLOGY, 1997/1998
President Dr. Pierre Duprat, Riom, France
President-Elect Professor Ramesh C. Tripathi, Columbia, South Carolina
Past-President Professor Keith Green, Augusta, Georgia
Secretary-Treasurer Dr. Robert B. Hackett, Fort Worth, Texas
Directors Dr. Masami Kojima, Ishikawa, Japan
Dr. Nobuo Takahashi, Ishikawa, Japan
Professor Eberhart Zrenner, Tiibingen, Germany
ORGANIZING COMMITTEE, FIFTH CONGRESS, ISOT,
OCTOBER 13-17, 1996
Chairman Professor Keith Green, Augusta, Georgia
Members Professor Henry F. Edelhauser, Atlanta, Georgia
Dr. Robert B. Hackett, Fort Worth, Texas
Professor David S. Hull, Augusta, Georgia
Professor David E. Potter, Atlanta, Georgia
Professor Ramesh C. Tripathi, Columbia, South Carolina
ix
x Board of Directors
CORPORATE SPONSORS
Alcon Laboratories, Inc., Fort Worth, Texas
Allergan, Irvine, California
Boehringer Ingleheim GmbH, Ingelheim, Germany
Ciba Vision Ophthalmics, Duluth, Georgia
Gillette Medical Evaluation Labs, Gaithersburg, Maryland
Laboratoire Chauvin, Montpellier, France
Merck and Co., Inc., West Point, Pennsylvania
Pfizer, Centre de Recherche, Amboise, France
Procter & Gamble Co., Cincinnati, Ohio
Santen Pharmaceutical Co. Ltd, Osaka, Japan
Senju Pharmaceutical Co. Ltd, Osaka, Japan
CONTENTS
Welcome and Opening of Congress
Keith Green
I. Cytochrome P450 and Arachidonic Acid Metabolism in the Corneal Epithelium:
Role in Inflammation .......................................... 3
Michal Laniado Schwartzman
2. The Effects of l2(R)HETE and Its Metabolite 8(R)HHDTrE on Corneal
Endothelial Function . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 21
Henry F. Edelhauser, K. Keven Williams, Glenn P. Holley, and
Wendell D. Woods
3. Protein-Thiol Mixed Disulfides and Thioltransferase in the Lens: A Review. . . . 27
Marjorie F. Lou
4. Corneal Lesions in Beagle Dogs Given Oral 5-Ethynyluracil Followed by
5-Fluorouracil ................................................ 47
Robert L. Peiffer, Jr., and 1. E. Dillberger
5. Corneal Damage following Continuous Infusion in Rats: Possible Explanation
and Preventative Measures ...................................... 55
Olivier Loget, Camelia Nanuei, Jean-Fran90is Le Bigot, and Roy Forster
6. Ultraviolet Light-Induced Damage in Rabbit Corneal Epithelial Cells in Vitro:
Protection with Absorption Filters ................................ 63
Mercedes Palmero, Alfonso Blanco, Juan L. Bellot, Nuria Alcoriza,
Irene Perez, and Alfredo Orts
7. The Effects of ad Libitum (AL) Overfeeding and Moderate Dietary Restriction
(DR) on the Incidence of Spontaneous Corneal Dystrophy in Control
Sprague-Dawley (SD) Rats. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 73
M.-F. Hubert, Ph. Laroque, G. Durand-Cavagna, P. Delort, and K. P. Keenan
8. Barotoxic Effects on Morphology and Viability of Trabecular Cells: A
Preliminary Report ............................................ 81
Brenda 1. Tripathi, Ramesh C. Tripathi, Junping Li, Ying Qian, W. Kosnosky,
and K. V. Chalam
xi
xii Contents
9. Topical Fluorescein Application Can Induce Iritis and Glaucoma: An Unusual
Case Report . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 87
Clayton Bryan, Junping Li, Brenda J. Tripathi, K. V. Chalam,
Vytautas Al Pakalnis, and Ramesh C. Tripathi
10. Ocular Toxicity of Sodium Diethylthiocarbamate, DDTC, in the Beagle Dog . . . 93
Stephen Bistner, Tom Palmer, and Lydia Dickrell
11. Do Therapeutic Doses of Ethambutol Cause Optic Nerve Toxicity? 97
Dinesh Talwar, Randeep Guleria, Anant Pai, and S. P. Garg
12. Testing of Ocular Viscoelastics by Injection into the Rabbit Vitreous: Historical
Control Data Resulting from Various Dosing Techniques .............. 103
P. J. Upman, K. A. Herkowski, and M. J. Shepherd
13. Effects of Antiviral Agents on Retinal Function in Vertebrate Retina . . . . . . . . . . 107
C. Luke, P. Walter, K. U. Bartz-Schmidt, R. Brunner, K. Heimann, and
W. Sickel
14. Experimental Implantation of Devices for Electrical Retinal Stimulation in
Rabbits: Preliminary Results. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 113
Peter Walter, Peter Szurman, RalfKrott, Uta Baum,
Karl-Ullrich Bartz-Schmidt, and Klaus Heimann
15. Nitric Oxide in Ocular Inflammation .... . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 121
J. B. Allen, M. C. McGahan, L. N. Fleisher, G. J. Jaffe, T. Keng, and
C. T. Privalle
16. Role of Nitric Oxide in Vascular Dysfunction Associated with Ocular Diseases. . 133
Ronald G. Tilton
17. Effects of the Inhibition of Nitric Oxide Synthase and Lipoxygenase on the
Development of Endotoxin-Induced Uveitis ........................ 151
Juan L. Bellot, Nuria A1coriza, Mercedes Palmero, Alfonso Blanco,
Rafael Espi, Claude Hariton, and Alfredo Orts
18. Evaluation of Two Rabbit Ocular Implantation Models Using
Polymethylmethacrylate Intraocular Lenses .................... ;... 159
John N. Norton, Robert B. Hackett, and Robert J. Munger
19. Characterization of Immortalized Lens Epithelial Cells as a Potential in Vitro
Alternative Model for the Cellular Toxicity and the Efficacy Evaluations
of Ocular Drug Candidates ...................................... 169
C. Yao, D. Wampler, Guo-Tung Xu, D. Crouch, D. Rodeheaver, R. Hackett,
and J. Veltman
20. Immortalization and Characterizations of Rabbit Corneal Epithelial Cell Lines
as Potential in Vitro Alternative Models for Evaluating the Cellular
Toxicity of Ocular Drug Candidates. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 181
C. Yao, D. Wampler, K. Hall, D. Crouch, R. Hackett, J. Veltman, and
D. Rodeheaver
