A Carcinogenicity Bioassay of
Isobutyl 2-Cyanoacrylate (IBC) in
Fischer-344 Rats — Final Report
Larry D. Brown, DVM, LTC, VC
Paul W. Mellick, DVM, COL, VC
Catherine D. Smith, DVM, MAJ, VC
and
Don W. Korte, Jr., PhD, LTC, MSC
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January, 1990
Toxicology Series: 187
LETTERMAN ARMY INSTITUTE OF RESEARCH PRESIOFO OF SAN FRANCISCO CALIFORNIA 94129
\ Carcinogenicity Bioassay of Isobutyl 2-Cyanoacrylate (IBC) in Fisclier-344 Rats - Final
Report (Toxicology Series 187)-
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(U) A Carcinogenicity Study of
Rats — Final Report
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Isobutyi 2-Cyanoacrylate (IBC) in Fischer-344
Institute
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Toxicology Series No. 187
18. SUBJECT TERMS ( Continue on reverse if necessary and identify by block number)
Chronic Toxicity/ Isobutyl 2-Cyanoacrylate, IBC,
Bucrylate®,-,’Mammalian Toxicology, Tissue
Adhesive; Carcinogenicity Bioassav/ Rat^ ; -
19. ABSTRACT < Continue on reverse if necessary and identify by block number)
This report covers the results from the second year of a two-year
^ 1 inogen i c i t y bioassay of the tissue adhesive, isobutyl 2— cyanoacrylate
(IBC). Four hundred seven 6-week-old Fischer-344 rats were randomized into
three groups (control, 10 p.1 IBC, and 100 Jil IBC), each group containing both
male and female animals. ^The IBC was administered by surgical implantation of
the liquid monomer directly onto the ventral capsule of the liver. The
monomer was allowed to polymerize before two-layer closure of the abdominal
incision. Control animals received 100 ^1 of isotonic saline, also by
surgical implantation. All animals were examined daily, and weighed and
palpated monthly. „A dose-related increase in the incidence of clinically
observed intra-abdominal masses was evident among IBC-treated animals of both
sexes. In addition to the masses and the more permanent sequelae of the
surgical procedure (xyphoid protuberance, corneal opacity) , the animals
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19 (cont.) ^presented with a variety of transitory clinical signs sporadically
throughout the first and second year. These signs were observed in all dose
groups, and could not be attributed to compound administration. The weight
gain of the two IBC treatment groups was comparable to that recorded for the
control group.
Three hundred five animals remained on study at the start of the second
year. During the second year, 118 animals died or were sacrificed
prematurely. Twenty-one were unscheduled deaths and 97 were unscheduled
sacrifices. At the end of the second year, the 187 remaining animals were
sacrificed. All animals (118 unscheduled and 187 scheduled) were evaluated by
necropsy during the second year. One hundred eighty-four of the animals that
received the IBC had fibrotic adhesions between the liver and the omentum,
peritoneal membrane, diaphragm, stomach, skin, and/or intestine. These
lesions were characterized histologically as foreign body granulomatous
reactions. Thirty-one rats treated with IBC developed sarcomas during the
second year. The first sarcoma was detected on day 399 after intra-abdominal
administration of the test material. Twenty-one of 31 animals with sarcoma
died or were sacrificed in a moribund condition, while 10 animals with sarcoma
survived until terminal sacrifice. Twenty-seven of 31 animals with sarcoma
had grossly detectable masses at necropsy. Four sarcomas were detected only
by microscopic examination. The liver was the most frequently affected organ^^
(27 of 31 animals had lesions in the liver) . Four IBC-treated rats (2 low-
dose males and 2 high-dose females) had hepatocellular carcinomas of the
liver, while controls had none. F-344 leukemia or large granular lymphocyte
leukemia (LGLL) occurred in 62 animals distributed among all groups, including
controls. Solid-state carcinogenesis mechanisms are the most probable cause
for the sarcomas, but humans, unlike rodents, fail to elicit a solid-state
carcinogenesis effect. The incidence of hepatocellular carcinomas was twice
that reported for rats of the same strain and age, which provides reason for
concern. However, the incidence of this tumor was not statistically
significant and there was no dose-response pattern by sex. All other gross or
histopathological findings were considered incidental to IBC treatment, or
were sequelae of the surgical procedure.
Results of this study indicate that the ?? sence of IBC in the abdominal
cavity had no effect on survival, weight gain, jr the clinical condition of F-
344 rats during the second year following its implantation. IBC did produce
sarcomas in the abdomen of 16% of the animals. The sarcomas were attributed
to a solid-state effect which is not present in man. A nonstatistically
significant increase in hepatocellular carcinomas was observed in 4 IBC-
treated rats but there was no clear evidence that this could be attributed to
the IBC implants. ,, o j ^ p
"7'
.-p
ABSTRACT
This report covers the results from the second year of a
two-year carcinogenicity bioassay of the tissue adhesive,
isobutyl 2-cyanoacrylate (IBC). Four hundred seven 6-week-
old Fischer-344 rats were randomized into three groups
(control, 10 |il IBC, and 100 ^.1 IBC) , each group containing
both male and female animals. The IBC was administered by
surgical implantation of the liquid monomer directly onto the
ventral capsule of the liver. The monomer was allowed to
polymerize before two-layer closure of the abdominal
incision. Control animals received 100 |il of isotonic
saline, also by surgical implantation. All animals were
examined daily, and weighed and palpated monthly. A dose-
related increase in the incidence of clinically observed
intra-abdominal masses was evident among IBC-treated animals
of both sexes. In addition to the masses and the more
permanent sequelae of the surgical procedure (xyphoid
protuberance, corneal opacity) , the animals presented with a
variety of transitory clinical signs sporadically throughout
the first and second year. These signs were observed in all
dose groups, and could not be attributed to compound
administration. The weight gain of the two IBC treatment
groups was comparable to that recorded for the control group.
Three hundred five animals remained on study at the
start of the second year. During the second year, 118
animals died or were sacrificed prematurely. Twenty-one were
unscheduled deaths and 97 were unscheduled sacrifices. At
the end of the second year, the 187 remaining animals were
sacrificed. All animals (118 unscheduled and 187 scheduled)
were evaluated by necropsy during the second year. One
hundred eighty-four of the animals that received the IBC had
fibrotic adhesions between the liver and the omentum,
peritoneal membrane, diaphragm, stomach, skin, and/or
intestine. These lesions were characterized histologically
as foreign body granulomatous reactions. Thirty-one rats
treated with IBC developed sarcomas during the second year.
The first sarcoma was detected on day 399 after intra¬
abdominal administration of the test material. Twenty-one of
31 animals with sarcoma died or were sacrificed in a moribund
condition, while 10 animals with sarcoma survived until
terminal sacrifice. Twenty-seven of 31 animals with sarcoma
had grossly detectable masses at necropsy. Four sarcomas
were detected only by microscopic examination. The liver was
the most frequently affected organ (27 of 31 animals had
lesions in the liver) . Four IBC-treated rats (2 low-dose
males and 2 high-dose females) had hepatocellular carcinomas
of the liver, while controls had none. F-344 leukemia or
large granular lymphocyte leukemia (LGLL) occurred in 62
animals distributed among all groups, including controls.
i
Solid-state carcinogenesis mechanisms are the most probable
cause for the sarcomas, but humans, unlike rodents, fail to
elicit a solid-state carcinogenesis effect. The incidence of
hepatocellular carcinomas was twice that reported for rats of
the same strain and age, which provides reason for concern.
However, the incidence of this tumor was not statistically
significant and there was no dose-response pattern by sex.
All other gross or histopathological findings were considered
incidental to IBC treatment, or were sequelae of the surgical
procedure .
Results of this study indicate that the presence of IBC
in the abdominal cavity had no effect on survival, weight
gain, or the clinical condition of F-344 rats during the
second year following its implantation. IBC did produce
sarcomas in the abdomen of 16% of the animals. The sarcomas
were attributed to a solid-state effect which is not present
in man. A nonstatist ically significant increase in
hepatocellular carcinomas was observed in 4 IBC-treated rats
but there was no clear evidence that this could be attributed
to the IBC implants.
Key Words: Chronic Toxicity, Isobutyl 2-Cyanoacrylate, IBC,
Bucrylate®, Mammalian Toxicology, Tissue Adhesive,
Carcinogenicity Bioassay, Rat
ii
PREFACE
TYPE REPORT: Chronic Carcinogenicity Bioassay GLP Final
Report
TESTING FACILITY:
US Army Medical Research and Development Command
Letterman Army Institute of Research
Presidio of San Francisco, CA 94129-6800
SPONSOR: US Army Medical Research and Development Command
US Army Institute of Dental Research
Washington, D.C. 20307-5400
Project Officer: Eric S. Koppelman, COL, DC
PROJECT/WORK UNIT/APC: Tissue Adhesive Project,
35162775A825, WU 015, APC TL11
GLP STUDY NUMBER: 83009
STUDY DIRECTOR: LTC Don W. Korte, Jr., PhD, MSC
Diplomate, American Board of Toxicology
PRINCIPAL INVESTIGATOR: LTC Larry D. Brown, DVM, MPVM, VC
Diplomate, American College of
Veterinary Preventive Medicine;
Dipl., American Board of Toxicology
PATHOLOGISTS: COL Paul W. Mellick, DVM, PhD, VC
Diplomate, American College of Veterinary
Pathology (ACVP)
MAJ Catherine D. Smith, DVM, VC
Diplomate, ACVP
TOXSYS™/DATA MANAGER: Yvonne C. LeTellier, BS
REPORT AND DATA MANAGEMENT:
A copy of the final report, study protocol, retired
SOPs, raw data, analytical, stability, and purity
data of the test compound, tissues, microslides,
and an aliquot of the test compound will be
retained in the LAIR Archives.
TEST SUBSTANCE: Isobutyl 2-Cyanoacrylate (IBC), Bucrylate®
INCLUSIVE STUDY DATES (YEAR 2) : 30 January 1985 -
14 February 1986
OBJECTIVE: The objective of this study was to evaluate the
carcinogenic/tumorigenic potential of isobutyl 2-
cyanoacrylate in male and female Fischer-344 rats
subjected to lifetime (2-year) exposure to the
implanted test material.
iii
ACKNOWLEDGMENTS
Richard A. Spieler, RLAT (AALAS) , SGT Thomas W. Johnson,
and Nancy J. Smith assisted in the study. SSG James D.
Justus and staff provided animal and facility management.
Dianna B. Johnson provided office management and secretarial
assistance for this study and preparation of the report. LTC
William G. Rodkey, DVM, Diplomate, American College of
Veterinary Surgeons, COL William B. Carpenter, DDS, and LTC
Eric S. Koppelman, DDS, performed the requisite surgery in
support of this project. Histology technicians were Lucille
Cote and Marge Henderson. CPT Dan Brogdon, DVM, Ocular
Hazards Division, was the veterinary ophthalmology consultant
to this study. CPT Gary M. Zaucha, DVM, collated the final
report. CPT Robert E. Harris, DVM, provided assistance with
collating the final report.
PAUL W. MELLI^K, DVM / DATE
COL, VC
Senior Pathologist
C. DAHLEM SMITH, DVM / DATE
MAJ, VC
Assistant Study Pathologist
DEPARTMENT OF THE ARMY
LETTERMAN ARMY INSTITUTE OF RESEARCH
PRESIDIO OF SAN FRANCISCO. CALIFORNIA 94129-6800
ATTENTION OF;
SGRD-ULZ-QA 19 January 1990
MEMORANDUM FOR RECORD
SUBJECT: GLP Compliance for GLP Study 83009
1. This is to certify that in relation to LAIR GLP Study 83009
the following inspections were made:
23 August 1983
17 January 1984
23 January 1984
17 February 1984
26 March 1984
17 May 1984
05 July 1984
02 August 1984
29 January 1986
Protocol Review
Weighing
Weighing/Dosing
Observation/Weighing
Observation
Observation
Observation/Weighing
Weighing
Observation/Necropsy
2. The institute report entitled "A Carcinogenicity Bioassay of
Isobutyl 2 -Cyanoacrylate (IBC) in Fischer-344 Rats — Final
Report," Toxicology Series 187, was audited on 2 January 1990.
to
CAROLYN M. LEWIS
Diplomate, American Board of
Toxicology
Quality Assurance Auditor
vi
TABLE OF CONTENTS
Volume 1
Page
Abstract . i
Preface . iii
Acknowledgments . iv
Signatures of Principal Scier .ists . v
Report of Quality Assurance Unit . vi
Table of Contents . vii
INTRODUCTION . 1
Objective of Study . 1
MATERIALS . 1
Test Substance . 1
Animal Data . 2
Husbandry . 2
METHODS . 3
Group Assignment/Acclimation . 3
Dosage Levels . 3
Preparation of Compound . 3
Chemical Analysis of IBC . 3
Test Procedures . 4
Clinical Observations . 4
Pathological Examinations . 5
Statistical Analyses . 6
Duration of Study . 6
Changes/Deviations from Protocol . 6
Storage of Raw Data and Final Report . 6
RESULTS . 7
Mortality . . . 7
Clinical Observations . 16
Gross Pathology . 23
Microscopic Pathology . 24
DISCUSSION . 31
vii
TABLE OF CONTENTS (cont.)
Page
CONCLUSION . 34
REFERENCES . 35
APPENDICES . 38
Appendix A. Chemical Data . 39
Appendix B. Animal Data . 4 6
Appendix C. Surgical Report . 48
Appendix D. Historical Listing of Study Events . 54
Appendix E. Glossary of Terms for
Clinical Observations . 57
Appendix F. Individual Animal Histories . 64
Appendix G. Gross Necropsy Observations,
Incidence Summary . 369
Appendix H. Microscopic Observations,
Incidence Summary . 37 9
Appendix I . Glossary of Terms for
Pathology Findings . 402
Appendix J. Pathology Individual Animal Data . 466
OFFICIAL DISTRIBUTION LIST . 1150
viii
A Carcinogenicity Bioassay of Isobutyl 2-Cyanoacrylate
(IBC) in Fischer-344 Bats -- Final Report--Brown et al.
INTRODUCTION
Isobutyl 2-cyanoacrylate (IBC) is being evaluated by the
U.S. Army Medical Department as a tissue adhesive for use in
sutureless wound closure, oral and maxillofacial surgery, and
in other surgical procedures. The use of this modality could
provide a time-saving and sometimes life-saving dimension to
the management of combat wounds. The U.S. Army Institute of
Dental Research (USAIDR) has been assigned the mission of
evaluating the therapeutic potential of IBC. As part of
their mandate, USAIDR has tasked the Toxicology Branch,
Letterman Army Institute of Research (LAIR) , to evaluate IBC
in a chronic carcinogenicity bioassay.
Results from the first year of the study indicate that
IBC has no effect on survival, weight gain, or the clinical
condition of rats during the first year following its
implantation. The only gross or histopathological finding
observed in the first year that was attributed to the IBC
treatment was the presence of adhesions and a granulomatous
reaction of the liver and those adjacent organs that came in
contact with the IBC. No tumors were observed during the
first year that could be attributed to IBC treatment (1) .
This report will review salient features of the first year
and address findings that occurred during the second year of
this study.
Objective of Study
The objective of this study was to evaluate the
carcinogenic/tumorigenic potential of isobutyl 2-
cyanoacrylate in male and female Fischer-344 rats subjected
to lifetime (2-year) exposure of the implanted test material.
MATERIALS
Test Substance
Chemical Name: Isobutyl 2-cyanoacrylate (IBC),
Bucrylate®
Chemical Abstract Service Registry No.: 1069-55-2
Molecular Formula: C8HnN02
Brown et al. — 2
Molecular Structure:
/COOH
CH—C^
Additional information on the test substance is
presented in Appendix A.
Animal Data
Two hundred nine male and 210 female 4-week-old Fischer-
344 (CDF) rats were received for this study on 11 Jan 84 from
Charles River Breeding Laboratories, Inc., Wilmington, MA.
They were identified individually with ear tags numbered
84D00001 to 84D00209 (inclusive) for the males and 84D00226
to 84D00435 (inclusive) for the females. Four males and 4
females were selected randomly for quality control necropsy
evaluation at receipt. The animal weights on the day
following receipt (12 Jan 84) ranged from 30-57 g. During
quarantine, three underweight females and one maloccluded
male were submitted to necropsy on 20 Jan 84. Additional
animal data are presented in Appendix B.
Husbandry
Animals used in this study were housed at LAIR in the
Toxicology Suite, a restricted access facility. Rats were
caged individually in stainless steel wire-mesh cages in
racks equipped with automatically flushing dumptanks. No
bedding was used in any of the cages. The diet, fed ad
libitum, consisted of Purina Certified Rodent Chow® Diet 5002
(Ralston Purina Company, St. Louis, MO). Tap water was
provided by automatic water valves on a central line. Water
was analyzed quarterly for impurities, bacteria, physical and
chemical properties, organic residues, pesticides, and heavy
metals. The animal room temperature and relative humidity
were continuously recorded. The room was maintained at
temperatures ranging from 20.0°C to 25.5°C, with a relative
humidity range of 35% to 60%, except for short periods
(spikes) during which cleaning of the room altered the
relative humidity, and on six occasions when increases up to
70-86% occurred for 4-14 hours due to steam outages or
servicing of the ventilation system fans. The photoperiod of
12 hours of fluorescent light per day was electronically
controlled- Air changes, cage size, and husbandry conformed
to National Research Council Institute of Laboratory Animal
Resources standards (2) . The LAIR animal facility is
CH,
I 3
HC — CHj
CH3
Brown et al.--3
accredited by the American Association for Accredited
Laboratory Animal Care.
METHODS
This study was performed in accordance with the
protocol, applicable amendments, and cited operating
procedures including: LAIR Standard Operating Procedure 0P-
STX-81, "Chronic Bucrylate Bioassay Procedures within
Toxicology GLP Suite and Administrative Areas" (3) ; OP-STX-
73, "Chronic Carcinogen Bioassay" (4); and FDA Nonclinical
Laboratory Studies, Good Laboratory Practice Regulations (5) .
Group Assignment/Acclimation
Study rats were randomized on 19 January 1984 into two
experimental dose groups of 68 males and 68 females each, and
a saline control group of 68 males and 67 females.
Allocation was accomplished by using the Beckman TOXSYS™
Animal Allocation Program (Beckman Instruments, Inc.,
Somerset, NJ) . The animals were acclimated for 12 days
before the day of dosing. During this period they were
observed daily for signs of illness.
Dosage Levels
The following test doses were administered: high-dose
group, 100 |Xl IBC/animal; low-dose group, 10 p.1 IBC/animal;
and vehicle control group, 100 |Xl saline/animal.
Exspar at ion, of Compound
Bucrylate® IBC tissue adhesive (lot 929-252, Ethicon,
Inc., Somerville, NJ) was received from the sponsor on 10
January 1984 as 750 0.5 ml scored ampules in individual
overwrap sterile bags. The IBC required no preparation prior
to implantation. It was stored at LAIR at room temperature
under darkness. Dosing of control animals was performed with
commercial sterile isotonic (0.9%) saline (Lot No. 56-329-FD-
05, expiration date 1 Sep 86, Abbott Labs, Chicago, IL) .
Chemical Analysis of IBC
Ethicon, Inc., provided data on infrared,
chromatographic, and chemical analysis of the IBC (Appendix
A). Lot 929-252 contained 99.9% (w/w) total monomer. Before
dosing, the LAIR Analytical Chemistry Group verified the
identity of the IBC by IR spectroscopy, confirmed the purity
!
Brown et al . — 4
by gas chromatography, and demonstrated the stability of the
IBC during the dosing period (Appendix A) .
Test Procedures
The fixed volume of neat IBC or saline each animal
received was based upon its assigned dosage group, and was
administered directly onto the ventral (inferior surface)
capsule of the liver. High-dose animals received 100 ill of
IBC, low-dose animals received 10 |ll of IBC, and control
animals received 100 ill of saline. Rats were 6 weeks of age
at dosing. Since the surgical survival rate for implantation
of this compound was unknown, all animals, regardless of
size, were subjected to the surgical procedure and dosed to
ensure that sufficient numbers would be available for
inclusion in the chronic phase of the study. Body weights at
dosing ranged from 29 g to 123 g, with the mean male and
female weights at 94.0 g and 73.8 g, respectively.
The test compound was implanted under sterile conditions
in the LAIR Operating Room Suite on 23 and 24 Jan 84. The
surgical laparotomy implantation procedure was performed
under xylazine/ketamine anesthesia. Following anesthesia,
surgical preparation, and midline incision, the animal's
liver was exposed by "tenting” the abdominal wall with either
ophthalmic retractors or tissue forceps. The IBC was applied
to the ventral capsule of the liver, usually the caudate
lobe, by using either a sterile tip 100 Jll or 10 }il fixed
volume Eppendorf micropipette. The IBC was then allowed to
polymerize for 2-3 minutes before closure. All pipettes used
in the study were shown to be accurate within ±2%. A two-
layer closure of bioresorbable 4-0 Vicryl® (Ethicon, Inc.)
and skin staples or skin clips was used. After the animals
recovered to sternal recumbency, they were returned to the
Toxicology Suite. A complete surgical report is provided in
Appendix C.
Clinical Observations
On the day of dosing and during the following 2-week
period, animals were checked intermittently throughout the
day. During the first postoperative week, 25 animals were
removed from the study due to underweight condition and/or
complications. Three hundred eighty-two animals recovered
satisfactorily and remained on study as of 1 Feb 84. After
the animals were stabilized, observations for mortality and
signs of toxicity or illness were reduced in frequency to
twice daily. An observation was performed according to the
following procedure: (a) each morning all animals were
observed closely for signs of toxicity or illness without
Brown et al.
disturbing them in the cage; (b) once a week the animals (20%
cf them per work day) were removed from their cages and
observed; (c) animals were observed after being returned to
their cages. A second "walk-through, live/dead check"
observation was performed every afternoon with only
significant observations recorded. Monthly, a more detailed
clinical examination was performed, body weights were
obtained, and the abdomens of all animals were gently
palpated. These data were recorded electronically on a
Beckman TOXSYS™ Data Collection Terminal. Daily
observat ions/clinical signs were recorded on written records
and significant changes entered into the TOXSYS workstation.
TOXSYS software on the LAIR Data General Computers, Models
MV8000 and C330, was used to analyze clinical signs and body
weight data.
Pathological Examinations
Animals that were moribund at the time of clinical
examination were euthanized by pentobarbital overdose,
exsanguinated by axillary incision, and necropsied. During
the second year, 21 animals died unexpectedly (unscheduled) ,
and 97 unscheduled sacrifices were required. Additionally,
187 animals were submitted for sacrifice at the end of the
second year, 27 Jan - 14 Feb 1986. Gross necropsy
examinations were performed, and tissues were collected from
each animal in accordance with LAIR OP-STX-32, "General
Pathology Procedures", OP-PSG-7, "Necropsy Procedure — Gross
Examination of Small Laboratory Animals", and OP-PSG-12,
"Histopathology — Trimming of Rodent Tissues."
The pathologic evaluation consisted of gross and
microscopic examination of major organs/tissues and all gross
lesions from sacrificed animals and animals found dead. The
following organs/tissues were examined microscopically: eyes
and lens, skin, subcutaneous tissue, mammary gland, brain (4
levels: anterior cerebral, midcerebral, midbrain,
cerebellum) , middle ears, auditory canal, sebaceous gland,
trachea, lungs, nasal region, sternum, heart, aorta, salivary
glands (parotid, submaxillary, sublingual) , Harderian
lacrimal and intraorbital lacrimal glands, exorbital lacrimal
glands, liver (2-4 sections of various lobes), pancreas,
esophagus, stomach, duodenum, jejunum, ileum, cecum, colon,
rectum, kidneys, urinary bladder, accessory sex glands (male
only — prostate, seminal vesicle, coagulating gland,
epididymis), testes/ovaries, uterus (horns and body),
skeletal muscle (2 sections, longitudinal and cross) , sciatic
nerve, tongue, pituitary, thyroid/parathyroid, adrenals,
thymus, spleen (2 cross sections), mesenteric lymph nodes,
femur (bone marrow), and vertebrae with spinal cord (3
Brown et al. — 6
sections: cervical, thoracic, and lumbar). These tissues
were preserved in 10% buffered formalin, trimmed, embedded in
paraffin, sectioned, and stained with hematoxylin and eosin
prior to microscopic examination. Necropsy data were
recorded and entered into a Xybion™ (Xybion Medical Systems,
Cedar Knoll, NJ) computerized data acquisition program
designed for a DEC VAX™ 750 computer. Microscopic findings
were entered into the computer directly as microslides were
read. Since the Xybion animal-numbering system was
incompatible with the TOXSYS numbering system used during the
"in-life" phases of the study, the animals had to be
renumbered by the Pathology Section as they were necropsied
in order to enter them into the Xybion Pathology Data System.
A cross reference of animal identification numbers is
presented in Appendix J.
Statistical Analyses
Statistical analyses were performed on the study
results. TOXSYS System programs were used to determine the
group mean animal body weights (EDS002) and the frequencies
of clinical signs (EDS057-61) . The Xybion Pathology Data
System was used to generate the pathology raw data listings,
summary pathology reports, lesion frequency data, and
terminal body weights (group mean, standard deviation,
Bartlett’s Test, ANOVA, and Dunnett's Test). The incidence
of microscopic lesions for each test group were compared to
the control group using the Kolmogorov-Smirnov two-tailed
test. The 5% (p ^ 0.05) level of significance was used for
all tests .
Duration of Study
The "in-life" period for the second year of the study
ran from 30 Jan 85 until 14 Feb 86, when the terminal
sacrifice was completed. Appendix D is a complete historical
listing of study events.
Changes/Devlationa from, Protocol
Performance of this study was in accordance with the
protocol and applicable amendments.
Storage of Raw Data and Final Report
A copy of the final report, study protocol and
amendments, raw data, relevant SOPs, analytical data for the
test compound, and an aliquot of the test compound will be
retained in the LAIR Archives.
Brown et al.--7
RESULTS
Mortality
One hundred eighteen animals died or were sacrificed
prematurely during the second year of the study (controls, 13
males, 22 females; low dose, 16 males, 19 females; high dose,
27 males, 21 females) . Of these, 21 unscheduled deaths were
recorded and 97 animals were euthanized because they were
moribund, had infections, had lost weight, or were in poor
condition (Tables la - Id) .
TABLE la
Listing of Unschadulsd Dsaths/Euthanixsd* Animals
1 Fab - 30 Apr 85
Toxicology
Dose
Animal No.
84D00-
Date
Clinical Outcome
Sex
Group
376
13
Feb
85
Died in cage
F
High IBC
157
26
Feb
85
Died in cage
M
High IBC
296
15
Mar
85
Sacrificed, large**
intra-abdominal mass
F
High IBC
170
23
Apr
85
Sacrificed, alopecia and
skin scabbing/scaling
(infection control)
M
Control
428
23
Apr
85
Sacrificed, perivaginal
fistula & discharge
F
Control
* Animals were sacrificed to conserve tissues in face of
imminent death, for infection control purposes, or for
humane reasons .
**Large - £ 20 mm in diameter
Brown et al. — 8
TABLE lb
Listing of Unscheduled Desths/Euthanized* Animals
1 May - 31 Jul 85
Toxicology
Animal No.
84DQQ- _
Date
Clinical Outcome
Sex
Dose
Group
422
7
May
85
Sacrificed, severe
dehydration
F
Low IBC
156
9
May
85
Died in cage
M
High IBC
423
10
May
85
Sacrificed, large**
intra-abdominal mass
F
High IBC
181
10
May
85
Sacrificed, large
intra-abdominal mass
M
High IBC
109
19
May
85
Sacrificed, large
intra-abdominal mass
M
High IBC
384
31
May
85
Sacrificed, skin lesions
neck (infection control)
F
Control
129
5
Jun
85
Large intra-abdominal
mass
M
High IBC
275
14
Jun
85
Large intra-abdominal
mass
F
High IBC
326
1
Jul
85
Died in cage
F
Low IBC
431
8
Jul
85
Large intra-abdominal
mass
F
High IBC
430
9
Jul
85
Died in cage
F
High IBC
415
17
Jul
85
Pallor with palpable
splenic mass
F
Low IBC
193
21
Jul
85
Died in cage
M
High IBC
091
30
Jul
85
Died in cage
M
High IBC
* Animals were sacrificed to conserve tissues in face of
imminent death, for infection control purposes, or for
humane reasons .
**Large - £ 20 mm in diameter
Brown et al. — 9
TABLE lc
Listing of Unscheduled Deaths/Euthanized* Animals
1 Aug - 31 Oct 85
Toxicology
Animal No.
84D00-
Date
Clinical Outcome
Sex
Dose
Group
099
1
Aug
85
Large** intra-abdominal
mass
M
High IBC
149
1
Aug
85
Emaciated and dehydrated
M
Low IBC
301
1
Aug
85
Malocclusion
F
Control
191
1
Aug
85
Infected subcutaneous
mass
M
High IBC
286
2
Aug
85
Pallor with palpable
abdominal mass
F
High IBC
388
2
Aug
85
Pallor with palpable
abdominal mass,
died in cage
F
Control
147
16
Aug
85
Large subcutaneous
perihumeral mass
M
Low IBC
407
16
Aug
85
Large subcutaneous
mass on thoracic wall
F
Low IBC
279
20
Aug
85
Marked weight loss and
perianal staining
F
Low IBC
081
28
Aug
85
Large subcutaneous mass
M
High IBC
426
28
Aug
85
Pallor with weight loss
F
Low IBC
074
30
Aug
85
Large intra-abdominal mass
with excessive weight loss
M
High IBC
* Animals were sacrificed to conserve tissues in face of
imminent death, for infection control purposes, or for
humane reasons .
**Large » t 20 mm in diameter
Brown efc al. — 10
TABLE lc (COnt.)
Listing of Unschsdulsd Deaths/Euthanized* Animals
1 Aug - 31 Oct 85
Toxicology
Dose
Animal No.
84D00-
Date
Clinical Outcome
Sex
Group
102
30
Aug
85
Large** intra-abdominal
mass and pallor
M
Low IBC
108
30
Aug
85
Skin mass over maxilla
M
High IBC
151
30
Aug
85
Pallor with large
intra-abdominal mass
M
High IBC
327
30
Aug
85
Large intra-abdominal mass
F
High IBC
338
30
Aug
85
Large intra-abdominal mass
F
High IBC
180
9
Sep
85
Large intra-abdominal mass
with weight loss
M
Low IBC
288
9
Sep
85
Emaciated
F
Control
363
13
Sep
85
Oral discharge
F
Low IBC
389
13
Sep
85
Cardiac murmur with
weight loss
F
Control
032
19
Sep
85
Large subcutaneous mass
M
Control
404
23
Sep
85
Died in cage
F
Control
260
25
Sep
85
Enteritis with weight loss
F
Low IBC
059
26
Sep
85
Large subcutaneous mass
M
Low IBC
095
26
Sep
85
Large intra-abdominal mass
M
High IBC
* Animals were sacrificed to conserve tissues in face of
imminent death, for infection control purposes, or for
humane reasons .
**Large = £ 20 mm in diameter
Brown et
TABLE lc (cont.)
Listing of Unscheduled Deaths/Euthanised* Animals
1 Aug - 31 Oct 85
Toxicology
Animal No.
84DQQ- _
Date
Clinical Outcome
Sex
Dose
Group
104
26
Sep
85
Large** intra-abdominal
mass
M
High IBC
124
26
Sep
85
Large splenic mass
M
Control
266
3
Oct
85
Large subcutaneous
mass on neck
F
Control
069
3
Oct
85
Large intra-abdominal
mass with weight loss
M
High IBC
368
8
Oct
85
Severe pallor from
hemorrhagic enteritis
F
Control
199
16
Oct
85
Deteriorated condition
and large palpable
intra-abdominal mass
M
High IBC
278
17
Oct
85
Large subcutaneous
mass over humerus
Y
Control
166
17
Oct
85
Large subcutaneous mass
M
Control
084
24
Oct
85
Pallor, weak, depressed
M
Low IBC
080
24
Oct
85
Died in cage
M
High IBC
203
24
Oct
85
Pallor, large
intra-abdominal mass
M
Low IBC
424
25
Oct
85
Weight loss, dehydrated,
depressed
F
High IBC
* Animals were sacrificed to conserve tissues in face of
imminent death, for infection control purposes, or for
humane reasons .
**Large * i 20 mm in diameter
Brown et al. — 12
TABLE Id
Listing of Unschsdulsd Deaths/Euthanized* Animals
1 Nov 85 - 14 Fab 86
Toxicology
Animal No.
84DQQ- _
Date
Clinical Outcome
Sex
Dose
Group
139
5
Nov
85
Large** intra-abdominal
mass with weight loss
M
High IBC
416
5
Nov
85
Large intra-abdominal mass
with deterioration
F
High IBC
164
8
Nov
85
Weight loss
M
Control
320
15
Nov
85
Large intra-abdominal mass,
anorexic
F
High IBC
390
15
Nov
85
Anorexic, pallor
F
Control
146
18
Nov
85
Died in cage
M
Low IBC
343
19
Nov
85
Large intra-abdominal mass
F
High IBC
367
19
Nov
85
Large mass lower abdomen
F
High IBC
414
19
Nov
85
Large subcutaneous mass
F
Control
273
18
Nov
85
Weight loss, palpable
intra-abdominal mass
F
High IBC
322
23
Nov
85
Died in cage after monthly
palpation, large splenic
mass
F
Low IBC
365
23
Nov
85
Splenic mass, died in cage
F
Control
182
26
Nov
85
Large intra-abdominal mass,
pallor
M
Low IBC
* Animals were sacrificed to conserve tissues in face of
imminent death, for infection control purposes, or for
humane reasons .
**Large - £ 20 mm in diameter
Brown et al . --13
TABLE Id (cont.)
Listing of Unschsdulsd Deaths/Euthanized* Animals
1 Mov 85 - 14 Fab 86
Toxicology
Animal No.
84D0fi-
Date
Clinical Outcome
Sex
Dose
Group
290
26
Nov
85
Pallor
F
Control
036
3
Dec
85
Anorexic, weight loss
M
Control
334
3
Dec
85
Pallor and emaciated
M
Control
392
3
Dec
85
Emaciated and pallor
F
Low IBC
041
11
Dec
85
Emaciated
M
Low IBC
062
11
Dec
85
Large** intra-abdominal
mass, rapid weight loss
M
High IBC
030
18
Dec
85
Anorexic, emaciated
M
Control
033
19
Dec
85
Died in cage
M
Low IBC
070
23
Dec
85
Rapid weight loss
M
Low IBC
051
23
Dec
85
Weight loss
M
Low IBC
359
23
Dec
85
Died in cage
F
Control
200
24
Dec
85
Weight loss, circumoral
staining
M
Control
399
29
Dec
85
Anorexic, emaciated, skin
pallor
F
Low IBC
078
3
Jan
86
Emaciated, pallor, large
intra-abdominal mass
M
High IBC
* Animals were sacrificed to conserve tissues in face of
imminent death, for infection control purposes, or for
humane reasons .
**Large = £ 20 mm in diameter
Brown et al . — 14
TABLE Id (cont . )
Listing of Unscheduled Deaths/Euthanized* Animals
1 Nov 85 - 14 Feb 86
Toxicology
Animal No.
84DQQ- _
Date
Clinical Outcome
Sex
Dose
Group
114
3
Jan
86
Pallor, emaciated, large**
intra-abdominal mass
M
High IBC
185
3
Jan
86
Large intra-abdominal mass,
pallor
M
High IBC
328
3
Jan
86
Pallor and emaciated
F
Low IBC
060
9
Jan
86
Large intra-abdominal mass
M
Low IBC
289
11
Jan
86
Died in cage
F
Low IBC
257
13
Jan
86
Large subcutaneous tumor
F
Low IBC
324
13
Jan
86
Acute weight loss
F
Control
345
13
Jan
86
Emaciated
F
Low IBC
089
14
Jan
86
Died in cage
M
High IBC
100
14
Jan
86
Convulsed and died in cage
M
High IBC
120
14
Jan
86
Moribund
M
Control
117
14
Jan
86
Moribund
M
Control
053
16
Jan
86
Two large intra-abdominal
masses
M
Low IBC
039
16
Jan
86
Weight loss
M
Control
198
16
Jan
86
Large intra-abdominal mass
M
Control
* Animals were sacrificed to conserve tissues ir face of
imminent death, for infection control purposes, or for
humane reasons .
**La’-ge = £ 20 mm in diameter
Brown et al. — 15
TABLE Id (COnt . )
Listing of Unschsdulsd Osaths/Euthanizsd* Animals
1 Nov 85 - 14 Fab 86
Toxicology
Dose
Animal No.
84D00-
Date
Clinical Outcome
Sex
Group
413
16
Jan
86
Subcutaneous swelling
between anus and vulva,
intra-abdominal mass
F
High IBC
280
17
Jan
86
Pallor, enlarged spleen
F
Control
356
17
Jan
86
Malocclusion, weight loss,
intra-abdominal mass
F
High IBC
397
17
Jan
86
Pallor, enlarged spleen
F
Control
425
17
Jan
86
Deteriorated condition,
hypothermic, with weight
loss
F
Low IBC
418
17
Jan
86
Splenic and liver masses,
hypothermic
F
Low IBC
346
21
Jan
86
Moribund
F
Low IBC
412
21
Jan
86
Died in cage
F
High IBC
172
22
Jan
86
Died in cage
M
High IBC
393
23
Jan
86
Deteriorated condition
F
High IBC
432
23
Jan
86
Died in cage
F
High IBC
115
24
Jan
86
Moribund
M
High IBC
096
27
Jan
86
Emaciated, hypothermic,
severe respiratory problem
M
Low IBC
* Animals were sacrificed to conserve tissues in face of
imminent death, for infection control purposes, or for
humane reasons .
**Large = £ 20 mm in diameter
Brown et al . — 16
TABLE Id (cont.)
Listing of Unscheduled Deaths/Euthanized* Animals
1 Nov 85 - 14 Fab 86
Toxicology
Animal No.
84D0Q-
Date
Clinical Outcome
Sex
Dose
Group
361
29
Jan
86
Emaciated, intra-abdominal
mass
F
Low IBC
179
29
Jan
86
Deteriorated condition
M
Control
302
3
Feb
86
Two intra-abdominal masses
emaciated, pallor
, F
High IBC
330
7
Feb
86
Emaciated, pallor,
perianal stain
F
Control
331
7
Feb
86
Splenic mass, pallor
F
Control
403
10
Feb
86
Emaciated, sudden onset
conjunctivitis
F
Control
* Animals were sacrificed to conserve tissues in face of
imminent death, for infection control purposes, or for
humane reasons .
Clinical Observations
A glossary of terms for clinical observations is
presented in Appendix E. Individual clinical observation and
body weight data are presented in Appendix F. The majority
of animals gained or maintained body weight throughout the
first 8 months of the second year of the study (observation
periods 14-23) . During the final 4 months (observation
periods 24-27), slight decreases in group mean body weights
were observed for treatment and control group males.
Decreases were observed for the females only at terminal
sacrifice (fasted body weight) . Mean body weights of IBC-
dosed and saline-treated control animals were comparable
throughout the second year for both sexes. Tables 2 (male)
and 3 (female) present mean monthly body weights by group.
Clinical signs closely duplicating those seen during the
first year of the study (1) were observed throughout the
second year. With the exception of clinically observed
Brown et al. — 17
masses, signs were generally routine, of minor consequence,
and were distributed relatively equally among the treatment
and control groups. Clinical sign categories observed during
the second year included ocular abnormalities (179 of 305
animals affected), masses (145 of 305), skin/fur
abnormalities (129 of 305), general signs (69 of 305),
respiratory abnormalities (23 of 305) , genitourinary
abnormalities (14 of 305), behavioral aberrations (12 of
305), postoperative complications (5 of 305), and
miscellaneous observations (21 ear tag reactions, 2
malocclusions, 1 cardiac irregularity) .
With the exceptions of the masses, ocular abnormalities,
and the few iatrogenic postoperative complications (xyphoid
protuberance and abdominal/peritoneal fistula) , clinical
signs developed rapidly, and were relatively mild and of
short duration. An incidence summary of clinical signs is
presented in Table 4 .
TABLE 2
Group Moan Body Weights : Malta -
Yaar Two of Two-Year IBC Carcinogenicity Bioassay*
Date Observation High Dose Low Dose
Period IBC IBC
Saline
Controls
14
Feb
85
14
396.5
(50)
400.9
(55)
404.2
(57)
14
Mar
85
15
404.2
(49)
407.8
(55)
410.3
(57)
11
Apr
85
16
407.5
(49)
409.5
(55)
414.8
(57)
9
May
85
17
410.7
(49)
415.7
(55)
420.9
(56)
6
Jun
85
18
417.8
(45)
419.6
(55)
422.7
(56)
2
Jul
85
19
416.2
(45)
419.4
(55)
422.3
(56)
1
Aug
85
20
420.6
(43)
421.8
(55)
425.8
(56)
29
Aug
85
21
415.7
(40)
422.4
(53)
42 7.3
(56)
26
Sep
85
22
417.8
(37)
423.5
(51)
426.1
(55)
24
Oct
85
23
417.8
(33)
425.5
(50)
431.5
(53)
21
Nov
85
24
407.5
(31)
415.6
(47)
420.3
(52)
19
Dec
85
25
406.3
(30)
412.8
(45)
416.7
(50)
16
Jan
86
26
401.4
(25)
403.8
(41)
404.4
(47)
27 Jan -
5 Feb 86**
27
376.2
(23)
377.5
(39)
376.8
(44)
* Data are presented as group mean value in grams, with n,
the number of animals in each group, in parentheses.
** Final sacrifice period, fasted body weights
Brown et al . — 18
TABLE 3
Group Moan Body Haights : Famalas -
Year Two of Two-Yaar IBC Carcinoganicity Bioassay*
Date
Observation High Dose
Period IBC
Low Dose
IBC
Saline
Controls
15
Feb
85
14
232.7
(40)
227.8
(52)
225.3
(51)
15
Mar
85
15
241.0
(40)
233.2
(52)
231.9
(51)
12
Apr
85
16
248.7
(39)
240.3
(52)
236.4
(51)
10
May
85
17
255.4
(39)
245.2
(51)
244.8
(50)
7
Jun
85
18
261.2
(38)
252.1
(51)
246.8
(49)
3
Jul
85
19
263.8
(37)
256.8
(50)
253.1
(49)
2
Aug
85
20
270.1
(34)
264.1
(49)
261.1
(48)
30
Aug
85
21
274.6
(33)
265.8
(46)
263.6
(47)
27
Sep
85
22
281.2
(31)
273.1
(44)
273.2
(44)
25
Oct
85
23
281.2
(31)
276.5
(44)
273.8
(41)
22
Nov
85
24
281.4
(26)
278.9
(44)
274.1
(39)
20
Dec
85
25
281.6
(25)
278.2
(42)
276.5
(36)
17
Jan
86
26
279.1
(25)
278.0
(37)
274.1
(34)
7-
14 Feb
86**27
261.2
(19)
264.6
(33)
256.7
(29)
* Data are presented as group mean value in grams, with n,
the number of animals in each group, in parentheses.
** Final sacrifice period, fasted body weights
The clinically observed masses included intra-abdominal
masses, subcutaneous masses, inguinal masses, cutaneous
masses of the ear or scrotum, a maxillary mass, a subscapular
mass, a swollen maxilla, and splenomegaly. Of these, only
the intra-abdominal group could be correlated to IBC-
treatment. The intra-abdominal masses were primarily
associated with the ventral aspect of the liver. An
increased incidence of intra-abdominal masses was observed
for the males relative to the females, and a dose response
was apparent for both sexes .
The ocular signs (conjunctivitis, corneal opacity,
opaque lens, prolapsed lens, hyphema, ocular discharge/
chromodacryorrhea, microphthalmia, exophthalmus/enlarged
globe, iris tear, and dilated pupil) observed in many of the
animals (179 of 305) were sequelae to drying
(keratoconjunctivitis sicca) of the eyes during surgery
(Appendix C) . Corneal ulcers formed within 7-14 days. These
lesions healed, leaving persistent corneal scars.
Brown et al . — 19
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cutaneous mass ear/scrotum
subscapular mass
splenomegaly
Incidence Summary of Clinical Signs
Brown et al . — 20
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Brown et al . — 21
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Brown et al . — 23
Some animals also had conjunctivitis and
chromodacryorrhea which persisted for long periods.
Streptococcus faecalis, a common normal flora bacterium, was
cultured from the affected eyes. The consulting
ophthalmologist reported that this low-grade ocular infection
was limited to the globe and its accessory structures.
Therefore, no treatment was rendered. Other postsurgical
complications included xyphoid cartilage protuberance/nodule
(due to accidental incision of the xyphoid cartilage in some
animals while attempting to expose the liver sufficiently)
and peritoneal fistula. Significant postoperative
complications occurred in less than 5% of all animals.
Gross Pathology
Incidence summary reports for gross necropsy
observations during year two are presented in Appendix G.
Twenty-one animals, 10 males and 11 females, were found
dead, and 97 animals (46 males and 51 females) were
euthanized prematurely during the second year of the study.
Compound- related lesions (liver adhesions) were observed in
70 of 83 IBC-treated animals in the unscheduled group. One
hundred eighty-seven animals (106 males and 81 females)
survived to the end of the study and were euthanized.
Compound-related lesions (liver adhesions) were observed in
111 of 114 IBC-treated animals.
Dense, tough, fibrous adhesions were observed on the
capsular surface of the liver in 48/50 Group 1 (100 p.1 IBC)
males, 34/40 Group 1 (100 )ll IBC) females, 52/55 Group 2 (10
H.1 IBC) males, and 47/52 Group 2 (10 |ll IBC) females. The
microscopic characteristics of this test compound- related
inflammatory reaction are described in detail below in the
paragraphs dealing with histologic findings. Only 1/57 Group
3 (saline control) males and 3/51 Group 3 females had grossly
evident adhesions on the liver. The adhesions in control
animals were very fine, delicate strands in marked contrast
to the extensive, tough, fibrous areas observed in IBC-
treated animals .
Liver masses were observed grossly in 9/50 Group 1 (100
H.1 IBC) males, 13/40 Group 1 (100 fil IBC) females, 3/55 Group
2 (10 p.1 IBC) males, and 0/53 Group 2 (10 )ll IBC) females.
Grossly, these irregularly-shaped masses were usually white
to light yellow/gray in color, and very firm. In several
masses there was gross evidence of hemorrhage and/or
necrosis. Gross observation revealed no liver masses in any
Group 3 (saline control) male or female rats. In some of the
IBC-treated animals, masses were noted in organs other than
Brown et al . — 24
the liver, including the diaphragm, stomach, intestines,
other abdominal organs, and in the thoracic cavity. Gross
appearance of these extrahepatic masses was similar to that
of the liver masses. Histologic examination revealed that
masses in the liver and other sites were sarcomas arising in
the compound-related chronic inflammatory reaction. The
incidence of these tumors, a detailed histologic description,
and anatomic distribution is provided in the paragraphs below
dealing with histologic findings .
Microscopic Pathology
In the text of this report, the description of
histologic lesions is limited to those lesions that can be
attributed to administration of the test compound, and
lesions or disease entities that may affect results or
interpretation of results. A complete listing of all
microscopic findings (neoplastic and non-neoplastic) in this
study is provided in Appendix H. Appendix I is a glossary of
pathologic terms used in this study. It includes a
definition, a brief morphologic description, and criteria for
severity grades of all microscopic lesions observed in this
study .
Non-Neoplastic Lesions:
An incidence summary for all non-neoplastic lesions in
this study is presented in Appendix H. Non-neoplastic
lesions of statistically significant (p £ 0.05) incidence
include compound-related inflammatory reactions in the liver
and different locations of the gastrointestinal tract in both
males and females receiving the high dose of IBC, hepatocytic
vacuolization in high-dose females, the presence of red blood
cells and/or hemosiderin within lymph nodes of high-dose
males and females, and reactive hyperplasia of lymph nodes in
males and females in both high and low dose groups .
Compound-related inflammatory reactions were present in
nearly all animals in both high and low dose IBC groups.
Table 5 presents the incidence and distribution of these
lesions in abdominal viscera. In most animals, the lesions
were located at the site where the test material was placed,
i.e., on the capsule of the liver and the adjacent diaphragm.
Fewer lesions were present on surfaces of the stomach,
different portions of the intestinal tract, spleen, and
pancreas. The microscopic characteristics of compound-
related inflammatory reactions were similar in all sites. In
histologic sections, the test material was a clear, slightly
yellow, homogeneous crystalline material. Surrounding the
test material there was a granulomatous foreign-body reaction
Brown et al . — 25
characterized by infiltration of macrophages, lymphocytes,
and large multinucleated foreign-body giant cells within
abundant fibrous connective tissue. Usually this lesion was
limited to the serosal surface of abdominal viscera. In some
cases, there was necrosis of underlying tissues and
penetration of the serosal surface by the inflammatory
response accompanied by regenerative hyperplasia of cells of
the organ involved. In four rats, the presence of the
compound caused necrosis of the intestinal wall.
Regenerating cells of the intestinal mucosa migrated through
the submucosa ani muscular tunics of the intestine and were
entrapped in the adjacent fibrous, granulomatous inflammatory
TABLE 5
Distribution of Compound-Related
Inflammatory Reactions: Scheduled and Unscheduled
Animals Combined, Year 2
Group
(Number in Group)
CTLS*
(57)
MALE
It
(50)
2§
(55)
CTLS*
(51)
FEMALE
It
(40)
2§
(52)
Liver
0
48
52
0
40
45
Diaphragm
0
41
19
0
38
25
Jejunum
0
14
0
0
13
0
Stomach
0
6
0
0
12
0
Duodenum
0
7
0
0
6
0
Ileum
0
7
0
0
4
0
Pancreas
0
3
0
0
1
0
Cecum
0
4
0
0
1
0
Colon
0
3
0
0
2
0
Spleen
0
1
0
0
1
0
Abdominal Cavity
0
1
3
0
0
0
* CTLS = Saline controls
t Group 1 = 100 *ll IBC
§ Group 2 3 10 |ll IBC
Brown et al. — 26
tissues. In these cases, the entrapped cells had essentially
normal histologic characteristics, except for their location
and their association with mild degenerative and atrophic
changes. There were no indications of cellular atypia,
nuclear pleomorphism, or abnormal mitotic activity. These
lesions were present in the jejunum in two females and one
male in the high dose group, and in the duododenum in one
high-dose female. No intestinal lesions of this type were
observed in control animals.
The incidence of hepatocytic vacuolization was
statistically significant only in female rats in the high
dose group. Seventeen of 40 animals in this group exhibited
the lesion, as compared to 8 of 51 control females. In other
treatment groups, the lesion was present, but the incidence
was not statistically significant. Hepatocytic vacuolization
consisted of small-to-large cytoplasmic vacuoles within
hepatocytes. In sections appropriately prepared and stained,
fat could be demonstrated. The vacuolated hepatocytes were
not uniformly distributed in the liver.
The incidence of reactive hyperplasia in lymph nodes was
significantly greater in male and female rats in both high
and low dose groups compared to control animals. Reactive
hyperplasia consisted of non-neoplastic, noninflammatory
increases in cellularity in lymph nodes. There were
increased numbers of cells in perifollicular areas of the
cortex. Medullary cords and sinuses contained large numbers
of plasma cells. Eosinophilic, protein-rich edema fluid may
have been present .
The presence of red blood cells and/or hemosiderin
pigment in lymph nodes occurred with increased frequency in
both males and females in the high dose group. Table 6 shows
the incidence or these changes in lymph nodes.
Neoplastic Lesions:
An incidence summary for all neoplasms, both malignant
and benign, is presented in Appendix H. Sarcomas that arose
in the compound-related inflammatory reaction were the only
neoplasms that exhibited a statistically significant
incidence. Thirty-one rats treated with IBC developed these
tumors. Table 7 displays the distribution of these lesions
by treatment group, sex, and whether in scheduled or
unscheduled animals. The first animal necropsied with a
compound- related sarcoma died on 26 February 1985, day 399
after intra-abdominal administration of the test material.
Brown et al. --27
TABLE 6
Incidence of Reactive Hyperplasia,
Red Blood Cells and/or Hemosiderin
in Lymph Nodes, Year 2
MALE FEMALE
Group
CTLS*
It
2§
CTLS*
It
2§
(Number in Group)
(57)
(50)
(55)
(51)
(40)
(52)
Reactive Hyperplasia
8
25**
29**
7
25**
24**
RBC ' s and/or Hemosiderin
12
24**
18
15
28**
17
* CTLS = Saline controls
t Group 1 = 100 Hi IBC
§ Group 2 = 10 Hi IBC
**Entries flagged with (**' are significantly different from
control at the 0.05 significance level using Kolmogorov-
Smirnov Two-Tailed Test.
Of the 31 animals with compound- related sarcomas, 21 died or
were sacrificed in a moribund condition prior to scheduled
termination of the study. Ten sarcoma-affected animals
survived until terminal sacrifice. Only 27 of the 31 animals
with sarcomas had grossly detectable masses at necropsy.
Four sarcomas were detected only by microscopic examination.
These sarcomas involved many organs in some animals,
through either multicentric sites of origin, or local
invasion, or metastasis. The histologic characteristics of
these tumors were extremely variable. The entire spectrum of
histologic differentiation of mesenchymal tissue was
represented in this group of tumors. Some tumors were well-
differentiated fibrosarcomas, osteosarcomas, or myxosarcomas,
while others were very anaplastic and poorly differentiated.
In some lesions, multiple types of histologic differentiation
occurred in the same tumor. Of the 31 compound-related
sarcomas in this study, 13 were predominantly fibrosarcomas,
12 were anaplastic sarcomas, 5 were osteosarcomas, and one
was a myxosarcoma. One anaplastic sarcoma had an abundance
of chondrocytes and cartilaginous matrix. Two other tumors
I
Brown et al. — 28
TABLE 7
Sarcomas Arising in Compound-Ralatad
Inflammatory Reaction
Tima of Sacrifice: Unscheduled or Terminal, Year 2
Group
CTLS*
MALE
It
2§
CTLS*
female
It
2§
Total
Unscheduled
0
9
3
0
9
0
21
Terminal**
0
6
1
0
3
0
10
Total
0
15
4
0
12
0
31
* CTLS - Saline controls
t Group 1 = 100 Hi IBC
§ Group 2 = 10 Hi IBC
**Terminal or final sacrifice (scheduled animals)
had large areas that resembled rhabdomyosarcoma, but no cross
striations could be demonstrated in sections stained with
phosphotungstic acid-hematoxylii: stains. The liver was the
most frequently affected organ, but it was not involved in
every case. Twenty-seven of the 31 animals with these tumors
had lesions in the liver. In one rat, only the duodenum was
involved, one animal only had a tumor in the ileum, and in
another, the sarcoma was limiued to the stomach and spleen.
Table 8 lists the anatomic distribution of these compound-
related sarcomas. Because of the multiple sites of
involvement, the primary site for these lesions is coded as
the abdominal cavity, and involvement of each individual
organ is coded as a metastatic lesion. Using this method of
computer entry, it was possible to tabulate the occurrence of
these sarcomas and document the organs involved without
duplicating incidence. The diagnosis: "Presence of
Metastatic Sarcoma" is used only when it is certain that the
sarcoma developed within the reaction to the test material.
TABLE 8
Anatomic Distribution of Sarcomas Arising in
Compound-Related Inflammatory Reaction**, Year 2
Tissue
CTLS*
MALE
It
2§
CTLS*
female
It
1
Total
Liver
0
12
3
0
12
0
2 7
Diaphragm
0
8
2
0
10
0
i 9
Mediastinal
0
4
0
0
2
0
6
Jejunum
0
2
2
0
2
0
6
Spleen
0
2
2
0
1
0
5
Pancreas
0
3
1
0
1
0
5
Stomach
0
1
1
0
2
0
4
Duodenum
0
3
0
0
1
0
4
Ileum
0
3
0
1
0
4
Lung
0
1
0
/■N
1
0
2
Lymph Nodes
0
0
0
0
2
0
2
Kidney
0
0
0
0
1
0
1
Cecum
0
1
0
0
0
0
1
Colon
0
1
0
0
0
0
1
* CTLS = Saline controls
t Group 1 = 100 n.1 IBC
§ Group 2 = 10 |ll IBC
**Includes both primary and metastatic sites
Six rats in this study had fibrosarcomas that did not
arise in the compound-related inflammatory reaction. Four of
these were female (1 control, 1 high dose, and 2 low dose)
animals in which sarcomas occurred in the subcutaneous tissue
of the inguinal region. In three of these animals, the
tumors invaded the adjacent pelvic cavity and involved the
Brown et al. --30
rectum. One male control rat had a fibrosarcoma that was
limited to the cortex of one kidney. One male in the high
dose group had a fibrosarcoma surrounding the metal
identification tag in the pinna of the external ear. Three
females (2 control and 1 high dose) had endometrial stromal
sarcomas. These lesions did not resemble the sarcomas that
arose in compound-related inflammatory reaction.
Four IBC-treated rats (2 low dose males and 2 high dose
females) had hepatocellular carcinomas in the liver. The
morphologic characteristics of hepatocellular carcinomas are
well documented in the literature. For this study, the
criteria of Maronpot et al. (6) were followed. Important
features of these tumors included irregular shape, cellular
atypia, local invasiveness, haphazardly arranged cells, broad
sheets of cells, trabecular patterns, and glandlike
formations of tumor cells. Hemorrhage, necrosis, vascular
invasion, and metastases were observed in several of these
lesions .
Large granular lymphocyte leukemia occurred in 62
animals in this study. The group distribution of this
malignant tumor of lymphoid cells is shown in Table 9. The
histologic characteristics of this common neoplasm in
Fischer-344 rats are described in the Glossary of Pathologic
Terms, Appendix I.
TABLE 9
Large Granular Lymphocyte Leukemia
Time of Sacrifice: Unscheduled or Terminal, Year 2
Group
CTLS*
MALE
It
2§
CTLS*
FEMALE
It
2§
Total
Unscheduled
3
9
9
9
3
9
42
Terminal**
2
1
7
5
3
2
20
Total
5
10
16
14
6
11
62
* CTLS = Saline controls
t Group 1 = 100 Hi IBC
§ Group 2 = 10 (11 IBC
**Terminal sacrifice or scheduled animals
There was no statistical significance for the i: Lder.ce tf
this lesion; however, 42 animals died or were sacrificed ir. c
moribund condition because of the presence of this disease.
Many animals in this study developed a variety of
malignant and benign tumors. Tumors of the testes, endocrine
glands, and mammary glands were the most common. There was
no statistically significant increase in incidence for any of
these miscellaneous tumors in I3C-treated animals compared tc
controls .
The individual animal pathology reports are provided in
Volume 2, Appendix J.
DISCUSSION
This report records the findings from the second year of
a two-year carcinogenicity bioassay of IBC . This includes
complete clinical histories and gross and microscopic
pathological data on all unscheduled and scheduled (final
sacrifice) animals surviving the first year of the study.
Clinical findings during the second year indicated that
male and female animals treated with IBC gained weight at the
same rate as the control animals. These findings also
indicated that, as a whole, the animals in this study
remained relatively healthy throughout the second year.
Clinical signs observed during this period were a
continuation of those seen during the first year (1), and
generally were of little clinical significance. Ocular
conditions, which were secondary to desiccation of the eyes
during surgery, were limited to the globe and accessory
structures, and had no significant impact on the animals'
health. Other postsurgical complications, e.g., xyphoid
protuberance, were also insignificant to the outcome of the
study .
One hundred eighteen unscheduled animals died or were
euthanized at various times during the second year. These
animals exhibited more aging and compound-related
complications than did animals in the first year. IBC-
treated animals in the unscheduled group had compound-related
gross fibrous adhesions between the liver and the diaphragm,
abdominal wall, and/or visceral organs. A similar lesion was
observed in IBC-treated animals euthanized at the final
sacrifice (scheduled animals) . Microscopically, these
lesions were characterized as a foreign-body granulomatous
reaction involving the liver capsule and parenchyma.
Brown et al. — 32
Analysis of the results of this study indicates that the
intra-abdominal administration of IBC is related to the
development of sarcomas in Fischer-344 rats. Thirty-one
(16%) of the IBC-treated animals and none of the controls
developed these tumors. The major concern is the mechanism
by which the test material exerts its carcinogenic effect.
The results of this study do not indicate definitively
whether chemical carcinogenesis or solid-state carcinogenic
mechanisms were involved in the induction of these tumors.
Solid-state carcinogenesis is a phenomenon which has
been recognized for nearly fifty years (7) . There is a large
body of literature documenting the occurrence of this
phenomenon, and comprehensive reviews of this topic have been
published (8,9,10). Solid-state carcinogenesis involves the
development of sarcomas in the subcutis or abdominal cavity
of laboratory rodents that have had solid, smooth-surfaced
material implanted in these sites. A wide variety of
materials, including numerous plastics, cellophane, teflon,
metals, and glass have been shown to induce sarcomas by this
mechanism. The chemical nature of the implanted material is
irrelevant to the production of tumors. The characteristics
essential for tumor production are the size and form of the
implant. A smooth surface is essential. Solid-state
carcinogenesis occurs only when the implanted material is a
film, sheet, or other large form having a smooth surface. If
the same material is pulverized and administered as a powder,
no tumors result. The tumors develop in the fibrous,
granulomatous, foreign-body reaction that envelopes the
implanted material. The tumors that result are invariably
sarcomas that have diverse histologic variation.
The sarcomas that were present in rats implanted with
IBC in this study probably developed as a result of solid-
state carcinogenesis. The characteristics of the implanted
material, the anatomic sites involved, and the histologic
differentiation of the sarcomas fulfill the criteria for this
mechanism. However, since a group of animals implanted with
pulverized IBC was not included in the experimental design,
chemical carcinogenic mechanisms, though an unlikely cause of
the sarcomas, cannot be completely ruled out on the basis of
these results.
Six animals in this study had sarcomas that were clearly
unrelated to the test material. Four were invasive
fibrosarcomas observed in the subcutis of the inguinal region
in female rats. The inguinal fibrosarcomas probably resulted
from malignant transformation of the connective tissue stroma
of mammary glands. The incidence of these tumors does not
differ significantly from that in published reports. The
fibrosarcoma that was present in the external ear adjacent to
Brown et al . — 33
the metal identification tag in one animal is interesting in
that it may represent an additional case of solid-state
carcinogenesis in response to a foreign body. The presence
of one sarcoma in the kidney of a control rat is interpreted
as a spontaneous lesion unrelated to the experiment, and of
little consequence.
Four IBC-treated rats in this study (2 low-dose males
and 2 high-dose females) developed hepatocellular carcinoma.
No control animals exhibited this lesion. Although the
incidence of this malignant liver tumor was not statistically
significant, these results may have biological significance
and provide reason for concern. The incidence of
hepatocellular carcinoma for IBC-treated male rats in this
study was 1.9%, while the incidence for treated females was
2.1%. In published reports documenting tumor incidence,
hepatocellular carcinomas occur at a rate of 0.2% in female
and 0.8% in male control Fischer-344 rats (11-16) . However,
the increased incidence of hepatocellular carcinoma did not
follow a dose-response trend characteristic of hepatocellular
tumors induced by chemical carcinogens .
Sixty-two rats in this study developed large granular
lymphocyte leukemia, a common neoplasm of lymphoid tissue in
Fischer-344 rats. This disease has been well-studied and
characterized in the literature (17,18,19). The incidence
and characteristics of this disease in rats used in this
study did not differ significantly from published
information. Forty-two rats died with this disease prior to
scheduled terminal sacrifice. The premature deaths of these
animals probably had little or no impact on the results or
conclusions drawn from this study.
Most of the rats treated with IBC had gross adhesions
and fibrous, granulomatous foreign-body reactions on the
liver and adjacent organs that came in contact with the test
material. These lesions persisted for the normal life-span
of the rat. As noted in the interim report covering the
first year of this study, the physical presence of the
compound and attendant response may have affected the
function and patency of the intestinal tract. The increased
incidence of hepatocytic vacuolization in livers of treated
animals indicates possible alterations in metabolism of these
cells. Although such altered metabolism could be due to
chemical toxicity, it is just as likely the result of local
circulatory disturbances caused by the presence of the
compound and associated foreign body reaction. The increased
incidence of reactive hyperplasia, red blood cells, and
hemosiderin pigment in lymph nodes of treated rats is not
surprising. Such changes normally occur in nodes draining
areas of chronic inflammation.
Brown et al. — 34
The results of this study do not elucidate fully the
carcinogenic potential of isobutyl 2-cyanoacrylate. Although
the data suggest the sarcomas were induced by solid-state
mechanisms, they are not definitive because of a lack of a
dose group that received ground polymerized IBC. The
incidence of hepatocellular carcinomas in treated animals, at
a rate more than twice that reported for rats of the same
strain and age in other studies (although a statistically
nonsignificant incidence), gives cause for concern. Because
of the potential usefulness of IBC as a tissue adhesive in
surgical and dental procedures, additional studies designed
to evaluate fully the carcinogenic potential and mechanisms
of this material should be conducted.
CONCLUSION
During the second year of this two-year carcinogenicity
bioassay of IBC, there were no treatment-related changes in
survival, weight gain, or clinical condition of the rats.
Compound-related lesions observed in animals during the
second year included adhesions and/or local granulomatous
reactions of the liver or other abdominal organs, and liver
or other soft tissue tumors or neoplasia. An increased
incidence of sarcomas was attributed to the chronic
implantation of IBC in the Fischer-344 rat. There was no
clear evidence that the hepatocellular carcinomas observed
were attributable to the IBC.
Brown et al. --35
REFERENCES
1. Brown LD, Smith CD, Lollini LO, Korte DW. A
carcinogenicity bioassay of isobutyl 2-cyanoacrylate
(IBC) in Fischer-344 rats — one-year interim sacrifice
report. Toxicology Series 144. Institute Report No.
262. Presidio of San Francisco, CA: Letterman Army
Institute of Research, March 1988.
2. National Institutes of Health. National Research
Council. Guide for the care and use of laboratory
animals. (5th revised ed.) Bethesda, MD : U.S.
Department of Health, Education and Welfare, 1985; NIH
Publication No. 85-23.
3. Chronic bucrylate® bioassay procedures within toxicology
GLP suite and administrative areas. LAIR Standard
Operating Procedure OP-STX-81. Letterman Army Institute
of Research, Presidio of San Francisco, CA: 21 March
1984 .
4. Chronic carcinogen bioassay. LAIR Standard Operating
Procedure OP-STX-73. Letterman Army Institute of
Research, Presidio of San Francisco, CA: 9 November
1983.
5. Food and Drug Administration. Nonclinical laboratory
studies, good laboratory practice regulations, final
rule. In: 21 CFR 58. Washington, DC: Food and Drug
Administration, 22 Dec 1978; 43 FR 59986-60025.
6. Maronpot RR, Montgomery CA, Boorman GA, McConnell EE.
National toxicology program nomenclature for
hepatoproliferative lesions of rats. Tox Pathol 1986;
14:263-273.
7. Turner FC. Sarcomas at sites of subcutaneously implanted
bakelite discs in rats. JNCI 1941; 2:81-83.
8. Bischoff F, Bryson G. Carcinogenesis through solid
surfaces. Progr Exp Tumor Res 1964; 5:85-113.
9. Lawrence WH. Tumor induction. Chapter 17. in: von Recum
AF, ed. Handbook of biomaterials evaluation: scientific,
technical, and clinical testing of implant materials.
1st ed. New York: Macmillan Publishing Co, 1986:188-197
(66 references) .
Brown et al . — 36
REFERENCES (cont . )
10. Woodward SC, Salthouse TN. The tissue response to
implants and its evaluation by light microscopy. Chapter
30. In: von Recum AF, ed. Handbook of biomaterials
evaluation: scientific, technical, and clinical testing
of implant materials. 1st ed. New York: Macmillan
Publishing Co, 1986:364-378 (32 references).
11. Haseman JK, Huff J, Boorman GA. Use of historical
control data in carcinogenicity studies in rodents. Tox
Pathol 1984; 12:126-135.
12. Haseman JK, Huff J, Rao GN, Boorman GA, McConnell EE.
Neoplasms observed in untreated and corn oil control
groups of F344/N Rats and (C57BL/6N x C3H/HeN) FI (B6C3F1)
Mice. JNCI 1985; 75:975-984.
13. Salleveld HA, Haseman JK, McConnell EE. Natural history
of body weight gain, survival, and neoplasia in the F-344
rat. JNCI 1984; 72:929-940.
14. National Institutes of Health. National Toxicology
Program. Toxicology and carcinogenesis studies of
dimethyl morpholinophosphoramidate (CAS No. 597-25-1) in
F344/N rats and B6C3F1 mice (gavage studies) . Research
Triangle Park, NC: US Department of Health and Human
Services, January 1986; Technical Report Series NTP No.
298 (NIH No. 86-2554) .
15. National Institutes of Health. National Toxicology
Program. Toxicology and carcinogenesis studies of HC red
no. 3 (CAS No. 2871-01-4) in F344/N rats and B6C3F1 mice
(gavage studies) . Research Triangle Park, NC: US
Department of Health and Human Services, January 1986;
Technical Report Series NTP No. 281 (NIH No. 86-2537) .
16. National Institutes of Health. National Toxicology
Program. Toxicology and carcinogenesis studies of Cl
basic red 9 monohydrochloride (pararosaniline) (CAS No.
569-61-9) in F344/N rats and B6C3F1 mice (feed studies) .
Research Triangle Park, NC: US Department of Health and
Human Services, January 1986; Technical Report Series NTP
No. 285 (NIH No. 86-2541) .
17. Ward JM, Reynolds CW. Large granular lymphocyte
leukemia, a heterogeneous lymphocytic leukemia in F344
rats. Am J Pathol 1983; 111:1-10.
Brown et al. --37
REFERENCES (cont . )
18. Stromberg PC. Large granular lymphocyte leukemia in F-
344 rats. Am J Pathol 1985; 119:517-519.
19. Losco PE, Ward JM. The early stage of large granular
lymphocyte leukemia in the F-344 rat. Vet Pathol 1984;
21:286-291.
Brown et al. — 38
Page
Appendix A. Chemical Data . 39
Appendix B. Animal Data . 4 6
Appendix C. Surgical Report . 48
Appendix D. Historical Listing of Study Events . 54
Appendix E. Glossary of Terms for
Clinical Observations . 57
Appendix F. Individual Animal Histories . 64
Appendix G. Gross Necropsy Observations,
Incidence Summary . 369
Appendix H. Microscopic Observations,
Incidence Summary . 37 9
Appendix I. Glossary of Terms for
Pathology Findings . 402
Appendix J. Pathology Individual Animal Data . 466
Brown et al. --39
Appendix A: CHEMICAL DATA
Chemical Name: Isobutyl 2-cyanoacrylate
Other Listed Names: Bucrylate®, 2-cyano-2-propenoic acid 2-
methyl-propyl ester, 2-cyanoacrylic acid isobutyl ester,
bucrilate, IBC, IBCA*
Chemical Abstracts Service Registry No.: 1069-55-2*
Therapeutic Category: Surgical aid (tissue adhesive)*
LAIR Code: TP 60
Chemical Structure:
COOH
0=N
Molecular Formula: C8H11N02
Molecular Weight: 153.18
Physical State: Clear colorless liquid
Boiling Point: 170°C*
Stability: Stable in sealed ampules. Polymerizes within
minutes on contact with air. Polymerizes in less
than 1 second on contact with ionic solutions,
e.g., saline or blood.*
Name of Contaminants and Percentages: See chemical data sheet
attached
CH,
I /
HC— CH^-CH—C^
CH,
Source: Ethicon, Inc.
Somerville, NJ 08876
Lot No.: 929-252
Analytical Data/Purity:
Infrared spectrophotometry was performed on 11, 23, and
25 Jan 84, and the results were identical to the
standard spectrum from Ethicon, Inc. Major absorption
peaks were observed at 2965, 1740, 1470, 1385, 1290,
1190, 980, 930, and 715 cm"1.
Brown et al. — 40
Appendix A (cont.) : CHEMICAL DATA
Analytical Data/Stability:
Samples of isobutyl 2-cyanoacrylate (IBC) were evaluated
by gas chromatography on 11, 23, and 25 Jan 84. t Thus,
IBC was analyzed prior to dosing, on the first day of
dosing, and the day following dosing. The chromatogram
for each analysis showed only one peak, with a retention
time of 3.3 min. These data support the sponsor's claim
that the IBC will not deteriorate inside the sealed
ampules .
* Windholz M. Merck index. 10th edition, 1983. Monograph
number 1433, Bucrylate®. Page 201-202. Merck & Co, Inc,
Rahway, NJ.
t O'Connor RJ. Memorandum for record, 26 Jan 1984, Subject:
Analysis report, GLP Study No. 83009, Analytical Chemistry
Group. Letterman Army Institute of Research, Presidio of
San Francisco, CA.
Brown et ai . — 41
Appendix A (cont . )
CHEMICAL DATA
ETHICON
INC.
SOMERVULE . NEW JERSEY
January 6, 1984
To: Dr. W. D. Sheffield cc: Mrs. S. L. Couchman
Dr. A. W. Fetter
Mr. J. P. O'Donnell
Dr. D. W. Regula
Subject* BUCRYLATE TISSUE ADHESIVE
TUMORGENICITY STUDY
The following material is being transmitted to you for initiation
of the tumorgenicity study:
Lot #929-252 (750 ampules)
0.5 ml
IBC-2
One hundred twenty-five ampules have been included for stability
assurance testing and another one hundred twenty-five ampules for
long-term retention as required by GLP regulations.
Attached are the finished goods test results and a reference
infrared spectrum for this lot. The primary sterility run number
is R315001 and the overwrap sterility run number is R343MB2.
Please let me know if I can answer any questions.
mem
Attachment
Brown et al. — 42
Appandix A (cont.): CHEMICAL DATA
Finished Goods Test Results
Lot #929-252
Test
Identification, Infra-Red
Total Monomer, % (W/W)
SO2, ppm (W/V)
Hydroquinone, % - (W/W)
Isobutyl Cyanoacetate, ppm (W/W)
Color
NIR Absorptivity, mg/absorbance unit
H2O, ppm (W/V)
Heavy Metals as Lead, ppm (W/W)
Isobutanol , ppm (W/V)
Viscosity, cps at 30° C
Resul t
Conforms to standard
99.9.
562
0.081
None detected
0.046 at 400 nanometer
0.0002 from 400-800 nanometers
2.188
<100
<10
725
2.3
\
Reference #929-252
Analytical Service Request #20071
Brown et al. — 43
U
13
a
o
co
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a
id
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li.
Id
I
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Appendix A (confc.) : CHEMICAL DATA 2 >/3
a
a
HAVENUMBERS
Brown et al. — 44
Appendix A (cont.): CHEMICAL DATA
reply to
attention Of:
SGRD-ULV-AC
DEPARTMENT OF THE ARMY
letterman army institute of =-search
PRESIDIO OF SAN FRANCISCO, CALIFORNIA 94t29
26 January 1984
MEMORANDUM FOR RECORD
SUBJECT: Analysis Report, GLP Study No. 83009, Analytical Chemistry Group
Date: 26 Jan 84
Sample: IBC-2 (Isobutyl“2-cyanoacrylate)
Lot: 929-252
I. Identity
The Infrared Spectrums 131, 132, 133 (11 Jan 84), 135, 136, 137 (23 Jan 84),
and 138, 139, 140 (25 Jan 84) are consistent with the Infrared Spectrum provided
by ETHICON (SR 20071 - 12/22/83-DFB).
Instrument: Perkin-Elmer Model 457
Red Tag 2912
FSN 6650-C1 9-5014
Methods: Analytical method AD-100B, identification of isobutyl-2-
cyanoarcylates, analytical chemistry, ETHICON, Inc. (9/16/70), was
used as the basis for analysis* The Infrared Spectrums were done
in two different ways* The first followed the above method with
the following exceptions: KBr (potassium bromide) was used for the
window material and the reference cell was a variable path length
cell that was matched to the sample cell. The second method was a
"Neat” film of the sample between KBr windows* The film metho£
provided additional information including a peak near 800 cm
which was masked by the solvent in the first method.
II. Purity
The gas chromatographic profiles of IBC-2 showed one major component
representation 1001 of the total peak area when it was run on 11 Jan 84, 23 Jan
84, and 25 Jan 84.
Methods: Analytical method AD-100B, identification of isobutyl-2-
cyanoacralates , analytical chemistry, ETHICON, Inc. (9/16/70), was
used as the basis for the analysis.
Brown et al. — 45
Appendix A (cont.) : CHEMICAL DATA
SGRD-ULV— AC 26 January 1984
SUBJECT: Analysis Report, GLP Study No. 83009, Analytical Chemistry Group
Instrument: Varian 4600
Column: 3% SP-2100 on 100/120
Injector: 200°C
Detector: 250°C
Carrier Gas: Nitrogen (20 cc/min)
Run Length: 15 minutes
Detector: FID
Sensitivity: 10-11
III. Conclusion
The above data indicates that the IBC-2, Lot 929-252, has not deteriorated
in the sealed vials provided by ETHIC0N and is consistent with the data provided.
TvW\X'
RICHARD J. O’CONNOR
Research Chemist
Analytical Chemistry Group
Brown et al. — 46
Appendix B : ANIMAL DATA
Species: Rattus norvegicus
Strain: Fischer-344 (CDF)
Source: Charles River Breeding Laboratories, Inc.
Wilmington, MA 01887
Reared at Kingston (K62) plant
Sex: Male and female
Date of birth: 13 December 1983
Method of randomization: Weight biased, stratified animal
allocation (TOXSYS Animal
Allocation Program, SOP OP-ISG-24)
Animals in each group: 68 male and 68 female animals, except
female control group totaled 67
animals
Condition of animals at start of study: Normal
Body weight range at dosing: 29 g - 123 g
(male mean « 94.0 g; female mean =* 73.8 g)
Toxicology In-Life
Identification Procedures (TOXSYS) :
Ear-tagging procedure (SOP-OP-ARG 1) , tag numbers
84D00001 to 84D00209 (inclusive) for males and
84D00226 to 84D00435 (inclusive) for females.
Pathology Identification Procedures:
Animals were assigned a three-digit number for data
entry into the Xybion Data Acquisition Computer. A
cross reference list for the TOXSYS assigned numbers
was generated by the LAIR Comparative Pathology
Branch (Appendix J) .
Pretest conditioning: Quarantine/acclimation 11-22 January
1984
Justification: The Fischer-344 laboratory rat (versus the
Sprague-Dawley or Charles River CD rat) has proven to
be a sensitive and reliable model for chronic
carcinogenesis bioassays due to its low incidence of
spontaneous mammary gland and liver cancer. This
strain is recommended by the NCI Carcinogenesis
Bioassay Program.
Brown et al. — 47
Appendix B (cont . ) : ANIMAL DATA
Group Codes :
Group
Toxicology Code
Pathology Code
High-Dose IBC
(100 ^ll)
A* (Red) t
1 § (High)
Low-Dose IBC
(10 ^1)
B* (Yellow) t
2 § (Low)
Saline Control
(100 jxl)
C* (White) t
3 § (CTL)
* Alphabetic code used on 2 x 3 inch cage card and on
animal's chest during surgical phase.
t Plastic cage card protector contained a bar-coded animal
number (84D00 - ) and a 0.5 inch square piece of color
coded tape.
§ Numerical code used to group pathology data within Xybion
computer software.
Brown et al. — 48
SGRD-ULV-P
Appendix C: SURGICAL REPORT
30 March 1984
MEMORANDUM FOR RECORD
SUBJECT: Surgical Report, GLP Study 83009
1. On 23 & 24 January 1984, surgery was performed in the
Operating Room, LAIR, on 407 six-week-old acclimated Fischer-
344 rats assigned to the Toxicology Services Group's (TSG)
chronic two-year Bucrylate® Carcinogenesis Bioassay.
Surgeons involved were: COL Carpenter and LTC Koppelman,
USAIDR, and LTC Rodkey, LAIR. Surgery was performed under
LAIR GLP Protocol 83009.
2. Surgery was necessary to enable the test substance
(Bucrylate) to be applied directly to the surface of the
liver of study animals. Surgery on 179 males occurred on 23
Jan, and surgery on the remaining 25 males and 203 females
occurred on 24 Jan 84 .
3. Animals were transported, one rack of 60 rats at a time,
to the Operating Room Services Group (ORSG) Surgical Suite
from the Toxicology Services Group Animal Suite. Racks were
covered with sterile sheets to provide for infection control
and a dark, quiet, unstressed environment. Surgery started
at 0730 hours on 23 Jan with animal number 84D00001 and
progressed through animal numbers sequentially to 84D00434 .
Animals were randomly assigned to the three dose groups.
Animals were presented to the surgeons in a random fashion
without regard to group assignment. Animals were fasted
(from food only) 1-4 hours prior to surgery.
4 . Each animal was examined for health, checked to verify
identification (ear tag, cage card bar code, and group
assignment tape), and weighed on an Arbor scale (TOXSYS
terminal recorded) . The scale was recalibrated each morning
prior to use. Male animals weighed approximately 100 g and
females 75 g each. Anesthesia consisted of an intramuscular
hindlimb injection of a mixture of xylazine HC1 (10 mg/kg)
and ketamine HC1 (50 mg/kg) . Anesthetic was prepared by LTC
Rodkey by mixing 5 ml ketamine (100 mg/cc) , 2 . 5 ml Rompun®
(20 mg/cc) and 42.5 ml of sterile saline. Dose calculations,
lot, and expiration of anesthetics and diluent are provided
in Incl #1.
Brown et al. --49
Appendix C (cont.): SURGICAL REPORT
5. Proper identification and controls on group assignment
for dosing were stressed. Color coded tape, containing the
animal's number, was placed on the tail of the animal while a
"back-up system" letter signifying dose group was placed on
the chest of the animal with surgical marker pen (black CMS
fine tip marking pen, lot #138-800) . Animals were prepared
for surgery by clipping the abdomen and caudal ventral half
of the thorax with a number 40 Oster™ blade and Oster
electric clipper. Animal anesthesia, weighing, and clipping
were performed by TSG technicians under MAJ Morgan's
supervision.
6. Rats were placed on a rat restraining board in the supine
position and the clipped area was scrubbed with povidone-
iodine surgical soap and disinfected with povidone-iodine
solution and alcohol. The rats were moved to the surgery
table and draped so that only the surgically prepared area
was exposed. LAIR surgical operating procedures applicable
to instrument sterilization, aseptic technique, and sterile
field were in effect. Surgical packs were exchanged,
cleaned, and autoclaved after every 6 animals. Surgeons
changed gloves after every six animals, and dosing personnel
changed gloves frequently.
7 . A midline laparotomy incision was made extending 2-3 cm
caudal from the xyphoid cartilage. The liver was exposed by
the surgeon using either ophthalmic surgical retractors or by
"tenting" the abdominal wall with forceps. Bucrylate (Lot
929-252; Ethicon, Inc.) or sterile saline was applied to the
inferior surface of the exposed liver (usually caudate lobe)
in amounts specified in the protocol. Dose Group 1, the high
dose IBC group, received 100 microliters (|il) of isobutyl 2-
cyanoacrylate (IBC); Dose Group 2 (low dose IBC) received 10
|il of IBC, and Group 3 (saline control) received 100 p.1 of
sterile isotonic saline (Lot 56-32 9-FD-05, Exp. 1 Sep 1986;
Abbott) . Dosing was performed by TSG personnel using fixed
volume Eppendorf micropipettes (calibrated 17 and 18 Jan 84)
with sterile disposable tips. One ampule of Bucrylate was
used per animal for dose groups 1 and 2 — any remaining test
compound was discarded.
8. One animal (84D00126) was misdosed and immediately
removed from the study. After application of the IBC, the
abdominal walls were retracted or "tented" for approximately
two minutes to allow for drying of the test substance.
Dosing was monitored by the principal investigator, MAJ Brown
(TOXSYS ID 10186) .
Brown et al . — 50
Appendix C (cont.) : SURGICAL REPORT
9. The laparotomy incision was closed using two layers. The
first consisted of 4-0 Vicryl® (Ethicon, Inc.) in a simple
continuous pattern for the abdominal fascia, muscle, and
peritoneum. The skin was closed using either 35 mm
Proximate® (Ethicon, Inc.) skin staples or 35 mm Michelle
skin clips .
10. Animals were recovered in clean, rat rack cages in the
autoclave room adjoining the Surgical Suite. Room
temperature in the recovery area was warm (29 . 1-31 . 9°C) .
After approximately 2 hours in the recovery area, the animals
were transferred back to the TSG Animal Suite, and given
water and food.
11. Animals were monitored postoperatively by LTC Rodkey and
TSG staff. Skin staples were removed on 31 Jan and 1 Feb 84
(7-10 days) by TSG veterinarians. Twelve of the 407 rats
died or were removed from the study during the first week
after surgery due to underweight condition, surgical
complications, and/or obstructed intestine due to Bucrylate
adhesions. Postoperatively, rat #84D00013 acquired an
infection along the line of incision. After one week of
treatment with hydrogen peroxide, the incision healed.
Approximately 50 animals were noted to have corneal opacities
one week postoperatively. Keratoconjunctivitis sicca (dry
eye) and subsequent ulcerative keratitis are fairly common
sequelae to rat surgery. The etiology is thought to be
related to drying of the cornea as the globe protrudes, and
under anesthesia, the eyelids fail to cover the cornea and
the blink reflex is absent. Ophthalmic ointment is probably
indicated in all rodent procedures using general level
anesthesia .
12. Overall, the surgery went very smoothly and animals
tolerated the procedure well. On 1 Feb 84, 382 animals had
recovered — the initial goal was to have at least 360
survivors for the study.
13. Personnel assisting in the surgery are listed in Incl
#2. Study records are on file listing, by animal, the
amounts of anesthesia administered, surgeon, and dosing
personnel. Ms. Janice M. Adams, Manager, Regulatory Affairs,
Ethicon, Inc., audited the surgery on 23 & 24 Jan 84. CPT
Carroll, LAIR, QAO also visited the Surgical Suite during
this period.
Brown et al.-~ 51
Appendix C (cont.): SURGICAL REPORT
14. In preparation for surgery, a meeting was held between
ORSG and TSG personnel on 13 Jan 84. The Ethicon videotape
on the surgical procedure was reviewed and technicians
practiced the dosing procedure using Eppendorf micropipettes
and one ampule of Bucrylate. Pilot surgery was performed on
20 Jan 84 . Eighteen rats were operatively laparotomized and
dosed according to simulated group assignments.
Incl
as
CF:
COL Carpenter
LTC Koppelman
MAJ Korte
Raw data Binder, 83009
Chief, Operating Room Services Group
Diplomate, Am Coll Vet Surgeons
I
i
Brown et al. — 52
Appendix C (cont.): SURGICAL REPORT
Enclosure One to Surgical Memorandum For Record, 30 March
1984
ANESTHESIA GLP STUDY 83009
Rat wt
Xylazine*
Ketaminet
Vol Mixtures
80 g
0.4 mg
4 mg
0.4 ml
100 g
0.5 mg
5 mg
0 . 5 ml
120 g
0 . 6 mg
6 mg
0 . 6 ml
140 g
0.7 mg
7 mg
0.7 ml
* Rompun®, 10 mg/cc, Haver-Lockart , Shawnee, KS.
t Vetalar®, 100 mg/cc, Parke-Davis, Morris Plains, NJ.
§ Anesthetic mixture contained 10 mg ketamine and 1 mg
xylazine (Rompun®) /ml
Mixtures Components
Xylazine (Rompun®) 10 mg/kg, 20 mg/cc, (Lot 260013, Jan 85
Exp. )
Ketamine (Vetalar®) 50 mg/kg, 100 mg/cc, (Lot 03793p, Jul 88
Exp . )
Saline Diluent*, (Lot 7C856X9, Nov 84 Exp.)
§ Anesthetic Mixture Formula: 5 ml ketamine soln + 2.5 ml
xylazine soln + 42.5 ml saline * 50 ml anesthetic mixture
* viaflex®, 0.9% NaCl Injection USP, Travenol
Laboratories, Inc . , Deerfield, IL.
Brown et al. — 53
Appendix C (cont.): SURGICAL REPORT
Enclosure Two to Surgical Memorandum For Record, 30 March
1984
LAIR PERSONNEL WORKING ON SURGICAL PHASE OF GLP STUDY 83009
Personnel
Group
Duty
MAJ
Korte, Don W. Jr
Toxicology
Study Director
MAJ
Brown, Larry D.
Toxicology
Principal
Investigator
MAJ
Morgan, Earl W.
Toxicology
TOXSYS, Presurgery
Prep, Recovery
SFC
Farmer, Charles N.
Toxicology
Scheduling
SP5
Kellner, Thomas P .
Toxicology
Dosing
SP5
Mullen, Lawrence
Toxicology
Dosing
SP5
Rodriquez, Justo
Toxicology
Prep
PFC
Sano, Steven K.
Toxicology
Prep, Late Night
Recovery
Ms .
Lewis, Carolyn M.
Toxicology
Dosing
Ms .
Coppes, Valerie G.
Toxicology
Initial Recovery,
Prep
Mr.
Dacey, John
Toxicology
Dosing
Mr .
Spieler, Richard A.
Toxicology
Primary Animal
Caretaker
Ms.
Hernandez, Susan
Toxicology
TOXSYS, Prep
Mr.
Sands, Edward M.
Toxicology
Prep
LTC
Rodkey, William G.
Operating Rm
Surgery
SSG
Del la Cerda, Maria V.
Operating Rm
Surgery
SSG
Davis, Garry
Operating Rm
Surgery
SP5
Weber, David
Operating Rm
Surgery
SP5
Aiken, Byron
Operating Rm
Surgery
SP5
Cornier-Garcia Juan
Operating Rm
Surgery
SP5
Stevens, Daniel
Operating Rm
Surgery
SP4
Peterson, Kimothy
Operating Rm
Surgery
PFC
Rothhammer, Gregory A.
Animal Res
Group
Prep
Brown et al. — 54
Appendix D
Date
11 Jan 84
12 Jan 84
11 - 22 Jan 84
19 Jan 84
20 Jan 84
23 Jan 84 - 29
Jan 85
23 Jan 84
24 Jan 84
24 Jan - 1
Feb 84
24,25,26,27,
or 28 Jan 84
HISTORICAL LISTING 07 STUDY EVENTS
Event
209 male and 210 female Charles River
(CDF) Fischer-344 rats were received.
Animals were checked for physical
condition, sexed, individually caged,
and fed.
Rats were ear-tagged and weighed.
Eight rats (4 male and 4 female) were
submitted for necropsy quality control.
Animals were observed daily during
quarantine/acclimation period.
Animals were weighed and randomized
into dose groups.
Three underweight animals and one
maloccluded animal were sacrificed.
All animals were observed twice daily
throughout the study for clinical signs
and mortality.
One hundred seventy-nine animals were
weighed, provided with
ketamine/xylazine anesthesia,
surgically laparotomized, and implanted
with IBC or saline according to dose
group .
Two hundred twenty-eight animals were
weighed, provided with
ketamine/xylazine anesthesia,
surgically laparotomized, and implanted
with IBC or saline according to dose
group .
All animals were observed frequently
during the 7-day postoperative
recovery period.
Twenty-five animals either died or were
sacrificed during the postoperative
period because of complications or
underweight conditions.
Brown et al. — 55
Appendix D (cont . ) : HISTORICAL LISTING OF STUDY
EVENTS
Date
Event
1 Feb 84
3 Feb 84 -
27 Jan 85
3,31 Mar, 8 Apr,
9,18,19,27 Jun,
14,16 Jul, 15 Sep,
13 Dec 84
12,19,23 or
24 Jan 84,
28 or 29 Jan 85
16 or 17 Feb,
15 or 16 Mar,
12 or 13 Apr,
10 or 11 May,
7 or 8 Jun,
5 or 6 Jul,
2 or 3 Aug,
30 or 31 Aug,
27 or 28 Sep,
25 or 26 Oct,
22 or 23 Nov,
20 or 21 Dec 84,
and 17 or
18 Jan 85
28 - 29 Jan 85
30 Jan 85
30 Jan 85 - 10
Feb 86
Three hundred eighty-two (93.9%) of
407 rats that went to surgery remained
on study.
Seventeen unscheduled animals were
necropsied during first year of study -
14 sacrificed due to poor condition and
3 died in cage .
Steam outages occurred, or animal
suite ventilation fans were down.
Spikes in room temperature and small
drops in relative humidity occurred
during these periods.
All animals were weighed.
All animals were examined, palpated by
veterinarian or toxicologist, and
weighed at 28-day intervals (monthly) .
Interim sacrifice. Sixty animals were
weighed, sacrificed, and necropsied.
Three hundred five rats remain "on
study" for second year of study.
One hundred eighteen unscheduled
animals were necropsied during second
year of study - 97 sacrificed due to
poor condition and 21 died in cage.
Brown et al. — 56
Appendix D
Date
27 Apr, 21 Aug,
26 Oct, 2 Nov,
14 Dec 85, 7 Jan
14 or 15 Feb,
14 or 15 Mar,
11 or 12 Apr,
9 or 10 May,
6 or 7 Jun,
2 or 3 Jul,
1 or 2 Aug,
29 or 30 Aug,
26 or 27 Sep,
24 or 25 Oct,
21 or 22 Nov,
19 or 20 Dec 85,
16 or 17 Jan 86
27 Jan - 14 Feb
14 Feb 86
(cont.): HISTORICAL LISTING 07 STUDY
EVENTS
ElYent
Steam outages occurred, or animal suite
ventilation fans were down. Spikes in
86 relative humidity and small drops in
room temperature occurred during these
periods .
All animals were examined, palpated by
veterinarian or toxicologist, and
weighed at 28-day intervals (monthly) .
86 Final sacrifice. One hundred and
eighty-seven animals were weighed,
sacrificed and necropsied.
Study "in-life” completed.
Brown et al. — 57
Appendix E: GLOSSARY OF TERMS FOR CLINICAL
OBSERVATIONS
Long-term (TOXSYS® Term) - Definition
1. General
a. Normal (NORMAL) - animal appears to be healthy,
exhibits no recognizable clinical signs.
b. Hunched Posture (HUNCH POS) - an increase in the
curvature of the thoracic spine as viewed from the
side .
c. Prostration (PROSTRATE) - animal stretched out in a
horizontal position but conscious.
d. Loss of Consciousness (LOSS CONS) - prostrate and
unresponsive to sensory stimuli (touch, sound, pain,
light, etc. ) .
e. Moribund (MORIBUND) - animal is near death.
f. Death (DEATH) - permanent cessation of all vital
body functions.
g. Emaciated (EMACIATED) - the animal appears to have
lost weight, but the skin appears hydrated (i.e.,
the skin does not remain in place when squeezed
together) .
h. Dehydrated (DEHYDRATE) - the animal appears to have
lost weight and skin remains in place when squeezed.
i. Pallor (PALLOR) - a lack of color to the skin or
eyes .
2 . Behavioral
a. Inactive (INACTIVE) - a decrease in the locomotor
activity of the animal.
b. Hyperactive (HYPERACT) - an increase in the
locomotor activity of the animal.
c. Irritable (IRRITABLE) - an increase in annoyance or
anger to slight stimulation.
Brown et al. — 58
Appendix X (cont . ) : GLOSSARY 07 TERMS FOR CLINICAL
OBSERVATIONS
d. Aggressive (AGGRESS) - animal is bold, wants to
fight, characterized by a desire to bite for no
apparent reason.
e. Vocalization (VOCAL) - production of sound from the
larynx .
f. Increased or Decreased Preening (IN PREEN or DE
PREEN) - an increase or decrease in the grooming
behavior of the animal.
g. Circling (CIRCLING) - repeated walking or running in
a circle.
h. Jumping (JUMPING) - springing or leaping around the
cage .
i. Chewing (CHEWING) - animal goes through the motion
of biting and/or grinding with no external stimulus.
j . Ataxia (ATAXIA) - loss of coordination characterized
by staggering or loss of gait.
k. Hypotonia (HYPOTONIA) - decrease in muscle tone.
l. Hypertonia (HYPERTONIA) - increase in muscle tone.
m. Catalepsy (TRANCE) - animal tends to remain in any
position in which it is placed.
n . Somnolence (DROWSY) - animal appears drowsy, but can
be aroused by prodding and resumes normal
activities .
o. Tremors (TREMORS) - a trembling or quivering of the
limbs or entire body.
p. Fasciculation (TWITCH) - twitching of the muscles
seen on the back, shoulders, hind limbs, and paws.
q. Writhing (WRITH) - twisting or wrenching the body
abnormally .
r. Paralysis (PARALYSIS) - loss or impaired motor
function in the limbs or entire body.
Brown et al. — 59
Appendix E (cont.): GLOSSARY OF TERMS FOR CLINICAL
OBSERVATIONS
s. Disoriented (DISORIENT) - animal appears dazed and
confused.
3. Convulsions
a. Tonic Convulsion (TONIC) - persistent contraction of
muscles with rigid extension of limbs.
b. Clonic Convulsion (CLONIC) - convulsion alternating
contraction and relaxation of muscles.
c. Tonic-clonic Convulsion (MIXED) - both types may
appear consecutively.
d. Opisthotonus (OPISTOT) - tetanic spasm in which the
back is arched and the head pulled towards the
dorsal position.
4 . Reflexes
a. Depressed Myotactic Reflex (PULL) - decreased
ability of animal to retract its hind limb when the
limb is pulled down.
b. Depressed Pinch Reflex (PINCH) - decreased response
(jerking away of limb) to pinching of toes.
c. Depressed Grasping Reflex (GRASP) - decreased
ability to take hold of finger firmly when hung from
it.
d. Depressed Righting Reflex (RIGHTING) - decreased
ability to assume normal position when the animal
has been placed on its side or back.
e. Depressed Corneal Reflex (CORNEAL) - decreased
response (closing of the eyelids) to touching of the
cornea .
f. Depressed Pupillary Reflex (PUPILLARY) - decreased
constriction of the pupil in the presence of light.
g. Increased Startle Reflex (STARTLE) - increased
response to external stimuli (e.g., touch, noise).
Brown et al. — 60
Appendix X (cont.): GLOSSARY OF TERMS FOR CLINICAL
OBSERVATIONS
h. Depressed Pinnal Reflex (PINNAL) - decreased
response (twitching of external ear) elicited by
stroking of inside surface of ear.
5. Respiratory
a. Increased or Decreased Respiratory Rate (IN RATE or
DE RATE) - an increase or decrease in the
repetitions of inhaling and exhaling air.
b. Increased or Decreased Respiratory Depth (IN DEPTH
or DE DEPTH) - an increase or decrease in the volume
of air inhaled or exhaled with each repetition.
c. Irregular Respiration (IRREGULAR) - any irregular
rate and/or depth of respiration. Since this can be
any pattern, a description should be given.
d. Apnea (APNEA) - transient cessation of breathing.
e. Gasping (GASPING) - deep, labored inspiration, often
accompanied by a wheezing sound.
f. Panting (PANTING) - rapid, shallow breathing.
g. Wheezing (WHEEZE) - raspy sound made with breathing.
h. Sneezing (SNEEZE) - animal makes sneezing-like
sounds .
i. Nasal Discharge (NASAL DIS) - a discharge from the
nose is produced. A description of the color is
required.
6. Ocular
a. Lacrimation (TEARING) - an increase in the
production of tears.
b. Chromodacryorrhea (RED TEARS) - production of red-
colored tears.
c. Miosis (MIOSIS) - decreased pupil size.
d. Mydriasis (MYDRIASIS) - increased pupil size.
Brown et al. — 61
Appendix X (cont.): GLOSSARY 07 TERMS FOR CLINICAL
OBSERVATIONS
e. Squinting (SQUINTING) - closing of the eyelids,
usually in response to light.
f. Exophthalmus (BULGING) - increased protrusion of the
eyeball .
g. Corneal Opacity (OPACITY) - an opaque spot or area
on the cornea .
h. Conjunctivitis (CONJUNC) - inflammation of the
conjunctiva, characterized by red, swollen eyelids.
i. Ptosis (PTOSIS) - drooping of the upper eyelid from
paralysis .
7. Gastrointestinal
a. Increased Salivation (IN SALIVA) - an increase in
the production of saliva.
b. Dried Mucous Membranes (DRY MOUTH) - drying of the
mucous membranes in the mouth, usually from
decreased salivation.
c. Retching (RETCHING) - a strong, unproductive gag
response .
d. Vomiting (VOMITING) - the expulsion of the contents
of the stomach through the mouth.
e. Diarrhea (DIARRHEA) - increased frequency and
liquidation of fecal discharges.
f. Scant Feces (SCANT) - decrease in the frequency of
fecal discharges.
g. Tarry Feces (TARRY) - blackish, watery feces often
due to blood in the feces.
8. Skin/ fur
a. Hyperemia (HYPEREMIA) - an increase in reddish color
of skin over entire body, usually from vasodilation
(i .e . , flushed) .
Brown et al. — 62
Appendix E (cont . ) : GLOSSARY OF TERMS FOR CLINICAL
OBSERVATIONS
b. Cyanosis (CYANOSIS) - a bluish discoloration of the
skin, often related to respiratory problems.
c. Jaundice (JAUNDICE) - a yellow discoloration of the
skin, often due to liver dysfunction.
d. Scaling (SCALING) - scaling of the skin.
e. Erythema (ERYTHEMA) - an increase in the redness of
the skin in small areas (i.e., not the entire body).
Location should be specified.
f. Bleeding (BLEEDING) - loss of blood. Location
should be specified.
g. Scab (SCAB) - a crust of hardened blood and serum
over a wound on the skin. Location should be
specified.
h. Edema (EDEMA) - the presence of large amounts of
fluid in the intercellular tissue spaces. Location
should be specified.
i. Ulceration (ULCERATN) - the formation of a break in
the skin or mucous membrane with loss of surface
tissue, disintegration and necrosis of epithelial
tissue, and often pus. Location should be
specified.
j. Necrosis (NECROSIS) - localized death of living
tissue. Location should be specified.
k. Alopecia (HAIR LOSS) - absence or loss of hair from
the skin where it normally is present . Location
should be specified.
l. Rough Coat (RGH COAT) - a rough appearance to the
coat due to any number of reasons, such as
piloerection, dullness, lack of grooming.
9. Miscellaneous
a. Urine, Feces - meant to be used with color
descriptors to describe any abnormal coloration.
Brown et al. — 63
Appendix E (cont . ) : GLOSSARY OF TERMS FOR CLINICAL
OBSERVATIONS
b. Stain, Material - meant to be used with color and
location descriptors to describe any abnormal stains
or material found on the coat .
c. Color Descriptors - clear, light, dark, yellow,
orange, red, blue, green, and brown.
d. Location Descriptors - head, mouth, eye, ear, nose,
neck, front leg, hind leg, thorax, abdomen, back,
side, flank, perianal, tail, left, right, and both.
Brown et al. — 64
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1/27/86 8:26:28 0000337 377.0 INTRAABDOMINAL MASS VENTRAL TO LIVER SIZE MEDIUM,
ENLARGED GLOBE LEFT EYE WITH MARKED OPACITY, EUTHANIZED
STUDY: 0083009 CARCINOGENICITY BIOASSAY OF ISOBUTYL 2-CYANO- PAGE 22
COMPOUND: ISOBUTYL 2-CYANOACRYLATE ACRYLATE (IBC) IN MALE AND FEMALE RATS. DATE: 6/09/87
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COMPOUND: ISOBUTYL 2-CYANOACRYLATE ACRYLATE (IBC) IN MALE AND FEMALE RATS. DATE: 6/09/87
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COMPOUND: ISOBUTYL 2-CYANOACRYLATE ACRYLATE (IBC) IN MALE AND FEMALE RATS. DATE: 6/09/87
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STUDY: 0083009 CARCINOGENICITY BIOASSAY OF ISOBUTYL 2-CYANO- PAGE 49
COMPOUND: ISOBUTYL 2 -CYANOACRYLATE ACRYLATE (IBC) IN MALE AND FEMALE RATS. DATE: 6/09/87
START DATE: 1/28/85 TIME: 14:40:13
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STUDY: 0083009 CARCINOGENICITY BIOASSAY OF ISOBUTYL 2-CYANO- PAGE 67
COMPOUND: ISOBUTYL 2-CYANOACRYLATE ACRYLATE (IBC) IN MALE AND FEMALE RATS. DATE: 6/09/87
START DATE. 1/28/85 TIME: 14:40:13
ANIMAL HISTORY EDS017 V4M11
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1/17/86 8:47:14 0000337 279.0 CONJUNCTIVITIS LEFT EYE SLIGHT
2/12/86 7:47:38 0034567 265.0 CONJUNCTIVITIS LEFT EYE SLIGHT, EUTHANIZED
Brown et al. — 305
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12/20/85 9:49:48 0000337 257.0 CORNEAL OPACITY BOTH EYE SLIGHT
12/23/85 10:54:22 0000337 ■* No observations recorded.
Brown et al.
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7/03/85 8:46:32 0000337 270.0 STAIN BROWN NOSE SLIGHT
8/02/85 10:12:08 0084799 250.0 OCULAR PALLOR SLIGHT, INTRAABDOMINAL SPLEENIC MASS SIZE LARGE
8/02/85 10:47:46 0034567 248.0 * No observations recorded.
Brown et al . --329
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„TUDY: 0083009 CARCINOGENICITY BIOASSAY OF ISOBOTYL 2-CYANO- PAGE 141
COMPOUND: ISOBUTYL 2-CYANOACRYLATE ACRYLATE (IBC) IN MALE AND FEMALE RATS. DATE: 6/09/87
Brown et al . — 366
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7/03/85 9:51:06 0000337 260.0 NORMAL
7/09/85 12:47:12 0069406 * No observations recorded
Appendix G (cont.): GROSS NECROPSY OBSERVATIONS, INCIDENCE SUMMARY
IETTERHAN ARHT INSTITUTE OF RESEARCH INCIDENCE SUMMARY REPORT FOR GROSS NECROPSY OBSERVATIONS PRINTED: 21-NOV-89
OIV OF RES SUPP, PATH SERV GP STUDY NUMBER: GLP83009 PAGE: 3
PRESIDIO OF SAN FRANCISCO, CA 94129 REPORT FOR UNSCHEDULED DEATHS: DAY 374 TO DAY 755 OF STUDY
Brown et al . — 371
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Appendix 6 (cont.): GROSS NECROPSY OBSERVATIONS, INCIDENCE SUMMARY
LETTERMAN ARmV INSTITUTE Of RESEARCH INCIDENCE SUMMARY REPORT fOR GROSS NECROPSY OBSERVATIONS PRINTED: 21-NOV-89
01V Of RES SUPP, PATH SERV GP STUDY NUMBER: GLP83009 PAGE: 4
PRESIDIO Of SAN fRANCISCO, CA 94129 REPORT fOR ftNAL SACRIFICE
Brown et al . — 378
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LETTERMAN ARMY INSTITUTE OF RESEARCH INCIDENCE SUMMARY OF MICROSCOPIC OBSERVAT IONSCALL NEOPLASMS) PRINTED: 22-NOV-89
DIV OIL RES SUPP, PAIN SERV GP STUDY NUMBER: GLP83009 PAGE: 1
PRESIDIO OF SAN FRANCISCO. CA 94129 PATHOLOG I ST ( S) : MELLICK, PAUL U., Smith, CBtherine D
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Appendix H (cont.): MICROSCOPIC OBSERVATIONS, INCIDENCE SUMMARY
LETTERMAN ARMY INSTITUTE OF RESEARCH INCIDENCE SUMMARY OF MICROSCOPIC OBSERVAT lONStMAL 1 CNANT NEOPLASMS) PRINTED: 22-NOV-69
01V OF RES SUPP, PATH SERV CP STUDY NUMBER: GLP83009 PACE: 2
PRESIDIO OF SAN FRANCISCO, CA 94129 PATHOLOGI ST (S) : MEL LICK, PAUL U., Saith, Catherine D
SPECIES: RAT/FISCNER'344 STUDY START DATE: 23-JAN-84 STUOY TYPE: CHRONIC/2 YR CARCINOGENIC
Brown et al. — 386
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TWO-TAILED TEST.
Appendix H (cont.): MICROSCOPIC OBSERVATIONS, INCIDENCE SUMMARY
LETTERHAN ARMY INSTITUTE Of RESEARCH INCIOENCE SUMMARY OF MICROSCOPIC OBSER VAT I ONSIHAL I CHANT NEOPLASMS) PRINTED: 22-NOV-B9
DIV OF RES SUPP, PATH SERV CP STUDY NUMBER: GLP83009 PAGE: 5
PRESIOIO OF SAN FRANCISCO, CA 94129 PATHOLOG I ST ( S) : MELLICK, PAUL U., Snith, Catherine D
SPECIES: RAT/F1SCNER-344 STUDY START DATE: 23-JAN-84 STUDY TYPE: CHRONIC/2 YR CARCINOGENIC
Brown et al
PRESENCE OF METASTATIC SARCOMA
PRESENCE OF METASTATIC NEOPLASM
Appendix H (cont.): MICROSCOPIC OBSERVATIONS , INCIDENCE SUMMARY
LETTERMAN ARMY INSTITUTE Of RESEARCH INCIDENCE SUNN ARY OF HICROSCOPIC OBSERVAT IONS(BENIGN NEOPLASMS) PRINTED: 22-NOV-89
OIV OF RES SUPP, PATH SERV GP STUDY NUMBER: GLP83009 PAGE: 1
PRESIDIO Of SAN FRANCISCO, CA 94129 PATHOLOGI ST (S) : MELLICK, PAUL U., Saith, Catherine 0
brown et al
NOTE: ENTRIES FLAGGED WITH A • (MINUS) ARE SIGNIFICANTLY DIFFERENT FROM CONTROL AT THE 0.05 LEVEL USING KOLMOGOROV-SMI RNOV
TWO-TAILED TEST.
Appendix H (cont.): MICROSCOPIC OBSERVATIONS, INCIDENCE SUMMARY
IETTERMAN ARMY INSTITUTE OF RESEARCH INCIDENCE SUMMARY OF MICROSCOPIC OBSERVAT IONS (BENIGN NEOPLASMS) PRINTED: 22-NOV-89
01 V OF RES SUPP. PATH SERV GP STUDY NUMBER: GLP83009 PAGE: 2
PRESIOIO OF SAN FRANCISCO, CA 94129 PAT HOLOGI ST ( S) : MELLICK, PAUL W., Smith, Catherine D
SPECIES: RAT/FISCNER-344 STUDY START DATE: 23-JAN-84 STUDY TYPE: CHRONIC/2 YR CARCINOGENIC
Brown et al. — 391
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TUO-TAILED TEST.
Appendix H (cont.): MICROSCOPIC OBSERVATIONS , INCIDENCE SUMMARY
LETTERMAN ARMY INSTITUTE OF RESEARCH INCIOENCE SUMMARY OF MICROSCOPIC OBSERVAT IONS ( SEN I CM NEOPLASMS) PRINTED: 22-NOV-B9
DIV OF R: $ SUPP, PATH SERV CP STUDY NUMBER: GLP83009 PACE: 3
Brown et ai. --392
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Appendix B (cont.): MICROSCOPIC OBSERVATIONS, INCIDENCE SUMMARY
LETTERMAN ARMY INSTITUTE Of RESEARCH INCIOENCE SUMMARY OF MICROSCOPIC OBSERVAT I ONS(BEN I CN NEOPLASMS) PRINTED: 22-NOV-89
01 V OF RES SUPP, PATH SERV CP STUDY NUMBER: GLPB3009 PACE: 4
PRESIDIO OF SAN FRANCISCO, CA 94129 PAT HOLOG1 ST (S) : HELL I CK , PAUL U., Snith, Catherine D
SPECIES: RAT/FISCHER*344 STUDY START DATE: 23-JAN-B4 STUDY TYPE: CHRONIC/2 YR CARCINOGENIC
Brown et al. — 393
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LETTERMAN ARMY IHSTITUTE Of RESEARCH IHCIOEHCE SUMMARY OF MICROSCOPIC OBSERVATIONS(NON-NEOPLASNS) PRINTED: 22-N0V-89
OIV Of RES SUPP, PATH SERV GP STUDY HUMBER: GLP83009 PAGE: 2
PRESIDIO OF SAH FRANCISCO, CA 94129 PAT HOLOG I ST ( S ) : MELLICK, PAUL U., Salth, Catherine D
SPECIES: RAT/FISCHER-344 STUDY START DATE: 23-JAN-84 STUDY TYPE: CHRONIC/2 YR CARCINOGENIC
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Appendix H (cont.): MICROSCOPIC OBSERVATIONS, INCIDENCE SUMMARY
LETTERNAN ARMY INSTITUTE OF RESEARCH INCIDENCE SUMMARY OF MICROSCOPIC OBSERVAT IONS(NON-NEOPL ASMS > PRINTED: 22-NOV-B9
DIV OF RES SUPP, PATH SERV OP STUDY NUMBER: GLPB3009 PACE: 4
PRESIDIO OF SAN FRANCISCO, CA >4129 PAT NOIOGI ST < S ) : NELLI CK , PAUL U., Saith, Catherine D
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Brown et al. — 402
Appendix I: GLOSSARY OF TERMS
FOR PATHOLOGY FINDINGS
GENERAL DIAGNOSES
In this study there were a few lesions which occurred
repeatedly and involved numerous organs and tissues. The
histologic characteristics of these lesions had very little
to do with their location or organ of involvement .
Repetition of morphologic descriptions and diagnostic
criteria for these lesions under each organ in this glossary
would be redundant. Therefore, these lesions are described
here under the heading of "General Diagnoses," and will be
referred to as appropriate under the organs in which they
occurred.
1. COMPOUND -RELATED INFLAMMATORY REACTION - The test material
was applied directly to the capsular surface of the liver as
a liquid, and allowed to polymerize. In many instances,
especially in animals in the high dose group, the
unpolymerized material ran off the liver and adhered to
adjacent abdominal viscera where polymerization occurred. In
histologic sections, the test material is a clear, slightly
yellow homogeneous crystalline material. The material
stimulates a granulomatous foreign-body inflammatory reaction
characterized by infiltration of macrophages, lymphocytes,
and large multinucleated foreign-body giant cells within
abundant fibrous connective tissue. Usually this lesion is
limited to the serosal surface of abdominal viscera. In some
cases, there is necrosis of underlying tissues and
penetration of the serosal surface by the inflammatory
response accompanied by regenerative hyperplasia of cells of
the organ involved. The most probable reason for the
necrosis, when it occurred, is the local compromise of
circulation by the presence of the test material or the
reaction to it. No attempt is made to grade the severity of
such lesions. They are simply coded as "Present." This
diagnosis is used only when there is unequivocal evidence of
the presence of test material. In cases where test material
is not present, a different diagnosis such as "Fibrosis" or
"Chronic Inflammation" is used, as appropriate.
2. LARGE GRANULAR LYMPHOCYTE LEUKEMIA - This is a common
neoplastic disease of Fischer-344 rats. Although the primary
site for this lesion is probably the spleen, leukemic
involvement frequently occurs early in the disease, and
neoplastic lymphocytes can be found in vascular spaces of
virtually every organ and tissue in the body. The neoplastic
cells are large, round lymphoid cells with abundant, finely
Brown et al. — 403
Appendix I (cont. ) : GLOSSARY OF TERMS
FOR PATHOLOGY FINDINGS
granular, weakly eosinophilic cytoplasm. Mitotic figures,
many of which are large and bizarre, are numerous. Because
of the characteristics of the Xybion computerized data
acquisition system, the primary site for this neoplastic
disease is coded under WHOLE BODY, thus documenting the
presence of the disease regardless of the organs involved.
It is coded as a metastatic lesion only in those organs in
which it alters normal histologic architecture or constitutes
a significant histologic feature. Using tnis method of
computer entry, it is possible to tabulate the occurrence of
this disease and document the significant organs involved,
without causing duplication in incidence data.
3. PRESENCE OF METASTATIC SARCOMA - A number of the animals
developed sarcomas within the fibrous, granulomatous reaction
incited by the test material . The sarcomas involve many
organs in some animals, either through local invasion of
malignant cells or by metastasis. The histologic
characteristics of thes.e tumors are extremely variable. The
entire spectrum of histologic differentiation of mesenchymal
tissue is represented in this group of tumors. Some tumors
are well-differentiated fibrosarcomas, osteosarcomas, or
myxosarcomas, while others are very anaplastic and poorly
differentiated. In some lesions, multiple types of
histologic differentiation occur in the same tumor. The
liver is the most frequent location for these lesions, but it
is not involved in every case. Therefore, the primary site
for these lesions is coded as the ABDOMINAL CAVITY, and the
involvement of each individual organ is coded as a metastatic
lesion. Using this method of computer entry it is possible
to tabulate the occurrence of these sarcomas and document the
organs involved without causing duplication of incidence
data. The morphologic characteristics and histologic
differentiation of each tumor are documented under the
ABDOMINAL CAVITY using the "special histologic comments"
feature of the Xybion program. This diagnosis is used only
when it is certain that the sarcoma developed within the
reaction to the test material . Sarcomas that developed
outside the abdominal cavity or in areas remote to the
application of the test material are not included under this
diagnosis .
4. PRESENCE OF METASTATIC NEOPLASM - This diagnosis is used
in cases in which neoplastic cells (other than sarcoma or
large granular lymphocyte leukemia) are present in organs or
tissues other than those of the site of origin. The lesion
I
Brown et al. — 404
Appendix I (cont.): GLOSSARY OF TERMS
FOR PATHOLOGY FINDINGS
is coded as + with the two-letter abbreviation of the organ
of origin. Example: an adenocarcinoma of the thyroid that
has metastasized to the lung is coded under lung as PRESENCE
OF METASTATIC NEOPLASM +TH.
BRAIN
1. ASTROCYTOMA - A neoplastic proliferation of astrocytes.
The tumor is composed of large and medium-sized cells with
large vesicular nuclei and cytoplasm that is not usually
intensely stained. Cytoplasm consists of numerous fibrils
which are tangled and crisscross in various directions. No
particular growth pattern is characteristic. These tumors
are usually small and well demarcated from adjacent tissue
which may be compressed or undergo liquefaction necrosis.
2. HYDROCEPHALUS - Enlargement or dilation of the ventricles
of the brain at the expense of adjacent parenchyma which
undergoes pressure atrophy or liquefaction necrosis.
3. LIQUEFACTION NECROSIS - A necrotic area in the central
nervous system. Necrotic tissue has been liquified. The
area appears microscopically as an unlined empty space with
frayed and irregular edges. Cells immediately adjacent to
the liquified area may show evidence of necrosis. Pink-
staining proteinaceous precipitate, lipofuscin-laden "gitter"
cells, red blood cells, neutrophils, and remnants of
destroyed tissue may or may not be present. The severity of
the lesion is graded based on size of the necrotic area:
1 = Diameter is less than than that of a 40X
microscopic field.
2 - Diameter is less than a 20X field.
3 = Diameter is less than a 10X field.
4 = Diameter is less than a 4X field.
4. PITUITARY TUMOR INVASION - Presence of neoplastic cells
from the anterior pituitary in, or adjacent to and
compressing brain tissue. These tumors do not usually
metastasize but may compress and destroy brain tissue
locally. Infiltration of meninges and ventricular spaces of
the brain may occur and is included under this diagnosis.
5. PERIVASCULAR LYMPHOCYTIC CELLULAR INFILTRATION - Presence
of non-neoplastic lymphocytes in perivascular spaces.
Brown et al. — 405
Appendix I (coat.): GLOSSARY OF TERMS
FOR PATHOLOGY FINDINGS
Severity grade criteria:
1 - Detectable.
2 - Involvement of an area up to size of 20X
microscopic field.
3 - Cuffs are three cell layers thick and involve
area greater than 20X microscopic field.
4 - Cuffs are more than three cells thick and/or
area of involvement is greater tnan 10X
microscopic field.
6. GLIOSIS - Non-neoplastic proliferation of fibrous
astrocytes and possibly other glial cells. Appears
microscopically as a focal or diffuse increase in glial
nuclei and increased density of internuclear areas. This
lesion frequently occurs at the periphery of areas of
liquefaction necrosis but is not limited to such areas.
Severity grade criteria:
1 - Detectable, area less than one 40X field.
2 = Area less than one 20X field.
3 - Area less than one 10X field.
4 - Area less than one 4X field.
5 - Area greater than one 4X field.
7. LARGE GRANULAR LYMPHOCYTE LEUKEMIA, METASTATIC - See
"General Diagnoses" above.
8. HISTIOCYTIC INFILTRATION, PERIVASCULAR - Presence of non-
neoplastic histiocytes in perivascular spaces. The lesion is
coded as "Present . "
XflACBSA
Tracheal glands are dilated in almost every animal
examined in the second year of this study. Since this change
is universal in animals in all treatment groups, it is
considered a normal aging change for this population and is
not coded.
1. NONSUPPURATIVE TRACHEITIS - Presence of mononuclear
inflammatory cells within or beneath the tracheal epithelium
and/or within the tracheal wall.
Brown et al . — 406
Appendix I (cont.) : GLOSSARY OF TERMS
FOR PATHOLOGY FINDINGS
Severity grade criteria:
1 = Presence of a few mononuclear cells within or
beneath the tracheal epithelium.
2 = Inflammatory cell infiltration of the tracheal
mucosa is prominent. Submucosal glands may be
infiltrated.
3 = Diffuse infiltration of the mucosa and
submucosa with inflammatory cells in the
tracheal lumen.
4 = Same as Grade 3 plus destruction of mucosal
and/or submucosal structures .
5 = Inflammatory infiltrate and destruction of
normal structure throughout the thickness of
the tracheal wall.
2. PRESENCE OF METASTATIC NEOPLASM - See "General Diagnoses"
above .
3. SUPPURATIVE TRACHEITIS - An acute inflammatory process
characterized primarily by neutrophils within the trachea.
Severity grade criteria:
1 - Presence of a few neutrophils within and
beneath the tracheal epithelium.
2 * Neutrophilic infiltration of tracheal mucosa
and submucosa is prominent . Submucosal glands
may be infiltrated.
3 = Neutrophils are present in the tracheal lumen
and diffusely infiltrate mucosa and submucosa.
4 * Similar to Grade 3 plus destruction of mucosal
and submucosal structures.
5 * Neutrophilic infiltrate and destruction of
normal structure throughout the thickness of
the tracheal wall.
TSXRQID fi LAMPS
1. FOLLICULAR HYPERTROPHY/HYPERPLASIA - Non-neoplastic
proliferation of thyroid follicular cells. Cells may be
increased in size, number, or both. Hyperplastic epithelium
may form follicles containing colloid, or form papillary
fronds supporting multiple layers of cells that extend into
large follicles. The lesion is coded as "Present."
2 . ADENOMA, FOLLICULAR - A benign tumor of thyroid follicular
cells characterized primarily by cords of cells or cells
Brown et al. — 407
Appendix I (cont.): GLOSSARY OF TERMS
FOR PATHOLOGY FINDINGS
forming follicular structures. These tumors are well-
demarcated, expansile lesions which cause compression and
atrophy of adjacent thyroid parenchyma.
3. PARAFOLLICULAR CELL HYPERPLASIA (C-CELL HYPERPLASIA) -
Focal or diffuse non-neoplastic proliferation of
parafollicular cells. Foci of hyperplastic cells are no
larger than a normal thyroid follicle. There is no
compression of adjacent thyroid tissue.. Severity grade
criteria :
1 = One to three nodules or less than 25% diffuse
glandular involvement .
2 = Three to six nodules or less than 50% diffuse
involvement.
3 = Six to ten nodules or more than 50% diffuse
involvement .
4 = More than ten nodules or more than 75% diffuse
involvement .
4. PARAFOLLICULAR CELL ADENOMA - Benign tumor of
parafollicular or "C" cells. These tumors are usually solid
in cellular arrangement, and are large enough to compress
adjacent tissue. There is no evidence of invasion of the
thyroid capsule or adjacent tissues. Cellular pleomorphism
may be prominent, but cells are usually uniform and slightly
elongated with ovoid or almost spherical nuclei. Cytoplasm
is sparse, homogeneous, or finely granulated and stained
weakly eosinophilic. Mitotic figures are rare.
5. PARAFOLLICULAR CELL ADENOCARCINOMA - Malignant neoplastic
proliferation of parafollicular or "C" cells. Cellular
morphology may vary little from adenoma described above .
Fusiform and palisade patterns occur frequently. Criteria
for malignancy is based on invasion of thyroid capsule and/or
infiltration of adjacent tissue or metastasis.
6. FOLLICULAR ADENOCARCINOMA - Malignant neoplastic
proliferation of follicular cells of the thyroid.
Microscopic patterns are similar to those of follicular
adenomas. There is usually very little structural and
cellular pleomorphism, and moderate, even low mitotic
activity. The consistent feature that distinguishes
follicular adenocarcinomas from the analogous type of benign
tumor is their invasiveness . These tumors invade the thyroid
capsule, adjacent tissues, lymphatics, and blood vessels.
Brown et al . — 408
Appendix I (cont . ) : GLOSSARY OF TERMS
FOR PATHOLOGY FINDINGS
7. COLLOID CYST - Presence of greatly enlarged (over twice
the size of an average follicle) colloid-filled cystic space
within the thyroid gland. Epithelial cells lining such cysts
are usually flattened. One or more colloid cysts may occur
within a single thyroid gland.
PARATHYROID GLANDS
No gross or microscopic lesions were recognized in
parathyroid glands of rats used in this study.
ESOPHAGPS
1. NECROHEMORRHAGIC ESOPHAGITIS - Necrosis and hemorrhage
accompanied by acute suppurative inflammation in the
esophagus. This was an uncommon lesion in Study GLP 83009.
When it did occur, it could be attributed to obstruction of
the esophagus by test material and attendant granulomatous
inflammatory response and fibrosis at, or near, the
esophageal hiatus of the diaphragm. Severity grade criteria:
1 = Small focal area of necrosis limited to the
esophageal mucosa and a mild local neutrophilic
infiltrate .
2 - Large area of necrosis extending through the
mucosa into the submucosa with prominent
suppurative exudate and hemorrhage.
3 = Similar to grade 2 but necrosis and hemorrhage
extend into the muscular wall of the esophagus .
4 => Necrosis, hemorrhage, and suppurative exudate
extend throughout the thickness of the
esophageal wall. There is destruction of large
amounts of esophageal tissue throughout its
thickness.
SA1IVARX fiLAHDS
Parotid, mandibular, and sublingual glands were examined
routinely. The gland in which the following lesions were
observed are identified by notations in the special
histologic comments on the Xybion program.
1. ATROPHY AND LOSS OF ACINAR TISSUE - This lesion consists
of absence of acinar secretory cells. Affected lobules
consist of ductal structures in a f ibrovascular stroma. Such
lesions are usually focal, affecting a small lobule of
salivary tissue.
Brown et al . — 409
Appendix I (coat . ) : GLOSSARY OF TERMS
FOR PATHOLOGY FINDINGS
Severity grade criteria:
1 = One lobule affected.
2 = Two or three lobules affected.
3 - Four to six lobules affected.
4 = More than six lobules affected.
2. INFLAMMATION, SUBACUTE - Presence of focal or diffuse
infiltrations of inflammatory cells (primarily lymphocytes,
macrophages, and plasma cells) possibly accompanied by
minimal to moderate loss of glandular tissue through
necrosis. Severity grade criteria:
1 - One to three foci of mononuclear cells no
larger than the diameter of a secretory acinus .
2 = Four to six mononuclear foci.
3 - Six to ten inflammatory cell foci or up to two
foci of necrosis no larger than the diameter of
a secretory acinus .
4 - More than ten inflammatory cell foci and/or
more than three foci of necrosis or diffuse
inflammatory involvement of more than 50% of
the salivary gland.
3. ADENOCARCINOMA - Malignant neoplastic growth of salivary
glandular or ductal epithelium. Neoplastic cells are
arranged in cords, nests, or acini often forming papillary
fronds or large glandular spaces filled with granular
basophilic secretory product . Cells are cuboidal to columnar
with pale-staining granular cytoplasm and round to slightly
oval vesicular nuclei. Neoplastic cells are usually rather
well differentiated and without pleomorphism. Mitotic
figures are not numerous. A small amount of fibrous stroma
is present and neoplastic epithelial cells infiltrate this
tissue. In some of the cystic glandular spaces there are red
blood cells and bright.ly eosinophilic rhomboid hemoglobin
crystals .
r.inrmt. CT.awn _ fHARDERIAN GLAND)
1. INFLAMMATION, SUBACUTE TO CHRONIC - Presence of focal or
diffuse infiltrations of lymphocytes, macrophages, and plasma
cells, possibly accompanied by minimal to moderate loss of
glandular tissue through either necrosis or atrophy.
Fibrosis may or may not be present. In most cases there is
intraductal accumulation of inspissated secretory material.
Brown et al. — 410
Appendix I (cont . ) : GLOSSARY OF TERMS
FOR PATHOLOGY FINDINGS
Severity grade criteria:
1 = One to three foci of mononuclear cells no
larger than the diameter of a secretory acinus.
2 = Four to six mononuclear foci; fibrosis may be
present .
3 = Six to ten mononuclear foci with or without
fibrosis and no more than two necrotic foci no
larger than the diameter of a secretory acinus .
4 * More than ten inf lammatory/f ibrotic foci and/or
three or more foci of necrosis, or diffuse
inflammation and fibrosis of more than 50% of
the gland.
2. ATROPHY AND/OR LOSS OF ACINAR TISSUE - Absence of acinar
secretory cells. Affected lobules consist of ductal
structures in a f ibrovascular stroma. Such lesions are
usually focal, affecting a small lobule of lacrimal gland
tissue. Severity grade criteria:
1 - One lobule affected.
2 * Two or three lobules affected.
3 = Four to six lobules affected.
4 - More than six lobules affected.
BXQRBITAIi LACRIMAL filANP
1 . ACINAR ATROPHY - Microscopic appearance and grading
criteria are identical to that of the Harderian gland
described above.
2. INFLAMMATION, SUBACUTE TO CHRONIC - Microscopic appearance
and grading criteria are identical to that of the Harderian
gland described above.
BBA&X
1. CARDIOMYOPATHY - This is a very common lesion in aging
Fischer-344 rats. In younger animals, it is usually seen as
mild to moderate focal myocarditis. As the rats age, the
disease progresses to myocardial degeneration characterized
by vacuolation and atrophy of myocardial cells followed by
fibrosis and loss of myocardial fibers. The heart is not
uniformly affected by these changes.
Brown et al. — 411
Appendix Z (coat . ) : GLOSSARY OF TERMS
FOR PATHOLOGY FINDINGS
Severity grade criteria:
1 = One to five small foci of lymphocytes between
myocardial fibers or around blood vessels.
2 = Six to ten foci of lymphocytes and/or minimal
to mild vacuolar change in myocardial fibers.
Fibrosis may be present but is limited to less
than 25% of the section.
3 = More than ten foci of lymphocytes and/or
vacuolization of myofibers. Mild fibrosis
involving no more than 50% of the section.
4 * More than half of the section is involved in
degeneration and fibrosis. Moderate to severe
myofiber atrophy is present.
2. ATR IOC AVAL EPITHELIAL MESOTHELIOMA - This lesion was not
observed in the second year of Study GLP 83009. In the first
year of this study, one rat developed this unusual tumor.
The lesion was completely described and discussed in the
interim report that covered the first year of this two-year
study .
3. MEDIAL HYPERTROPHY OF MUSCULAR ARTERIES - Thickening of
the muscular medial layer of the arteries in the myocardium. -
Severity grade criteria:
1 - Minimal detectable thickening.
2 * Mild thickening, less than twice normal
thickness .
3 ■ Moderate thickening of the media, greater than
twice the normal thickness, often producing
distortion of arterial lumen.
4 ■ Marked thickening of the media, approximately
three times the normal thickness, with marked
distortion and constriction of the artsrial
lumen .
4. MURAL THROMBUS - Lesion consists of a mass of fibrin
intermixed with red blood cells and neutrophils attached to
the endocardial surface. Adjacent myocardial cells may
undergo degeneration and necrosis and infiltration of
inflammatory cells. The lesion is graded as "Present."
5. LARGE GRANULAR LYMPHOCYTE LEUKEMIA - See "General
Diagnoses" above.
Brown et al. — 412
Appendix I (cont.) : GLOSSARY OF TERMS
FOR PATHOLOGY FINDINGS
6. PRESENCE OF METASTATIC NEOPLASM - See "General Diagnoses"
above .
lpngs
1. FOCAL HYPERPLASTIC PROLIFERATION OF TYPE 2 ALVEOLAR
EPITHELIAL CELLS WITH OR WITHOUT INFLAMMATORY CELL
INFILTRATION - Non-neoplast ic proliferation of alveolar type
2 cells. This lesion frequently occurs in centriacinar
regions of the lung at the junction of conducting airways and
exchange tissue. It also occurs near pulmonary adenomas in
alveoli whose ventilation has been obstructed by the tumor.
In these areas, alveolar septae are lined continuously by
type 2 epithelium. Affected alveoli are frequently
collapsed. Type 2 cell proliferation is frequently
accompanied by infiltration of alveolar macrophages both
within affected alveolar lumens and within the interstitium.
Severity grade criteria:
1 - Focal lesion less than the diameter of a 20X
microscopic field.
2 - Lesion is larger than the diameter of a 20X
field but smaller than that of a 4X field.
3 - As many as three focal lesions with diameters
no larger than that of a 4X field may be
present .
4 - More than four focal lesions with diameters as
large as a 4X field are present.
2. PLEURITIS WITH SUBJACENT CHRONIC PNEUMONIA - Presence of
inflammatory cells and fibrin on and in the visceral pleura.
Inflammatory cells, fibrin, and possibly the replacement of
type 1 alveolar epithelium with :ype 2 cells are present in
adjacent pulmonary parenchyma. Severity grade criteria for
this lesion are as follows:
1 - Area of inflammation is less than the diameter
of a 20X microscopic field.
2 - Area of inflammation is greater than a 20X
field but less than a 10X field.
3 ■ Involvement of more than 75% of a lung lobe.
4 - Involvement of the entire area of 2 or more
lobes .
3. PULMONARY EDEMA - Presence of protein-rich (pink-staining)
fluid within pulmonary alveoli.
Brown et al. — 413
Appendix I (cont.): GLOSSARY OT TERMS
TOR PATHOLOGY FINDINGS
Severity grade criteria:
1 = Edema fluid in up to 10 alveoli.
2 = Edema fluid in 10-50 alveoli.
3 = Edema fluid in 25% to 50% of the alveoli in one
lobe .
4 = Edema fluid in 25% to 50% of alveoli in 2 or 3
lobes .
5 = Edema fluid in more than 50% of the alveoli in
all lobes.
4. VASCULAR CONGESTION - Pulmonary vascular spaces are
distended with large amounts of blood. Since the animals
that were euthanized were killed by exsanguination while
under barbiturate anesthesia, the amount of blood in the
pulmonary vasculature is extremely variable. Animals that
died naturally have much more blood in their lungs. For
these reasons, vascular congestion was coded only when the
congestion constituted a prominent histologic characteristic
of the lung.
5. THROMBUS - Presence of a mass of fibrin mixed with red
blood cells and leukocytes attached to the lumenal wall of a
vessel. Tissues supplied by the thrombosed vessel may
undergo ischemic necrosis and infiltration of inflammatory
cells. Severity grade criteria for this lesion are as
follows :
1 = Thrombus is present; secondary ischemic changes
involve fewer than 50 alveoli .
2 - Thrombus is present; secondary ischemic changes
involve up to 25% of a- lung lobe
3 * Thrombus is present in one to three lobes with
ischemic change affecting less than 50% of the
tissues in affected lobes.
4 - Thrombus is present in three or more lobes
and/or ischemic change affects more than 50% of
the tissue in involved lobes.
6. MINERAL I Z AT I ON OF PULMONARY ARTERIES - Focal dense
deposits of mineral within the wall of large to medium-sized
arteries in the lung. Severity grade criteria for this
lesion are as follows:
1 - A single focus of mineral which produces no
distortion of the vessel wall.-
Brown et al. — 414
Appendix I (cont.): GLOSSARY 07 TERMS
FOR PATHOLOGY FINDINGS
2 * Two or three small foci of mineralization which
produce no distortion of the vessel wall.
3 = Four or more small foci of mineral which
distort the vessel wall minimally, or one
larger focus which causes moderate distortion
of the vessel wall.
4 = More than one large focus which causes moderate
distortion of the vessel wall.
7. PNEUMONIA, GRANULOMATOUS - The infiltration of
lymphocytes, macrophages, and neutrophils with variable
numbers of large multinucleated giant cells. Necrosis may be
present in the center of granulomas. These lesions are
usually focal or multifocal and are located within
centriacinar areas, proximal alveoli, alveolar ducts, and
terminal bronchioles. Severity grade criteria for this
lesion are as follows:
1 = Less than 10% of the lung tissue affected.
2 = 10% to 25% of the lung tissue affected.
3 = 25% to 50% of the lung tissue affected.
4 = More than 50% of the lung tissue is affected.
8. PNEUMONIA, INTERSTITIAL, CHRONIC - Presence of chronic
inflammation within the pulmonary parenchyma. These
inflammatory lesions usually do not have any particular
anatomic orientation. They may be focal, multifocal, or
diffuse. Lesions consist of infiltrations of macrophages,
lymphocytes, and neutrophils into the interstitium and
alveoli, and the replacement of the normal mature type 1
alveolar epithelial cells with type 2 pneumocytes . Fibrosis
of the interstitium may be present in older lesions.
Multinucleated giant cells are not present. Severity grade
criteria for this lesion are as follows:
1 = Less than 10% of the lung tissue affected.
2 - 10% to 25% of the lung tissue affected.
3 - 25% to 50% of the lung tissue affected.
4 - More than 50% of the lung tissue is affected.
9. PERIVASCULAR LYMPHOID AGGREGATIONS (CUFFING) - Presence of
lymphoid tissue, lymphocytes, primitive reticular cells, and
plasma cells in perivascular connective tissue. This
diagnosis is used only when definite vascular orientation of
the lymphoid tissue is evident. Since severity grading of
such a lesion is irrelevant, the lesion is coded only as
being "Present."
Brown et al. — 415
Appendix I (cont.): GLOSSARY 07 TERMS
FOR PATHOLOGY 7 I HD I MGS
10. LARGE GRANULAR LYMPHOCYTE LEUKEMIA, METASTATIC - Presence
of neoplastic lymphocytes within the vascular spaces,
perivascular tissues, and parenchyma of the lung. This
lesion is coded only when large numbers of neoplastic ceils
constitute a prominent histologic feature and/or when the
normal histologic structure of the lung is destroyed or
effaced by the presence of neoplastic cells.
11. PRESENCE OF METASTATIC NEOPLASM - Presence of neoplastic
cells (other than lymphocytes or sarcoma cells which have a
specific diagnosis) anywhere within the lung. Lesion is
coded as + with the two-letter abbreviation for the organ or
tissue of the primary site. Example: + TH indicates
metastatic neoplasm from the thyroid.
12. ALVEOLAR HEMORRHAGE - Presence of red blood cells within
the alveolar spaces of the lung. In almost all instances in
this study, this lesion is caused by aspiration of blood at
the time of euthanasia, and is unrelated to the experimental
treatment . Severity grade criteria for this lesion are as
follows :
1 = Blood in less than 10 alveoli.
2 = Blood in 10 to 50 alveoli.
3 * Blood in 25% of the alveoli.
4 = Blood in 25% to 50% of the alveoli.
13. PERIBRONCHIAL LYMPHOID HYPERPLASIA - Normal non¬
neoplastic lymphoid aggregates were present in peribronchial
connective tissues of nearly every animal in this study.
This lesion is coded only when the amount of lymphoid tissue
appears to be excessive. Usually in such cases there are
other inflammatory lesions in the lungs. Severity grade
criteria for this lesion are as follows:
1 * Detectable increase in lymphoid tissue limited
to airway submucosa and/or peribronchial
connective tissue.
2 - Increase in submucosal lymphoid tissue which
extends through the airway epithelium.
3 - Increase in submucosal and peribronchial
lymphoid tissue which distorts or compresses
airway lumens or adjacent parenchyma.
4 = Increase in lymphoid tissue which causes
moderate to marked compression of airway lumens
and adjacent parenchyma.
Brown et al . — 416
Appendix I (cont . ) : GLOSSARY OF TERMS
FOR PATHOLOGY FINDINGS
14 . BRONCHIOLAR/ALVEOLAR ADENOMA - Benign tumor of
bronchiolar epithelial or alveolar epithelial origin. These
lesions are usually small focal proliferations of cuboidal to
columnar epithelial cells which compress adjacent pulmonary
tissue. Cells are frequently arranged' in long serpentine
cords. Cells that are usually very well differentiated and
uniform have poorly stained clear cytoplasm and small basally
located ovoid nuclei. Few mitotic figures are present.
15. PRESENCE OF METASTATIC SARCOMA - Presence of neoplastic
mesenchymal cells anywhere within the parenchyma of the lung
or on the pleural surface. The primary site for these tumors
in this study is the abdominal cavity where the tumors
develop in the fibrous connective tissue constituting part of
the granulomatous foreign-body reaction incited by the
presence of the test material. The pulmonary lesions are
coded as + AC indicating presence of the metastatic sarcoma
in the lung with the primary site being the abdominal cavity.
Histologic characteristics of the tumor are documented in
special histologic comments under Abdominal Cavity.
xamia
1. PLEURITIS - Presence of acute, subacute, or chronic
inflammatory reaction on the surface of the thymus. This
lesion includes the infiltration of neutrophils, mononuclear
inflammatory cells, and the proliferation of fibroblasts on
the surface of the thymus . Severity grade criteria for this
lesion are as follows:
1 = Inflammatory lesion less than the diameter of
one 40X microscopic field.
2 = Inflammatory lesion less than the diameter of
one 20X microscopic field.
3 = Inflammation involves 25% to 50% of the thymus.
4 = Inflammation involves more than 50% of the
thymus .
2. ADENOMA, ENDOCRINE ORIGIN, NOT OTHERWISE SPECIFIED - A
small (less than 1 mm in diameter) circumscribed
proliferation of cells characterized by finely granular
weakly eosinophilic cytoplasm and small, round to ovoid
nuclei. Cells are arranged in small nests and cords
separated by delicate f ibrovascular stroma. The lesion is
situated within thymic tissue. Histologically, the cells
comprising this small adenoma resemble parafollicular
Brown et al. — 417
Appendix I (cont.): GLOSSARY OF TERMS
FOR PATHOLOGY FINDINGS
("C" cells) of the thyroid or cells from the parathyroid
glands. Carotid or aortic body origin cannot be ruled out.
Only one such lesion was observed in Study GLP 83009.
3. THYMOMA - Benign neoplastic proliferation of thymic
epithelial cells. The lesion is a well-demarcated, un¬
encapsulated proliferation of round to oval cells having
eosinophilic cytoplasm with poorly demarcated cellular
boundaries and fairly dense round to ovoid nuclei. Mitotic
figures are rare. Cells are arranged in nests and bundles
separated by very fine fibrous stroma. There are a few
widely scattered cells or clusters of cells which are
partially keratinized. The lesion is confined to one fairly
large lobule of the thymus. There was only lesion of this
type observed in Study GLP 83009.
4. ADENOCARCINOMA, NOT OTHERWISE SPECIFIED, SITE OF ORIGIN
UNDETERMINED - This unusual lesion situated within the thymus
consists primarily of proliferating epithelial cells and very
few lymphocytes. Epithelial cells are arranged in small
nests or cords with some papillary forms. The lesion is well
demarcated from adjacent fat, but is not encapsulated. Cells
have large round to oval vesicular nuclei and abundant
eosinophilic cytoplasm with indistinct plasma membranes.
Mitotic figures are rare. Scattered throughout the tumor are
a few spaces filled with eosinophilic material, a few
degenerating epithelial cells, and inflammatory cells. There
was only one lesion of this type observed in Study GLP 83009.
SPLEEN
Because of the method of euthanasia used in this study,
the amount of blood in the spleen varies considerably. Since
this feature has nothing to do with the experimental
treatment or toxic effects of the test material, no diagnoses
of "splenic congestion" or other indication of the amount of
blood in the spleen are recorded.
1. LYMPHOID HYPERPLASIA OF SPLENIC CORPUSCLES - Non-
neoplastic proliferation of lymphoid cells in splenic white
pulp and perifollicular areas. Severity grade criteria for
this lesion are as follows:
1 = Detectable increase in diameter of splenic
corpuscles that exceeds that of the average
spleen.
Brown et al. — 418
Appendix I (cont.): GLOSSARY or TERMS
FOR PATHOLOGY FINDINGS
2 ■ Increase in diameter of splenic corpuscles up
to twice normal size.
3 ■ Increase in diameter of splenic corpuscles two
to three times normal size.
4 * Marked increase in diameter of splenic
corpuscles such that white pulp areas are
nearly confluent.
2. FIBROSIS, CAPSULAR - Non-neoplastic proliferation of
fibrous connective tissue in the splenic capsule. This may
be part of an adhesion caused by the test material, but this
diagnosis is not used when test material is present. If test
material is present, diagnosis #11 below is used. Severity
grade criteria for Fibrosis, Capsular are as follows:
1 = Focal area of fibrosis less than diameter of
one 40X microscopic field.
2 =*> Two or three focal areas of fibrosis, similar
to those in grade 1, or one area involving 10%
to 25% of the surface of a cross-section of
spleen .
3 - Fibrosis involving between 25% to 50% of the
surface of a splenic cross-section.
4 - Fibrosis involving more than 50% of the surface
of a splenic cross-section.
3. INFARCTION, CHRONIC - Sharply demarcated area(s) of
splenic parenchyma comprised primarily of fibrous connective
tissue and/or splenic reticular network with variable numbers
of red blood cells and hemosiderin-laden macrophages.
Severity grade criteria for this lesion are as follows:
1 = One focal area of infarction approximating the
area of one 40X microscopic field.
2 » One or more areas of infarction whose total
area is between 10% to 25% of the cross-
sectional area of the spleen.
3 - One or more areas of infarction occupying 25%
to 50% of the cross-sectional area of the
spleen .
4 - One or more areas of infarction occupying more
than 50% of the cross-sectional area of the
spleen .
4. LARGE GRANULAR LYMPHOCYTE LEUKEMIA, METASTATIC - This
common neoplastic disease of Fischer-344 rats usually begins
in the spleen. In very early cases, there is a decreased
Brown et al. — 413
Appandix I (cont.): GLOSSARY OF TERMS
FOR PATHOLOGY FINDINGS
number of normal lymphoid cells in white pulp (lymphoid
depletion) , and proliferation of neoplastic lymphocytes in
red pulp areas. Neoplastic cells are large, round, and have
abundant finely granular, weakly eosinophilic cytoplasm and
large round vesicular nuclei. Mitotic figures are numerous
and some of these are large and bizarre. As the disease
progresses, the numbers of neoplastic cells increase greatly,
causing severe splenic enlargement. Infarction and necrosis
are common in severely affected spleens. Because of the
features of the Xybion®; program, the primary site for this
entity was coded under Whole Body, and each organ having
significant involvement was coded as having a metastatic
lesion .
5. EXTRAMEDULLARY HEMATOPOIESIS - In most of the animals in
this study, only a few hematopoietic cells are present in the
spleen. This diagnosis is used only in the few animals
having fairly large numbers of hematopoietic cells in the
spleen. No attempt is made to indicate the severity of this
change. The lesion is indicated as "Present."
6. HEMOSIDERIN PIGMENTATION (RED PULP) - Most rats in this
study have small amounts of hemosiderin pigment in splenic
red pulp. However, this finding is coded only when there
appears to be substantially more pigment present than in the
average rat spleen. The change is graded as "Present" with
no attempt to quantify it with a severity grade.
7. SMOOTH MUSCLE HYPERTROPHY, CAPSULE AND TRABECULAE -
Presence of increased size of smooth muscle cells within
trabeculae and capsule increasing the thickness of these
structures. Change coded as "Present" with no attempt to
grade severity.
8. HISTIOCYTIC INFILTRATE, CAPSULE AND OMENTUM - Presence of
histiocytes on the splenic capsule and adjacent omentum.
Graded as "Present."
9. BENIGN HYPERTROPHIC NODULE - One or more sharply
demarcated nodules which elevate the splenic capsule and
consist of non-neoplastic proliferation of lymphoid cells.
Some of these structures may resemble greatly enlarged
splenic corpuscles except that the central artery is usually
absent. This lesion is graded as "Present."
10. PRESENCE OF METASTATIC SARCOMA - See comments and
Brown et al. — 420
Appendix I (cont.): GLOSSARY OF TERMS
FOR PATHOLOGY FINDINGS
description under "General Diagnoses" above.
11. COMPOUND-RELATED INFLAMMATORY REACTION - See comments and
description above under "General Diagnoses."
12. PRESENCE OF METASTATIC NEOPLASM - See comments and
description above under "General Diagnoses."
LYMPH NODES
In routine histologic evaluation of animals from this
study, the mediastinal nodes, mesenteric nodes, and nodes in
the cervical connective tissue adjacent 'to salivary glands
(collectively referred to as "cervical nodes") were examined.
Diagnoses for all nodes are coded under the single heading
"lymph nodes" in the Xybion computer program. The specific
nodes having a coded lesion are annotated in "special
histologic comments" section of the program.
1. LYMPHOID HYPERPLASIA - Non-neoplast ic proliferation of
lymphoid cells in cortical and perifollicular areas of the
lymph node. Severity grade criteria for this change are as
follows :
1 * Detectable increase in diameter of lymphoid
follicles .
2 =■ Increase of lymphoid follicles up to twice
normal size.
3 = Increase of lymphoid follicles to two or three
times normal size.
4 - Nearly confluent proliferation of lymphoid
cells in cortex of the node.
2. RED BLOOD CELLS, HEMOSIDERIN AND/OR ERYTHROPHAGOCYTOSIS
WITHIN MEDULLARY SINUSES - Finding is self-explanatory.
Graded as "Present."
3. LARGE GRANULAR LYMPHOCYTE LEUKEMIA, METASTATIC - See
description and comments under "General Diagnoses" above.
4. HISTIOCYTIC INFILTRATION, SUBCAPSULAR AND MEDULLARY
SINUSES - Lymph nodes from most rats in this study have
moderate numbers of histiocytic cells in medullary areas.
This finding is coded only when these cells are very
numerous. The change is coded as "Present."
Brown et al. --421
Appendix I (cont.): GLOSSARY OF TERMS
FOR PATHOLOGY FINDINGS
5. REACTIVE HYPERPLASIA — Non-neoplastic, noninflammatory
increase in cellularity in lymph nodes. Lymphoid follicles
are increased in size and number. There are increased
numbers of cells in perifollicular areas of the cortex.
Medullary cords and sinuses frequently contain large numbers
of plasma cells. Eosinophilic protein-rich edema fluid may
be present. Change is coded as "Present."
6. PRESENCE OF METASTATIC NEOPLASM - See description and
comments under "General Diagnosis" above.
7. DILATED AND/OR CYSTIC MEDULLARY SINUSES - Self-
explanatory. Coded as "Present."
8. PRESENCE OF METASTATIC SARCOMA - See description and
comments under "General Diagnoses" above.
LIVER
1. COMPOUND RELATED INFLAMMATORY REACTION - See description
and comments under "General Diagnoses" above.
2. BILE DUCTULE EPITHELIAL HYPERPLASIA/ CHOLANGIOFIBROSIS -
Non-neoplastic proliferation of bile ducts frequently
accompanied by periportal fibrosis. Fibrosis is considered a
part of this lesion and is not coded separately. This is a
very frequently observed lesion in rats in this study. The
change is usually fairly uniform in different lobes of the
liver. Severity grading is based on the number of bile
ductule cross sections (lumens) in the average portal triad:
1 = Three lumens.
2 * Four to 15 lumens .
3 = 15 to 25 lumens.
4 = More than 25 lumens.
3. HEPATITIS - Subacute inflammatory lesions in the liver.
These lesions are usually focal or multifocal in this study.
They consist of small focal accumulations of macrophages,
lymphocytes, and occasional neutrophils within the hepatic
parenchyma. Necrosis or degeneration of hepatocytes within
these inflammatory cell foci are observed occasionally.
Severity grade criteria are based on the number of
inflammatory cell foci present:
1 = One to three foci.
Brown et al. — 422
Appendix I (cont.): GLOSSARY OF TERMS
FOR PATHOLOGY FINDINGS
2 - Four to 10 foci.
3 * Ten to 20 foci.
4 = More than 20 foci.
4. NON-NEOPLASTIC FOCI AND AREAS OF CELLULAR ALTERATION -
Three distinctive foci or areas of cellular alteration are
present in livers of rats in this study. These lesions are
named for the morphologic characteristics of their component
cell populations, e.g., basophilic cell foci, clear cell
foci, or eosinophilic cell foci. These lesions usually
consist of a uniform cell type, although they may
occasionally contain mixtures of cell types. Lesions equal
to or smaller than the size of a liver lobule are foci while
a lesion larger than a lobule is called an area. Cellular
arrangement within these lesions varies little from normal
hepatic parenchyma. The cellular appearance and staining
characteristics within these lesions is distinctly different
from adjacent normal cells. Hepatic cords of the lesion
merge imperceptibly with those of the surrounding tissue
without compression. Foci or areas of cellular alteration
may be single or multiple, and different morphologic types
may occur in the same liver section. Their distribution
within the liver is not uniform, and they may coexist with
any other type of hepatic lesion.
4A . FOCUS OF CELLULAR ALTERATION, BASOPHILIC CELLS - Cells
are usually slightly smaller than normal and cytoplasm is
distinctly basophilic in hematoxylin and eosin stained
sections. The plates of hepatocytes may be tortuous due to
increased numbers of cells.
4B . FOCUS OF CELLULAR ALTERATION, CLEAR CELLS - A sharply
demarcated focus or area of cells having a clear zone around
the nucleus in which, in appropriately stained sections,
glycogen can be demonstrated. Cells may be of normal size or
enlarged.
4C . FOCUS OF CELLULAR ALTERATION, EOSINOPHILIC CELLS - A
well-demarcated focus or area of hepatocytes which have
acidophilic cytoplasm causing a "ground glass" appearance.
Inclusions may be present in the cytoplasm. Such cells are
usually enlarged with enlarged nuclei and prominent nucleoli.
Cords may be slightly irregular. Severity grade criteria for
these lesions are as follows:
1 * One focus.
Brown et al . — 423
Appendix Z (cont . ) : GLOSSARY 07 TERMS
FOR PATHOLOGY FINDINGS
2 * Two to four foci, or one area alone or in
combination with 1 to 4 foci.
3 = Five to eight foci, or two to three areas.
4 = Eight or more foci, or four or more areas.
5. HEPATOCYTIC VACUOLATION - Presence of small to large
intracytoplasmic vacuoles within hepatocytes . In sections
appropriately prepared and stained, fat can be demonstrated.
Such change is not uniform within the liver. Severity grade
criteria for this change are as follows:
1 = Minimal detectable involvement.
2 = 10% to 20% of the hepatocytes are vacuolated.
3 * 20% to 40% of the hepatocytes are vacuolated.
4 - More than 40% of the hepatocytes are
vacuolated.
6. TELANGIECTASIS - Dilatation of hepatic sinusoids. Dilated
sinusoids are usually filled with blood. Severity grade
criteria for this lesion are as follows:
1 = Focal dilatation of sinusoids occupying a
diameter of one 40X microscopic field.
2 - Widely scattered multiple foci occupying an
area of one 40X microscopic field.
3 - 10% to 20% of the liver section affected.
4 - More than 20% of the liver section affected.
7. NECROSIS - Death of hepatocytes. This diagnosis is used
to indicate necrosis of hepatocytes without any particular
anatomic pattern. Necrosis is designated as either focal or
multifocal, and a severity grade is indicated. See Necrosis,
Periacinar and Necrosis, Hepatocytic, Individual Cells below
for necrotic lesions having specific anatomic patterns of
distribution. Severity grade criteria for the diagnosis.
Necrosis, are as follows:
1 - Necrotic area is no larger than a 40X
microscopic field.
2 - Combined areas of focal or multifocal necrotic
lesions are less than 10% of the liver section.
3 - Combined areas of focal or multifocal necrotic
lesions are 10% to 20% of the liver section.
4 = Combined areas of focal or multifocal necrotic
lesions are 20% to 40% of the liver section.
Brown et al. — 424
Appendix I (cont.): GLOSSARY or TERMS
FOR PATHOLOGY FINDINGS
5 - Combined areas of focal or multifocal necrotic
lesions are greater than 40% of the liver
section .
8. FIBROSIS, CAPSULAR, (NO COMPOUND) - Presence of increased
fibrous connective tissue on the capsule of the liver. There
is minimal inflammatory cell infiltration and no foreign-body
giant cells. This lesion is coded as "Present."
9. PERIPORTAL MONONUCLEAR CELLULAR INFILTRATION - Presence of
lymphocytes, macrophages, and plasma cells in the periportal
connective tissue. Severity grade criteria for this lesion
are as follows:
1 = Small, widely scattered foci not to exceed more
than three foci per liver section.
2 = Four to six small foci of mononuclear cells.
3 * Six to 10 small foci or presence of three or
more foci that are as large as a liver lobule.
4 = More than ten small foci or more than four
large foci .
10. CYSTIC DEGENERATION - Presence of focal or multifocal
areas characterized by cysts with pale eosinophilic amorphous
material, hepatocytes that are enlarged by the presence of
clear cytoplasmic vacuoles, and an occasional necrotic
hepatocyte. There may be slight peripheral compression of
adjacent hepatic parenchyma. The lesion is coded as
"Present . "
11. HEPATOCYTIC DEGENERATIVE CHANGES (NON-NECROTIC) -
Presence of diffuse areas in which hepatocytes show some or
all of the following changes: cellular enlargement, nuclear
enlargement, nuclear hyperchromasia, multiple nuclei,
microvesicular cytoplasmic change. Affected hepatocytes are
in normal arrangement and necrosis is not present. This
change occurs most frequently in livers severely affected
with large granular lymphocyte leukemia. Severity grade
criteria are based on both the number of hepatocytes affected
(percent of sectional area) and the severity of the
cytological abnormalities listed above:
1 - Minimal cytological abnormality affecting less
than 10% of the section.
2 - Mild cytological abnormalities and/or more than
20% of the section affected.
Brown et al . — 425
Appendix I (cont. ) : GLOSSARY OF TERMS
FOR PATHOLOGY FINDINGS
3 = Moderate cytological abnormalities and/or more
than 40% of the section affected.
4 = Marked cytological abnormalities and/or more
than 50% of the section affected.
12. NECROSIS, HEPATOCYTIC, INDIVIDUAL CELLS - Presence of
coagulative necrosis of individual hepatocytes . There is no
specific anatomic orientation or pattern to the necrotic
lesion. This lesion is most frequently observed in cases of
large granular lymphocyte leukemia or the nonspecific
multifocal hepatitis described in diagnosis #3 above.
Occasionally, necrotic cells are present within areas of
hepatocytic vacuolization and adjacent to areas of compound-
related inflammatory reaction. Severity grade criteria are
based on the number of necrotic hepatocytes per high power
microscopic field:
1 = One to three necrotic cells per high power
field. The area affected is limited to that of
a 20X field.
2 = One to three necrotic cells per high power
field, with large diffuse areas of involvement.
3 * Four to six necrotic hepatocytes per high power
field; diffuse area of involvement.
4 - More than seven necrotic hepatocytes per high
power field; diffuse involvement. If necrosis
involves foci of hepatocytes rather than
individual cells, the diagnosis of NECROSIS (#7
above) is used with appropriate distribution
modifier and severity grade.
13. BENIGN HYPERPLASTIC NODULE (S) - Spherical proliferation
of hepatocytes without cytologic atypia. Normal hepatic
architecture is present but it may be distorted; portal
triads may be present . There is mild compression of adjacent
parenchyma. Hepatocytes within a focus of hyperplasia are
usually uniform and have a homogeneous growth pattern, but
features such as hypertrophy, cytoplasmic vacuolation, and
increased numbers of mitoses may be present. Often the
distinction between focal hyperplasia and a focus of cellular
alteration rests solely on the degree of cytologic alteration
and compression of adjacent parenchyma. Hyperplastic lesions
may reach several millimeters in diameter and are frequently
seen as relatively distinct lesions in' histologic sections.
The lesion is coded as "Present" with an indication of
multifocal distribution if multiple lesions are present.
Brown et al. — 426
Appendix I (cont. ) : GLOSSARY OF TERMS
FOR PATHOLOGY FINDINGS
14 . NECROSIS/ PERIACINAR - Coagulative necrosis of
hepatocytes with a definite orientation around central veins.
In more severe cases the necrotic change may bridge from
central vein to central vein, or from central vein to portal
areas. Stromal collapse may occur; the necrotic area may be
filled with blood. Variable numbers and types of
inflammatory cells may be present. Adjacent lobules and/or
the capsule may be distorted. Changes -are usually uniform
with most or all the lobules affected. Severity grade
criteria:
1 = Minimal detectable necrosis around central
veins .
2 = Definite necrosis involving nearly all
periacinar hepatocytes in nearly all lobules.
3 = Bridging of periacinar areas by necrotic cells
and accompanying inflammatory cells .
4 = Necrosis and bridging of periacinar areas with
stromal collapse and blood pooling.
15. LARGE GRANULAR LYMPHOCYTE LEUKEMIA, METASTATIC - See
comments and description under "General Diagnoses" above.
16. FIBROSIS, PARENCHYMAL (SCARRING) - Presence of fibrous
connective tissue and minimal inflammatory cell infiltrate
within the liver parenchyma. This lesion occurs most
frequently near areas of compound-related inflammatory
reaction. Severity grade criteria:
1 = An area of fibrosis no larger than that of a
40X microscopic field.
2 = A fibrotic area as large as a 20X microscopic
field.
3 = A fibrotic area as large as 2 to 4 liver
lobules .
4 * A fibrotic area larger than 5 liver lobules.
17. HEPATOCYTE COALESCING MICROVESICULAR (FATTY) CHANGE
LEADING TO NECROSIS AND MINERALIZATION - Microscopically,
this lesion consists of microvesicular cytoplasmic change in
hepatocytes, rupture and disintegration of affected cells,
consequent enlargement of adjacent sinusoids, and the
presence of nearly colorless to light blue mineralized
crystals. The lesion usually has a focal or multifocal
distribution. Frozen sections stained with oil-red-0 or
Sudan Black demonstrate the presence of fat in vacuolated
hepatocytes near the dilated sinusoids. Numerous crystals
Brown et al . — 427
Appendix I (cont.) : GLOSSARY 07 TERMS
FOR PATHOLOGY FINDINGS
are present in these areas. Sections stained with Alizarin
Red-S and Von Kossa stain demonstrate that the crystals
contain both calcium and phosphate. Periodic Acid-Schiff
stains are noncontributory. The interpretation of these
findings is that fatty degenerative changes in hepatocytes
lead to necrosis and subsequent saponification of the
accumulated lipid. Severity grade criteria:
1 = Changes occur in small widely scattered foci.
2 = Foci are moce numerous and have a random
distribution. At least one focus per 20X
microscopic field is present, but is restricted
to one liver lobe .
3 = At least one focus per 20X field is present in
more than one liver lobe.
4 = Large numbers of foci (one per 40X field) are
present in one or more hepatic lobes.
18. PRESENCE OF METASTATIC SARCOMA - See comments and
description under "General Diagnoses" above.
19. HEPATOCELLULAR CARCINOMA - Malignant neoplasm of
hepatocytic origin. Diagnostic criteria for hepatocellular
carcinoma are well documented in the literature. The
criteria followed in this study were those of Maronpot et
al.. Toxicologic Pathology, 14:263-273, 1986. Criteria of
importance include cellular atypia, irregular shape, local
invasiveness, haphazardly arranged cells, broad sheets of
cells, trabecular patterns, and glandlike formations.
Vascular invasion or metastases are not essential for making
the diagnosis of carcinoma, but may be present. Hemorrhage
and necrosis may be present .
20. PRESENCE OF METASTATIC NEOPLASM - See descriptions and
comments under "General Diagnoses" above.
KIPHBX
1. PROGRESSIVE RENAL DISEASE - A progressive complex of
degenerative changes affecting all anatomic components of the
renal cortex and medulla. Interstitial changes begin as
small aggregates of mononuclear inflammatory cells and
progress to interstitial fibrosis and focal mineralization.
Tubular epithelial cells undergo degenerative changes such as
cytoplasmic vacuolization and accumulation of hyaline
droplets. Cells may become flattened due to accumulation of
1
Brown et al. — 428
Appendix I (cont.): GLOSSARY OF TERMS
FOR PATHOLOGY FINDINGS
eosinophilic fluid in the' lumen, or they may become
basophilic and hyperplastic during regenerative attempts.
Tubular basement membranes are frequently thickened.
Ultimately, both tubular dilatation and atrophy occur.
Glomerular changes consist of thickening of Bowman's capsule,
pericapsular fibrosis, hypercellularity of the glomerular
capillary tuft, and thickening of the mesangial matrix.
These changes progress to glomerular sclerosis and/or atrophy
with cystic dilatation of Bowman's space. Hyalinization of
arteriole walls and mineralization of tubular basement
membranes and necrotic tubular epithelial cells may be
present in severe stages of the disease. Severity grade
criteria :
1 = There are occasional aggregates of lymphocytes
near small vessels and between tubules. An
occasional tubule may be dilated and contain a
hyaline cast .
2 =* More tubules are dilated and contain casts.
Tubules have degenerative changes and basement
membranes are thickened. Glomeruli may be
hypercellular . Up to 25% of the renal cortex
is affected.
3 = Numerous tubules are dilated and contain
hyaline material. Tubular regeneration may be
present. Interstitial and periglomerular
fibrosis is present. Glomerular tufts are
thickened and hypercellular and a few glomeruli
are atrophied and dilated. Renal capsular
surface is irregular. Up to 50% of the kidney
is involved.
4 = Tubular dilatation, casts, necrosis, and
mineralization are widespread. Marked
interstitial fibrosis, glomerular atrophy and
dilatation, and irregularities of the capsular
surface are present. There is hyalinization of
small vessel walls. More than 50% of the
kidney is involved.
2. SARCOMA, NOT OTHERWISE SPECIFIED - Presence of a malignant
mesenchymal tumor within the kidney. Only one such lesion
was detected in this study in an animal that did not have a
sarcoma that developed within the fibrous reaction to the
test material. The animal having this lesion is a male in
the control group. This lesion is a well-differentiated
fibrosarcoma. Since no other lesion of this type can be
found in this animal, it is assumed that the kidney is the
Brown et al. — 429
Appendix I (cont.): GLOSSARY OF TERMS
FOR PATHOLOGY FINDINGS
primary site.
3. HEMORRHAGE, ACUTE - Presence of extravasated blood within
the kidney. Probably this lesion is induced during necropsy
procedures. The lesion is coded only as "Present."
4. HEMOSIDEROSIS (BROWN GRANULAR PIGMENT) IN TUBULAR
EPITHELIAL CELLS - Self-explanatory. This lesion is coded as
"Present . "
5. CYST (S) , CORTICAL - Presence of one or more cystic spaces
within the renal cortex. Cysts are lined by flattened
epithelium and may be either empty or filled with pale
homogeneous eosinophilic fluid. While this may be a
manifestation of progressive renal disease, this lesion is
coded separately if the cysts are more than three times the
diameter of a renal tubule. The lesion is coded as
"Present . "
6. INFARCT, CHRONIC WITH FIBROSIS, WITH OR WITHOUT
MINERALIZATION - Presence of well-demarcated, usually wedge-
shaped areas in the cortex composed primarily of fibrous
connective tissue and a few pigment-laden macrophages. A few
degenerating or necrotic tubular epithelial cells and mineral
deposits may be present. At the periphery of the lesion
there may be an infiltration of mononuclear inflammatory
cells and occasional areas of tubular regeneration. The
lesion is coded as "Present."
7. LARGE GRANULAR LYMPHOCYTE LEUKEMIA, METASTATIC - See
description and comments under "General Diagnoses" above.
8. FIBROSIS, CAPSULE - Proliferation of non-neoplastic
fibrous connective tissue with minimal infiltration of
mononuclear inflammatory cells in the renal capsule. The
lesion is coded as "Present."
9. PRESENCE OF METASTATIC SARCOMA - See description and
comments under "General Diagnoses" above.
10. PRESENCE OF METASTATIC NEOPLASM - See description and
comments under "General Diagnoses" above.
PRINARY BLADDER
1. TRANSITIONAL CELL PAPILLOMA - The presence of a neoplastic
Brown et al. — 430
Appendix I (cont.): GLOSSARY 07 TERMS
FOR PATHOLOGY FINDINGS
proliferation of transitional epithelium. The cells
comprising this tumor are well-differentiated transitional
epithelial cells. They are arranged in anastomosing fronds
which protrude into the lumen of the urinary bladder.
Mitotic figures are not very numerous. An occasional tumor
cell is undergoing coagulative necrosis. The tumor is highly
vascularized. There is no evidence of neoplastic
infiltration into the submucosa of the bladder nor invasion
of vessels or lymphatics.
2. CHRONIC INFLAMMATORY CELL INFILTRATION - Presence of
lymphocytes, macrophages, and plasma cells within the mucosa
and submucosa of the urinary bladder. . Severity grade
criteria :
1 * Minimal detectable inflammatory cell
infiltration into the submucosa.
2 = Mild inflammatory cell infiltration which may
involve both mucosa and submucosa. Less than
25% of the circumference of the bladder is
involved.
3 - Moderate infiltration of the mucosa and
submucosa causing thickening of these layers
and/or involving 25% to 50% of the
circumference of the bladder.
4 =* Marked thickening of mucosa and submucosa by
inflammatory cells involving more than 50% of
the circumference of the bladder.
PROSTATE
1. ACUTE SUPPURATIVE PROSTATITIS - Acute infiltration of
neutrophils into glandular or interstitial tissues of the
prostate. Necrosis may be present in more severe cases.
Severity grade criteria:
1 - Minimal detectable suppurative inflammation
involving less than 10% if the prostate.
2 - Neutrophilic infiltration involving 10% to 25%
of the prostate.
3 * Neutrophilic infiltration involving 25% to 50%
of the prostate. Small areas of necrosis may
be present.
4 * Infiltration of neutrophils involves more than
50% of the prostate. Necrotic areas up to the
diameter of a 20X microscopic field may be
Brown et al. — 431
Appendix I (cont.): GLOSSARY 07 TERMS
FOR PATHOLOGY FINDINGS
present .
2. CHRONIC PROSTATITIS - Infiltration of lymphocytes,
macrophages, plasma cells, and a few neutrophils into
glandular or interstitial areas of the prostate. The
secretory product is frequently inspissated in affected areas
and appears as small eosinophilic or basophilic particles
intermixed with inflammatory cells. Mineralization may be
present. This lesion frequently coexists with hyperplastic
changes in the glandular epithelium but the hyperplasia is
coded separately since either lesion can occur independently.
Severity grade criteria:
1 = Minimal detectable inflammatory cell
infiltration .
2 = Inflammatory cell infiltration involves 10% to
25% of the prostate.
3 *» Inflammatory cell infiltration involves 25% to
50% of the prostate.
4 = Inflammatory cell infiltration involves more
than 50% of the prostate..
3. BENIGN HYPERPLASIA - Hyperplastic proliferation of the
glandular epithelium of the prostate. Secretory cells are
larger and more numerous than normal . They may be piled two
to three cell layers thick on the basement membrane. There
is no cellular atypia and cells are distributed in normal
anatomic arrangement. This change may exist with, or
independent of inflammatory lesions and thus is coded
separately. Severity grade criteria:
1 = Hyperpl 3tic changes involve up to 10% of the
glandular epithelium.
2 = Hyperplastic changes involve 10% to 25% of the
epithelium.
3 * Hyperplastic changes involve 25% to 50% of the
epithelium.
4 = Hyperplastic changes involve more than 50% of
the epithelium.
4. MICROCALICULI, PROSTATIC URETHRA - Presence of particulate
material in the prostatic urethra. The material consists of
an amalgam of proteinaceous or mineralized material that has
variable staining characteristics presumably due to
variations in mineral content. There may be mild
infiltrations of mononuclear inflammatory cells within and
beneath the urethral epithelium. The lesion is coded as
Brown et al . — 432
Appendix I (cont.): GLOSSARY OF TERMS
FOR PATHOLOGY FINDINGS
"Present . "
5. PRESENCE OF METASTATIC SARCOMA - See descriptions and
comments under "General Diagnoses" above.
COAGULATING GLAND
No lesions were recognized in the coagulating glands of
rats used in this study.
SEMINAL VESICLE
1. GENERALIZED ATROPHY - Presence of atrophic changes in the
glandular epithelium of the seminal vesicle. Epithelial
cells in affected glands are low columnar to cuboidal,
smaller than in normal actively secreting glands, and the
meager cytoplasm stains weakly eosinophilic. Glandular
lumens contain very little secretory product in contrast to
normal glands which are distended with this material. This
change is coded as "Present."
2. PRESENCE OF METASTATIC SARCOMA - See descriptions and
comments under "General Diagnoses" above.
EPIDIDYMIS
1. PRESENCE OF METASTATIC SARCOMA - See descriptions and
comments under "General Diagnoses" above.
i&ax&a
1. TUBULAR ATROPHY - The cells lining seminiferous tubules
are reduced in number, and the tubules are reduced in
diameter. This change is invariably present in cases of
interstitial cell adenoma of the testis. Consequently, this
lesion is not coded when an interstitial cell tumor is
present, since the presence of the tumor itself indicates
that tubular atrophy is present. Tubular atrophy is coded
when testicular neoplasia was not present. Severity grade
criteria for tubular atrophy are as follows:
1 - There is absence or reduction in the number of
spermatozoa or spermatids in seminiferous
tubules .
2 - In addition to criteria in grade 1, there is
reduction in the innermost layers of
spermatogenic cells. A few large
multinucleated cells (degenerating
Brown et al. — 433
Appendix I (cont.): GLOSSARY OF TERMS
FOR PATHOLOGY FINDINGS
spermatocytes) may be free in the tubular
lumens .
3 * Only a few spermatogenic cells are present
along with a complete layer of Sertoli cells on
the basement membrane. Multinucleated cells
may be present.
4 * There is complete absence of spermatogenic
cells. Seminiferous tubules contain only
Sertoli cells.
2. INTERSTITIAL CELL HYPERPLASIA - There is focal or
multifocal proliferation of interstitial cells. These are
large cells with round nuclei and abundant eosinophilic
cytoplasm which may be finely vacuolated. They are situated
between seminiferous tubules. The change is considered
hyperplasia when foci of interstitial cells are no larger
than the diameter of a seminiferous tubule and there is no
compression of adjacent tissue. Foci of interstitial cells
larger than the diameter of a tubule, or that compress
adjacent tissue are coded as interstitial adenomas. If both
adenoma and hyperplasia is present, only the adenoma is
coded. Severity grade criteria:
1 * One to three foci of hyperplastic interstitial
cells are present.
2 - Four to six foci are present .
3 * Seven to ten foci are present .
4 = More than ten foci are present .
3. MESOTHELIOMA - Neoplastic proliferation of mesothelial
cells, arranged in multiple papillary fronds, arising from
the tunica albuginea of the testis. The papillary structures
are supported by a connective tissue stalk that contains
blood vessels. The neoplastic mesothelial cells may be
arranged in a single layer of flattened cells, or the cells
may be cuboidal and piled up to form small nodules. Mitotic
figures are usually infrequent.
4. INTERSTITIAL CELL ADENOMA - A benign tumor of interstitial
(Leydig) cells. These tumors are composed of cells of four
distinct morphologic types. The most common is a medium¬
sized hexagonal cell with distinct cell boundaries having
eosinophilic cytoplasm surrounding a regular, round or oval
vesicular nucleus. The nucleus has a delicate chromatin
network and a single small basophilic nucleolus. The second
cell type is larger with finely or coarsely vacuolated
cytoplasm. A third cell type is small, elongated or spindle
Brown et al . — 434
Appendix I (cont.): GLOSSARY OF TERMS
FOR PATHOLOGY FINDINGS
shaped, with granular eosinophilic cytoplasm and variably-
sized, round, oval, or spindle-shaped nuclei which may be
vesicular or pyknotic. The fourth type of cell resembles a
lymphocyte with scanty cytoplasm and a small round nucleus
with a "wheel-like" chromatin pattern. Neoplastic cells are
arranged in cords, fascicles, islands, and nests, and usually
show an endocrine pattern of vascularity. The stroma is
usually delicate, but may be hyalinized or even calcified.
These tumors are highly vascular and often there are large,
distended endothelial-lined spaces filled with blood.
Invariably, there are secondary lesions in the testis when
interstitial cell adenoma is present. Atrophic or
degenerative changes affecting seminiferous tubules are
almost always present, and hemorrhage, necrosis, and
mineralization may occur within the tumor. These lesions are
not coded separately when interstitial adenoma is present.
5. PERIARTERITIS NODOSA - An acute, subacute, or chronic
inflammatory lesion involving small or medium-sized muscular
arteries in the testis. This lesion is characterized by sub-
endothelial edema, damage to the elastic membrane, fibrinoid
or hyaline necrosis of the media, and inflammatory cell
infiltration into all layers of the arterial wall.
Inflammatory cells are most abundant in the adventitia and
are composed of neutrophils, lymphocytes, and plasma cells
with fewer macrophages and eosinophils . It occurs as a focal
or segmental lesion with some areas of an artery severely
affected, and other areas essentially normal. No attempt is
made to grade the severity of this lesion. It is coded as
"Present . "
6. PRESENCE OF METASTATIC SARCOMA - See descriptions and
comments under "General Diagnoses" above.
7. PRESENCE OF METASTATIC NEOPLASM - See descriptions and
comments under "General Diagnoses" above.
1. COMPOUND-RELATED INFLAMMATORY REACTION - See descriptions
and comments under "General Diagnoses" above.
2. DILATATION OF THE UTERINE LUMEN (HYDROMETRA) - There is
dilatation of the uterine lumen which is usually empty. The
endometrium and underlying stroma may be slightly atrophic.
The lesion is coded as "Present."
Brown et al. — 435
Appendix I (cont.) : GLOSSARY OF TERMS
FOR PATHOLOGY FINDINGS
3. PYOMETRA - There is suppurative inflammation involving the
uterine lumen, endometrium, endometrial glands, and stroma.
Small foci or areas of necrosis may be present in areas
severely affected. Severity grade criteria:
1 = Presence of a few neutrophils within the
endometrium.
2 = Moderate numbers of neutrophils are present
within the endometrium, endometrial glands, and
stroma .
3 = Neutrophilic infiltration as in grade 2 and
presence of neutrophils within the uterine
lumen .
4 = Changes as in grade 3 plus distention of the
uterine lumen with suppurative exudate and/or
the extension of inflammatory process into the
uterine musculature.
4. ENDOMETRIAL STROMAL POLYP - These lesions consist of
polypoid masses which protrude from the uterine wall into the
lumen. The mass is covered by essentially normal endometrial
surface epithelium. Within the mass there are relatively
normal-appearing uterine glands; some may be dilated and
cystic. The mass consists primarily of dense or loosely
arranged f ibrovascular stroma containing collagen and
numerous small vessels . Some smooth muscle cells may be
present. A few mitotic figures may be present in both stroma
and epithelium. Focal ulceration of the epithelium
accompanied by inflammatory cell infiltration may be present.
The lesion is coded as "Present."
5. CYSTIC DILATATION OF ENDOMETRIAL GLANDS - Self-
explanatory. Coded as "Present."
6. LYMPHOCYTIC INFILTRATE - Presence of lymphocytes within
the endometrium, stroma, or uterine wall. Severity grade
criteria:
1 - There are a few lymphocytes within the
endometrium.
2 - There is mild lymphocytic infiltrate in the
endometrium and around uterine glands.
3 - There are moderate numbers of lymphocytes in
the endometrium and endometrial stroma.
4 * The lymphocytic infiltrate involves
endometrium, stroma, and extends into the
uterine musculature.
Brown et al . — 436
Appendix I (cont. ) : GLOSSARY Or TERMS
FOR PATHOLOGY FINDINGS
7 . ENDOMETRIAL STROMAL SARCOMA - A malignant proliferation of
endometrial stromal cells. These are usually highly cellular
masses which may protrude into the uterine lumen or invade
the uterine musculature. Cells are usually spindeloid with
elongated dense hyper chromatic nuclei and scanty amounts of
cytoplasm which are either weakly eosinophilic or nearly
colorless. Cells are arranged in a variety of patterns
including parallel arrays, interlacing bundles, or haphazard
proliferations. Cells often are fairly anaplastic and
mitotic figures may be numerous. Hemorrhage and necrosis are
common especially in the large polypoid masses. The surface
epithelium and endometrial glands are usually normal,
although inflammation and degeneration of these components
may occur. These tumors differ from stromal polyps in their
increased cellularity, cellular atypia, and invasiveness. No
metastatic lesions of this type were observed in this study.
8. ENDOMETRITIS, SUBACUTE - Subacute inflammatory reaction
involving the endometrium. There is infiltration of
neutrophils, lymphocytes, macrophages, and plasma cells into
the endometrial epithelium, underlying stroma, and uterine
glands. This lesion differs from pyometra (Diagnosis #3) in
that the inflammatory cell population is mixed and no
suppurative exudate is present in the uterine lumen. The
mixed cell population differentiates this lesion from the
pure lymphocytic infiltrate described in Diagnosis #6 above.
Severity grade criteria for this lesion:
1 - There is minimal infiltration of mixed
inflammatory cells in the endometrium.
2 = There is mild infiltration of inflammatory
cells in endometrium, and into and around
uterine glands .
3 * There is moderated infiltration of inflammatory
cells in endometrium and all areas of the
stroma. Minimal amounts of necrosis may be
present in these areas .
4 - There are marked mixed inflammatory cell
infiltrate and areas of necrosis that involve
endometrium, stroma, and uterine musculature.
9. LARGE GRANULAR LYMPHOCYTE LEUKEMIA, METASTATIC - See
descriptions and comments under "General Diagnoses" above.
10. DEGENERATION, NECROSIS AND INFLAMMATION OF UTERINE STROMA
- This unusual lesion is characterized by t abundance of
necrotic debris and fibrin within the uterine lumen.
Brown et al. — 437
Appendix I (coat.): GLOSSARY OF TERMS
FOR PATHOLOGY FINDINGS
degeneration, necrosis, and proliferation of endometrial
stromal cells, dilatation of endometrial glands, moderate
mixed inflammatory cell infiltration into all layers of the
uterine wall, and the presence of many large cells with
abundant poorly stained cytoplasm. These cells are situated
primarily on the lumenal surface of the uterus but in some
areas extend through the stroma and infiltrate the uterine
musculature. Sections stained with periodic acid-Schiff,
alcian blue, and mucicarmine stains failed to characterize
the cytoplasmic content of these cells. Their identity and
character remain unknown. This unusual lesion was observed
in only one rat, a female in the Control group that survived
until terminal sacrifice. The morphologic characteristics of
this lesion do not correspond to the criteria of the other
more readily recognized uterine lesions observed in this
study, hence this descriptive diagnosis is given.
11. LEIOMYOSARCOMA - A malignant neoplasm of smooth muscle
origin. This is a highly cellular tumor characterized by
spindeloid cells arranged in interlacing bundles, and
situated in the wall of the uterus. The cells are large and
spindeloid to fusiform with moderate amounts of eosinophilic
cytoplasm and elongated nuclei with blunt or rounded ends.
The cells are well differentiated and mitotic figures are not
numerous. The tumor infiltrates and separates adjacent
normal smooth muscle cells in an irregular fashion and
invades the adjacent endometrial stroma.
OVARIES
No attempt is made to document ovarian changes that
occur as a result of different stages of the estrus cycle, or
that result from normal variations in hormonal stimulation.
Only changes considered abnormal are documented in this
study .
1. FOLLICULAR CYSTS - Presence of large cystic structures in
the ovarian cortex. Cysts are lined by a layer of granulosal
cells which varies considerably in thickness. Degeneration
and atrophy of the lining cell layers are common and there
may be a few degenerating cells free within the pale
eosinophilic fluid that fills the cystic lumen. The cysts
are coded as "Present."
2. CYSTIC CORPORA LUTEA - Presence of cystic structures in
the ovarian cortex. Cysts are lined by a layer of luteal
Brown et al . — 438
Appendix I (cont.): GLOSSARY OP TERMS
TOR PATHOLOGY FINDINGS
cells that varies considerably in thickness. Degeneration,
atrophy, and infiltration of a very few mononuclear
inflammatory cells may occur. The lumen of the cyst may be
empty or filled with pale eosinophilic fluid. The cysts are
coded as "Present.”
3. PARA-OVARIAN CYST(S) - Presence of a cystic structure
located adjacent to the ovary but does not involve ovarian
tissue. Frequently this lesion consists only of a thin
fibrous strand of tissue (the wall of the cyst) which may be
lined by a single layer of flat "endothelial-like" cells.
Ovaries adjacent to these cysts may be small and atrophic.
Para-ovarian cysts are coded as "Present."
4. INFLAMMATORY CELL INFILTRATION - The presence of
lymphocytes, macrophages, plasma cells, or (rarely)
neutrophils within ovarian tissues. This lesion is observed
infrequently. Severity grade criteria are subjective
assessments of the number of inflammatory cells present:
1 = Minimal inflammatory cells present.
2 * Mild inflammatory cell infiltration.
3 = Moderate inflammatory cell infiltration.
4 - Marked inflammatory cell infiltration.
5. LARGE GRANULAR LYMPHOCYTE LEUKEMIA, METASTATIC - See
descriptions and comments under "General Diagnoses" above.
6. PRESENCE OF METASTATIC NEOPLASM - See descriptions and
comments under "General Diagnoses" above.
QUQPBHPM
1. COMPOUND-RELATED INFLAMMATORY REACTION - See description
and comments under "General Diagnoses" above.
2. PRESENCE OF METASTATIC SARCOMA - See descriptions and
comments under "General Diagnoses" above.
3. PRESENCE OF METASTATIC NEOPLASM - See descriptions and
comments under "General Diagnoses" above.
4. MUCOSAL EROSION/ULCERATION - Necrosis and sloughing of the
epithelium on the mucosal surface. In an erosion, the
necrosis is limited to the epithelial layer; the basement
membrane is intact. An ulceration consists of necrosis that
Brown et ai . — 439
Appendix I (cont . ) : GLOSSARY OT TERMS
FOR PATHOLOGY FINDINGS
involves the surface epithelium, extends through the basement
membrane, and affects the underlying submucosa. In both
lesions, tissues adjacent to necrotic areas are infiltrated
with neutrophils, lymphocytes, and macrophages. In chronic
ulcers, there may be fibrous connective tissue proliferation
and regenerating mucosal epithelium at the periphery of the
lesion. These lesions are coded as "Present."
5. PRESENCE OF MUCOSAL EPITHELIAL CELLS WITHIN INTESTINAL
WALL AND ADJACENT FIBROUS/GRANULOMATOUS INFLAMMATORY REACTION
- In some animals the test material adhered to the intestinal
wall inciting the usual foreign-body inflammatory response.
In some of these animals, there is chronic ulceration of the
epithelium at this location. Microscopic examination reveals
the presence of regenerating intestinal epithelial cells in
the submucosa, within the muscular layers, in subserosal
locations, and within the adjacent chronic granulomatous
inflammatory tissue. These entrapped cells have essentially
normal histologic characteristics except for their location
and occasional degenerative or atrophic changes. There are
no indications of cellular atypia, nuclear pleomorphism, or
abnormal mitotic activity characteristic of neoplasia. This
change is interpreted as regeneration of intestinal
epithelium which has migrated into, and become entrapped in
an ongoing chronic inflammatory response that affects the
entire thickness of the intestinal wall. This lesion is
coded as "Present."
JBJPMPM
1. COMPOUND-RELATED INFLAMMATORY REACTION - See "General
Diagnoses" above.
2. ACUTE PERITONITIS - The presence of neutrophils, fibrin,
necrotic debris, and mononuclear inflammatory cells on the
serosal surface. No test material, foreign-body giant cells,
or fibrosis are present. Severity grade is based on
subjective assessment of the intensity and extent of the
inflammatory process :
1 - Minimal inflammation.
2 ■ Mild inflammation.
3 - Moderate inflammation.
4 = Marked inflammation.
3. ENTERITIS, SUBACUTE - Consists of the infiltration of
Brown et al. — 440
Appendix I (cont . ) : GLOSSARY 07 TERMS
FOR PATHOLOGY FINDINGS
lymphocytes, macrophages, plasma cells, and a few neutrophils
into the mucosa, lamina propria, submucosa, and muscular wall
of the jejunum. In more severe cases there may be small
areas of necrosis in the layers involved. Severity grade
criteria :
1 = Minimal inflammatory cell infiltration in
mucosa and/or lamina propria.
2 = Mild inflammatory cell infiltration with edema,
in mucosa, lamina propria, and extending into
the submucosa.
3 = A moderate inflammatory infiltrate and edema
involves mucosa, lamina propria and submucosa
causing increased thickness of these layers.
Small foci or areas of necrosis may be present
in the mucosa.
4 = A marked inflammatory cell infiltrate
accompanied by edema, involves mucosa, lamina
propria, submucosa, and extends into the
muscular coats. Foci or areas of necrosis are
present in the mucosa and lamina propria and
may involve deeper layers .
4. MUCOSAL EROSION/ULCERATION - Except for location in the
jejunum, this lesion is similar to that described in
Diagnosis #4 under DUODENUM above.
5. PRESENCE OF MUCOSAL EPITHELIAL CELLS WITHIN INTESTINAL
WALL AND ADJACENT FIBROUS /GRANULOMATOUS INFLAMMATORY REACTION
- Except for location in the jejunum this lesion is similar
to that described ir. Diagnosis #5 under DUODENUM above.
6. PRESENCE OF METASTATIC SARCOMA - See "General Diagnoses"
above .
7. FIBROVASCULAR ADHESION, SEROSA - Self-explanatory.
Minimal inflammatory cell infiltration, no test material and
no foreign-body giant cells are present. Lesion is coded as
"Present . "
8. PRESENCE OF METASTATIC NEOPLASM - See "General Diagnoses"
above .
ILEUM
1. COMPOUND-RELATED INFLAMMATORY REACTION - See "General
Brown et al . — 441
Appendix I (cont . ) : GLOSSARY or TERMS
FOR PATHOLOGY FINDINGS
Diagnoses" above.
2. LARGE GRANULAR LYMPHOCYTE LEUKEMIA, METASTATIC - See
"General Diagnoses" above.
3. PRESENCE OF METASTATIC SARCOMA - See "General Diagnoses"
above .
4. LYMPHOID HYPERPLASIA - This change involves the gut-
associated lymphoid tissue in the ileum, and consists of
increased size and number of lymphoid follicles, increased
number of large, pale, immature lymphocytes in germinal
centers and perifollicular areas, increased mitotic activity
in lymphoid cells, and the extension of lymphoid cells from
the submucosa into the lamina propria and mucosal layers of
the ileum. This change is coded as "Present."
5. PRESENCE OF METASTATIC NEOPLASM - See "General Diagnoses"
above .
FAMgRfifta
1. ACINAR (EXOCRINE) ATROPHY - This lesion consists of the
absence or reduction in number of acinar secretory cells.
Affected lobules contain only ductal structures in a
f ibrovascular stroma. Such lesions are usually focal
affecting a small lobule of pancreatic tissue. Severity
grade criteria:
1 = One lobule affected.
2 = Two or three lobules affected.
3 = Four to six lobules affected.
4 = More than six lobules affected.
2. CHRONIC INFLAMMATION - Infiltration of neutrophils
lymphocytes, macrophages, and plasma cells into acinar areas,
stromal tissues, and serosal surfaces of the pancreas. There
may be variable amounts of edema, fibrin deposition,
fibrosis, tissue necrosis, and mineralized deposits in
necrotic areas depending on the severity and age of the
lesion. Severity grade criteria:
1 = Minimal focal to multifocal inflammatory cell
infiltration .
2 = Mild focal to diffuse inflammatory cell
infiltrate with or without fibrosis, affecting
Brown et al . — 442
Appendix I (cont.): GLOSSARY or TERMS
FOR PATHOLOGY FINDINGS
up to 50% of the pancreas .
3 = A few small foci of necrosis may be present
along with moderate inflammatory cell
infiltration and fibrosis.
4 = Numerous foci or large areas of necrosis which
may be accompanied by mineralization.
Inflammatory cell infiltrate and fibrosis are
marked and diffuse.
3. ISLET CELL ADENOMA - Benign neoplastic proliferation of
pancreatic islet cells. These adenomas are usually nearly
spherical proliferations of medium-sized, well-differentiated
islet cells. The cells are arranged in small nests, packets,
or short cords supported by very delicate f ibrovascular
stroma. Cytoplasm is weakly eosinophilic and has distinct
cellular boundaries. Nuclei are round and fairly small with
condensed chromatin. Mitotic figures are sparse. The tumors
are discrete and compress adjacent tissues slightly.
4. PERIARTERITIS NODOSA - An acute, subacute, or chronic
inflammatory lesion involving small to medium-sized muscular
arteries in the pancreas. The lesion is characterized by
subendothelial edema, hyaline, or fibrinoid necrosis of the
media, and infiltration of all layers of the arterial wall by
inflammatory cells. Inflammatory cell infiltration is most
prevalent in the adventitia and consists of neutrophils,
lymphocytes, and plasma cells with fewer macrophages and
eosinophils. The lesion is usually focal or segmental with
some areas of an artery being severely affected and other
areas essentially normal. The lesion is coded as "Present."
5. ACINAR HYPERPLASIA - Focal or multifocal non-neoplastic
proliferation of pancreatic acinar secretory cells. Within
an affected lobule, there are increased numbers of secretory
cells which are either normal size or slightly smaller than
normal. The cells are crowded, but are arranged in
essentially normal fashion relative to basement membranes.
Hyperplastic cells are usually slightly hyperchromatic but
often lack normal numbers of zymogen granules. Severity
grade criteria:
1 - One pancreatic lobule is affected.
2 * Two or three lobules are affected.
3 = Four to six lobules are affected.
4 = More than six lobules are affected.
6. COMPOUND-RELATED INFLAMMATORY REACTION - See "General
Brown et al. — 443
Appendix I (cont.) : GLOSSARY OF TERMS
FOR PATHOLOGY FINDINGS
Diagnoses" above.
7. PRESENCE OF METASTATIC SARCOMA - See "General Diagnoses”
above .
8. LARGE GRANULAR LYMPHOCYTE LEUKEMIA, METASTATIC - See
"General Diagnoses" above.
9. PRESENCE OF METASTATIC NEOPLASM - See "General Diagnoses"
above .
10. CYSTIC DUCT - Cystic dilatation of one or more ducts
within the pancreas. Dilated area is more than three times
the diameter of a normal duct . The lumen is usually empty
and the lining epithelium may be flattened and atrophic. The
lesion is coded as "Present."
CECUM
1. COMPOUND-RELATED INFLAMMATORY REACTION - See "General
Diagnoses" above.
2. PERIARTERITIS NODOSA, ARTERIES IN CECAL WALL OR MESENTERY
- See descriptions and comments for Diagnosis #4 under
PANCREAS above. The characteristics of the arterial changes
are similar in both organs.
3. PRESENCE OF METASTATIC SARCOMA - See "General Diagnoses"
above .
4. ADENOMATOUS POLYP - This lesion is a large polypoid mass
attached to the wall of the cecum by a broad base. The
intralumenal surface of the mass is covered by well-
differentiated epithelium arranged in long tortuous tubular
glands. The lamina propria between glands is slightly
separated by edema and a mild uniform infiltration of
lymphocytes and a few plasma cells. The bulk of the mass
consists of the underlying stroma which is characterized by
numerous endothelial-lined spaces that vary considerably in
size and shape. Most of the vascular spaces are small and
slit-like, although there are a few that are larger and
irregular in shape. Most of these spaces are empty. Between
the vascular spaces there are numerous loosely-arranged
fibrocytes and small foci of mononuclear inflammatory cells.
A few small muscular arteries are present in this area. Only
one lesion of this type was observed in this study. It
occurred in a female rat in the control group.
Brown et al. — 444
Appendix I (cont . ) : GLOSSARY OF TERMS
FOR PATHOLOGY FINDINGS
5. REACTIVE LYMPHOID HYPERPLASIA, SUBMUCOSA - This change is
essentially identical to that in the ILEUM. See diagnosis #4
under ILEUM above for a detailed description.
6. EDEMA OF THE SUBMUCOSA AND/OR LAMINA PROPRIA - The
cellular elements and connective tissue in the submucosa and
lamina propria are separated by the presence of weakly
eosinophilic edema fluid. This lesion is coded as "Present."
7. MONONUCLEAR CELL INFILTRATION - The lamina propria and
submucosa are infiltrated by small numbers of lymphocytes,
plasma cells, and macrophages. The lesion is coded as
"Present."
RE C TOM
1. FIBROSARCOMA, LOCALLY INVASIVE - These tumors are highly
cellular and consist of spindeloid cells with varying amounts
of eosinophilic cytoplasm and oval to elongated nuclei.
Mitotic figures may be very numerous and large bizarre forms
occur occasionally. The cells are arranged in broad sheets,
parallel arrays, and interlacing bundles. In more anaplastic
tumors, a definite cellular pattern may be difficult to
detect. Sections stained with Masson's trichrome stain
usually reveal the presence of abundant collagen. The most
probable primary site for this tumor is the inguinal or
perineal subcutaneous tissue. Three fibrosarcomas were
present in this location in Study GLP 83009. All three
animals were females; one in the control group, one in the
high-dose group and one in the low-dose group. In all three
animals, the tumors were confined to the inguinal or perineal
subcutis with local invasion of adjacent pelvic viscera. In
none of these cases was there evidence of the sarcoma
elsewhere in the abdominal cavity. No test material or
granulomatous inflammatory lesions were observed in
association with these perirectal tumors.
C.QJL&H
1. COMPOUND-PELATED INFLAMMATORY REACTION - See "General
Diagnoses" above.
2. CHRONIC COLITIS WITH MUCOUS GLAND HYPERPLASIA AND
HYPERSECRETION - The mucosa, lamina propria, and submucosa
are infiltrated with lymphocytes, macrophages, plasma cells,
and an occasional neutrophil. Many of the glands in the
Brown et al. — 445
Appendix I (cont . ) : GLOSSARY OF TERMS
FOR PATHOLOGY FINDINGS
mucosa are distended with mucus. Small amounts of mucus
adhere to the mucosal surface and are present in the lumen.
Epithelial cells in the mucosal glands are hyperplastic.
Severity grade criteria are not applicable since only two
animals in this study had this lesion.
3. PRESENCE OF METASTATIC SARCOMA - See "General Diagnoses"
above .
4. POLYP, CYSTIC, WITH MUCINOUS EPITHELIAL HYPERPLASIA AND
OSSEOUS METAPLASIA AND/OR MINERALIZATION OF THE STROMA -
These unusual lesions consist of large polypoid growths which
extend into the lumen of the colon. The mass is covered by
colonic epithelium which in some areas is ulcerated and
accompanied by a chronic inflammatory response consisting of
mononuclear cell infiltration and fibrosis. Within the mass
are numerous large cystic spaces that are lined by flattened
epithelium containing numerous mucus-secreting cells. These
cystic cavities are distended with mucus that contains a few
inflammatory cells and small particles of cellular debris.
The stroma between the mucus-filled cysts consists of
numerous slit-like endothelial-lined vascular spaces, fibrous
connective tissue which is very dense in some areas and
loosely arranged and edematous in others, and a multifocal to
diffuse infiltration of mononuclear inflammatory cells. In
some areas the dense fibrous stroma is mineralized and in
other places there are spicules of metaplastic bone. The
adjacent colonic mucosa is ulcerated, infiltrated with
inflammatory cells, and contains areas of fibrous connective
tissue proliferation and foci of hyperplastic (regenerating)
epithelial cells. These lesions occur in only two animals;
both males in the high-dose group. In both cases there are
serosal adhesions of the colon that could be attributed to
the presence of the test material. In one case, the cecum
and its cystic polypoid mass are adhered to the surface of
the liver. It is probable that the presence of the test
material an'’, the reaction to it contributed to the
development of these unusual lesions in the colon. The
lesion is coded as "Present."
STQMAfia
Mucosal glandular dilatation was observed
microscopically in almost every rat that was necropsied
during the second year of this study. Since this change is
universally present in all three experimental groups, it is
Brown et al . — 446
Appendix I (cont.) : GLOSSARY or TERMS
rOR PATHOLOGY FINDINGS
considered as a normal aging change and is not coded.
1. COMPOUND-RELATED INFLAMMATORY REACTION - See "General
Diagnoses" above.
2. SEROSAL FIBROSIS - The presence of fibrous connective
tissue proliferation on the serosal surface. Minimal numbers
of inflammatory cells may be present. There is no test
material or foreign-body giant cells. The lesion is coded as
"Present . "
3. ULCERATION, NONGLANDULAR AREA - There is necrosis and
sloughing of the squamous epithelial lining of the non-
glandular portion of the stomach. Mononuclear inflammatory
cell infiltration, edema, and proliferation of small amounts
of fibrous connective tissue may be present at the periphery
of the ulcer and in underlying stomach wall. The lesion is
coded as "Present."
4. MUCOSAL AND/OR SUBMUCOSAL EDEMA - Cellular elements of the
stomach mucosa and/or submucosa are separated by the presence
of pale eosinophilic edema fluid. This lesion may occur in
either the glandular or squamous -lined portions of the
stomach. The lesion is coded as "Present."
5. LARGE GRANULAR LYMPHOCYTE LEUKEMIA - See "General
Diagnoses" above.
6. PRESENCE OF METASTATIC SARCOMA - See "General Diagnoses"
above .
7. SQUAMOUS CELL PAPILLOMA - There is a well-defined
proliferation of the squamous epithelium of the stomach. The
proliferating epithelial cells are well differentiated and
are arranged in blunt papillary projections which extend into
the lumen. The surface of the growth is usually keratinized.
Proliferation of basal cells can be seen. The growth does
not extend beyond the basement membrane . The mucosa and
submucosa adjacent to papillomas are usually infiltrated by
mononuclear inflammatory cells.
8. EROSION AND/OR ULCERATION OF THE GLANDULAR MUCOSA - There
is necrosis and sloughing of the epithelial cells in the
glandular portion of the stomach mucosa. In an erosion, the
necrosis is confined to the epithelial lining; in the case of
ulceration, the necrotic process extends beyond the basement
membrane to involve the underlying submucosa. Adjacent to
Brown et al. — 447
Appendix I (cont.): GLOSSARY 07 TERMS
FOR PATHOLOGY FINDINGS
the area of necrosis, there is usually infiltration of
mononuclear inflammatory cells and, in chronic cases, fibrous
connective tissue proliferation. Severity grade criteria:
1 = Small focal area of necrosis less than the
diameter of a 20X microscopic field.
2 = An area of necrosis less than the diameter of a
10X microscopic field.
3 = The necrotic area extends beyond the basement
membrane and occupies an area as large as a 10X
microscopic field.
4 = The ulcerated area is greater than the diameter
of a 4X microscopic field.
SKELETAL MPSCLE
1. ACUTE MYOSITIS - This is acute inflammation of skeletal
muscle tissue. Muscle fibers are separated by infiltration
of neutrophils and fewer macrophages and lymphocytes. In
more severe cases there is coagulative necrosis of muscle
fibers and phagocytosis of the necrotic cellular debris.
Severity grade criteria:
1 * Minimal detectable infiltration of neutrophils.
2 * Mild infiltration of neutrophils and a few
macrophages in an area up to the diameter of a
10X microscopic field.
3 *> Coagulative necrosis of muscle tissue with
neutrophil infiltration. The size of the
necrotic area is less than a 20X microscopic
field.
4 = Necrosis of muscle and neutrophilic
infiltration. The necrotic area exceeds the
diameter of a 20X field.
2. CHRONIC MYOSITIS - Consists of chronic inflammation of
skeletal muscle. Muscle cells are separated by infiltration
of mononuclear inflammatory cells in which large macrophages
predominate. In more severe cases there is necrosis of
muscle fibers and the phagocytosis of necrotic debris by
macrophages. Muscle fiber regeneration and fibrous
connective tissue proliferation may be present. Severity
grade criteria:
1 = Minimal detectable infiltration of mononuclear
inflammatory cells.
Brown et al. — 448
Appendix I (cont.): GLOSSARY 07 TERMS
70R PATHOLOGY FINDINGS
2 Mild infiltration of mononuclear inflammatory
cells. Fibrosis may be present. The lesion is
focal and does not exceed the diameter of a 10X
microscopic field.
3 = There is necrosis of muscle cells with
phagocytosis of debris by macrophages.
Regeneration may be present. The area of
necrosis is less than that of a 20X microscopic
field.
4 = Lesion is similar to grade 3; the necrotic area
is larger than a 20X field.
3. CHRONIC INFLAMMATION RESTRICTED TO FASCIA - This lesion
consists of infiltration of lymphocytes, macrophages, and
plasma cells into the fascia dividing bundles of skeletal
muscle fibers. In addition, there may be increased amounts
of fibrous tissue in these septae. There is no damage or
inflammatory cell infiltration into adjacent muscle bundles.
Severity grade criteria:
1 = Minimal inflammatory cell infiltration
involving an area smaller than a 20X
microscopic field.
2 « Mild inflammatory cell infiltration involving
an area smaller than a 10X field.
3 = Inflammatory cell infiltration involving an
area larger than a 10X field.
4 = Inflammatory cell infiltration involving an
area larger than a 4X field.
SCIATIC NSRYtt
No lesions were observed in sciatic nerves of rats on
this study.
TQHSUB
1. MONONUCLEAR CELLULAR INFILTRATION - There is focal,
multifocal, or diffuse infiltration of mononuclear
inflammatory cells between skeletal muscle fibers in the
tongue. Severity grades are based on subjective assessment
of the number of cells present:
1 = Minimal
2 - Mild
3 = Moderate
4 Marked
Brown et al. — 449
Appendix I (cont . ) : GLOSSARY OF TERMS
FOR PATHOLOGY FINDINGS
2. PERIARTERITIS - Inf lanunatory cell infiltration of the
adventitia of small to medium-sized arteries and adjacent
tissues. Severity grades are based on subjective assessment:
1 = Minimal
2 =• Mild
3 = Moderate
4 = Marked
3. MEDIAL HYPERTROPHY AND MINERALIZATION OF MEDIUM-SIZED
MUSCULAR ARTERIES - There is thickening of the muscular layer
of the arterial wall. Several vessels in the same tongue
section are often affected. Hyali nization and mineralization
of hypertrophied muscle may be present. The lesion is coded
as "Present."
SKIN
1. COMPOUND-RELATED INFLAMMATORY REACTION - See "General
Diagnoses" above.
2. INFLAMMATORY EXUDATE ON SKIN SURFACE - There is a mixture
of neutrophils, macrophages, fibrin, and cellular debris on
the surface of the skin. Severity grades are based on the
amount of surface area involved relative to different
microscopic magnifications:
1 = Area is less than the diameter of a 20X field.
2 = Area is less than the diameter of a 10X field.
3 = Area is less than the diameter of a 4X field.
4 - Area is larger than the diameter of a 4X field.
2. PROCEDURE-RELATED GRANULOMATOUS CELLULITIS, SUBCUTIS -
Compound- related inflammatory reactions in the subcutis are
similar to those in other locations. See "General Diagnoses"
above .
3. NONSUPPURATIVE DERMATITIS - There is a subacute
inflammatory process involving the epidermis and dermis. The
predominant change involves infiltration of lymphocytes,
macrophages, plasma cells, and fewer neutrophils and
eosinophils into these areas. The inflammatory cells are
present within the epidermis, along the basement membrane,
and between adnexal structures in the dermis . Severity
grades are based on the amount of inflammatory cell
infiltration :
Brown et al. — 450
Appendix I (eont . ) : GLOSSARY OF TERMS
FOR PATHOLOGY FINDINGS
1 - Minimal detectable inflammatory cell
infiltrate .
2 = Mild diffuse infiltrate.
3 = Moderate numbers of inflammatory cells
4 = Affected area is nearly solidly infiltrated.
4 . CELLULITIS - An acute, subacute, or chronic inflammatory
process in subcutaneous tissue characterized by inflammatory
cell infiltration. Necrosis, cellular debris, and fibrin may
be present in more severe cases. No te3t material or
foreign-body giant cells are present. Severity grade
criteria :
1 * Minimum detectable inflammatory cell
infiltration in the subcutaneous tissues.
2 = Mild inflammatory cell infiltration. May be
focal (less than the diameter of a 10X field)
or diffuse.
3 = Moderate numbers of inflammatory cells
distributed either focally or diffusely. Small
foci of necrosis, less than the diameter of a
4 OX field may be present.
4 * Marked inflammatory cell infiltration and/or
large areas of necrosis.
5. KERATOACANTHOMA (INVERTED PAPILLOMA), ANATOMIC SITE TO BE
SPECIFIED - A benign, well-encapsulated tumor, typically
raised above the surrounding epidermis, with a central crater
or pore that is filled with keratin. The neoplastic
epidermis lining the crater contains many keratinized pearls,
which are particularly numerous near the center of the tumor.
There is sharp demarcation between tumor epithelium and the
surrounding dermis. The anatomic location is documented
using the special histologic comment feature of the Xybion
program.
6. EROSION/ULCERATION OF THE SKIN SURFACE - An erosion is
necrosis and sloughing of the surface epithelium. The
basement membrane is intact. An ulceration is necrosis of
the skin which extends beyond the basement membrane to
involve the underlying dermis. Usually, there is
infiltration of neutrophils, lymphocytes, and macrophages at
the periphery of such lesions. In chronic cases there may be
fibrosis and attempts at epithelial regeneration as well.
The lesion is coded as "Present."
Brown et al. — 451
Appendix I (eont.): GLOSSARY OF TERMS
FOR PATHOLOGY FINDINGS
7. BASAL CELL TUMOR - Benign tumor of basal cell origin.
Basal cells are usually arranged in long serpentine ribbons
or small nests. The tumors are well demarcated from adjacent
tissues in the dermis. The tumor cells are small with small
amounts of lightly basophilic cytoplasm and round to oval
vesicular nuclei. Mitotic figures are rare. There is a
minimal amount of fine fibrous stroma. There is no evidence
of invasion or metastasis.
8. BASAL CELL CARCINOMA - A malignant neoplasm of basal cell
origin. Cellular morphology and growth patterns are very
similar to the benign basal cell tumor. Criterion that
distinguishes malignant tumors is their invasiveness of
adjacent tissue. Tumor cells are not confined by the
enveloping capsule and invade adjacent tissue.
9. FIBROMA - Benign tumor of fibrous connective tissue.
These are well-demarcated proliferations of well-
differentiated fibrocytes. Cells are arranged in parallel
fashion or interlacing bundles. Nuclei are small and
elongated. Mitotic figures are rare. These tumors are not
highly cellular and contain an abundance of mature collagen.
10. ACANTHOSIS - A non-neoplast ic thickening of the
epidermis. The entire layer of the epidermis is thickened.
The rete ridges are elongated, irregular, and extend into the
dermis for a variable distance. Severity grade criteria:
1 = Epidermis is twice normal thickness.
2 = Epidermis is three times normal thickness.
3 = Epidermis is four times normal thickness.
4 = Epidermis is more than four times normal
thickness .
11. HYPERKERATOSIS - Thickening of the stratum corneum by
keratin accumulation. Severity grade criteria:
1 - Stratum corneum is twice normal thickness.
2 = Stratum corneum is three times normal
thickness .
3 * Stratum corneum is four times normal thickness.
4 « Stratum corneum is more than four times normal
thickness .
12. SQUAMOUS PAPILLOMA - A small superficial pedunculated
nodule consisting of neoplastic masses of mature keratinizing
epithelial cells. Cells are in progressive stages of
Brown et al . — 452
Appendix I (cont.): GLOSSARY OF TERMS
FOR PATHOLOGY FINDINGS
keratinization often occurring in concentric whorls. There
is no evidence of deeper invasion. The superficial location
and the mature, highly keratinized, noninvasive growth
distinguish papillomas from carcinomas. These tumors have a
central core of dermis covered by layers of stratified
squamous epithelium with marked hyperkeratosis and
parakeratosis .
13. PREPUTIAL GLAND ADENOMA - Well-differentiated, benign
tumor of the preputial gland. Adenomas are composed
primarily of glandular tissue with small nests of squamous
cells scattered about. Eosinophilic granules are very
prominent in the cytoplasm of acinar cells. These tumors
grow in lobular fashion with smooth borders, and they may
become very large.
14. CLITORAL GLAND ADENOMA - Well-differentiated, benign
tumor of the clitoral gland, the female counterpart of the
male preputial gland described above. Microscopic
characteristics are similar to those of preputial gland
adenomas .
15. INFLAMMATION, NOT OTHERWISE SPECIFIED, PREPUTIAL GLAND -
Presence of lymphocytes, macrophages, neutrophils, or plasma
cells within the preputial gland. This lesion is coded as
"Present . "
16. NEUROFIBROSARCOMA, SUBCUTANEOUS, LOCATION TO BE SPECIFIED
- Microscopically, these tumors are composed of spindle-
shaped cells arranged in circular whorls or wavy fasciculi.
They closely resemble fibrosarcomas but differ in that cells
tend to have the form of plump spindles and retain the
whorled, curly arrangement. The location of these tumors is
documented in the special histologic comments feature of the
Xybion program.
17. FIBROSARCOMA - Malignant neoplasm of fibrous connective
tissue. Tumor cells with their collagenous fibrils are
arranged haphazardly and run aimlessly in a variety of
directions. Fasciculi of cells lying in the same plane are
often seen. A high degree of cellularity, hyperchromat ic
staining of nuclei, and a tendency for the nuclei to be
plump, stellate, and bizarre indicate malignancy. Mitotic
figures may be very numerous.
18. EPIDERMAL INCLUSION CYST - One or more small cysts
Brown et al. — 453
Appendix Z (cont.): GLOSSARY OF TERMS
TOR PATHOLOGY FINDINGS
located within the dermis and surrounded by a thin fibrous
capsule. The cyst wall consists of flattened squamous
epithelium without adnexal structures. The cyst is filled
with concentrically laminated masses of keratin and amorphous
cellular debris. Intense inflammatory reaction may occur
around these lesions if the cyst ruptures. This lesion is
coded as "Present . "
MAMMARY GLANDS
1. HYPERPLASIA AND/OR HYPERTROPHY OF ACINAR TISSUE -
Increased size and number of mammary secretory cells. These
cells are arranged in lobules. In hyperplastic glands, the
lobules become larger and closer together. Cells are
cuboidal to low columnar, and crowded together on the
basement membrane to the point that mild piling up of cells
occurs. Often these cells are actively secreting and acini
become distended with slightly basophilic granular or foamy
secretory product . Mammary hyperplasia occurs in both sexes
although it is more prevalent and usually more severe in
females. The same severity grade criteria are used for both
sexes :
1 =* Foci of acinar cells are widely scattered.
Most are less than the diameter of a 4 OX
microscopic field.
2 - Acinar foci are more numerous but small. The
largest are larger tha:. a 40X field but smaller
than a 20X field.
3 * Extensive acinar tissue is present. It is
nearly confluent but there are a few uninvolved
areas .
4 - Confluent secretory tissue is present.
2. GALACTOCOELE - Marked cystic dilatation of a mammary duct.
The dilated duct is lined by flattened ductal epithelium and
is filled with secretory product. The lesion is coded as
"Present . "
3 . FIBROADENOMA - A benign tumor of mammary origin in which
there is proliferation of both epithelial and connective
tissue components. Histologically, fibroadenomas vary
considerably in their structural composition. Either the
epithelial or the connective tissue component may
predominate. Usually there is a concomitant growth of
connective tissue stroma, glandular and ductal cells. Ducts
Brown et al . — 454
Appendix I (cont.): GLOSSARY OF TERMS
FOR PATHOLOGY FINDINGS
may become surrounded by layers of fibrous connective tissue
and the histological appearance becomes that of single acini
or tubules separated from each other by concentric layers of
loose connective tissue. The secretory epithelium is usually
only one cell layer thick and bears the same relation to
myoepithelium and basement membrane as it does in the normal
mammary gland.
4. DILATATION (ECTASIA) OF DUCTS AND DUCTULES - Dilatation
of mammary ducts occurs independently of mammary acinar
hyperplasia and is therefore coded independently. Dilated
ducts often contain pale eosinophilic secretory material.
This lesion is coded as "Present.”
5. MAMMARY ADENOCARCINOMA - A malignant tumor that is derived
from glandular epithelium. The epithelium is arranged in
glandlike structures surrounding a lumen. Acinar spaces may
be orderly and regular or may vary considerably in size and
shape. Eosinophilic or basophilic secretion is often present
in glandular spaces. The epithelium varies from low cuboidal
to tall columnar cells and may be several cell layers thick.
Nuclei are large and mitotic figures are numerous. In some
adenocarcinomas, the acinar spaces are completely filled with
tumor cells and no lumens are present. Stroma within cell
masses is usually scanty. Papillary projections can form,
however. Stromal invasion by neoplastic epithelial cells is
common. Necrosis and mononuclear inflammatory cell
infiltration can occur and are more frequent in larger
tumors .
HQSB/TVBBlHftlBa
1. ACUTE INFLAMMATION - Presence of suppurative inflammation
within the nasal cavity. Necrosis may be present in more
severe lesions. Severity grade criteria:
] * Minimal detectable infiltration of neutrophils.
1 - Mild infiltration of neutrophils.
3 * Moderate infiltration of neutrophils.
Suppurative exudate is present within nasal
passages .
4 * Marked neutrophilic infiltration. Suppurative
exudate is present in nasal passages. Necrosis
with destruction of nasal tissues is present.
Brown et al. — 455
Appendix I (cont.): GLOSSARY OF TERMS
FOR PATHOLOGY FINDINGS
2. SUBACUTE INFLAMMATION - Infiltration of lymphocytes,
macrophages, and plasma cells into tissue of the nasal
cavity. Necrosis may be present in more severe lesions.
Severity grade criteria:
1 = Minimal infiltration of mononuclear
inflammatory cells .
2 = Mild mononuclear cell infiltration.
3 = Moderate mononuclear infiltration. Exudate is
present in nasal passages.
4 = Marked mononuclear cell infiltration. Exudate
is present in nasal passages. Necrosis with
destruction of nasal tissues is present.
3. MIXED INFLAMMATORY CELL INFILTRATION, NASAL CAVITY,
SINUSES, TURBINATES OR NASOLACRIMAL DUCTS - This diagnosis is
used primarily for small focal inflammatory lesions in the
nasal cavity. The exact location of the lesion is documented
in the special histologic comments of the Xybion program.
Most of the lesions coded under this diagnosis are
inflammatory foci adjacent to nasolacrimal ducts.
Inflammatory cell foci are very common in this location in
rats used in Study GLP 83009. Severity grade criteria:
1 = Minimal inflammatory cell infiltration.
2 = Mild inflammatory cell infiltration.
3 =* Moderate inflammatory cell infiltration;
cellular exudate is present within a natural
anatomic space, e.g., the lumen of the
nasolacrimal duct.
4 = Marked inflammatory cell infiltrate. Exudate
is present within a natural anatomic space.
Small amounts of necrosis may be present.
BONE
Bone and bone marrow were examined from the STERNUM.
FEMUR, and VERTEBRAE as well as incidental locations such
as th« nasal cavity,- and middle and inner ear. The diagnoses
coded for bone marrow from all these sites are described
below.
1. MYELOID HISTIOCYTOSIS - This is an unusual lesion that
affects bone marrow uniformly in an affected animal. The
marrow contains large numbers of large histiocyte-like cells.
No microorganisms were detected in sections stained by
Brown et al . — 456
Appendix Z (cont. ) : GLOSSARY 07 TERMS
FOR PATHOLOGY FINDINGS
Gomori's Mathenamine Silver stain. Periodic Acid-Schiff
(PAS), Giemsa, or Goodpasture stains. Cells contained
diastase-resistant PAS-positive material. Whether this
lesion is inflammatory or neoplastic in nature is unknown.
The lesion is coded as "Present.”
2. HYPERPLASIA, MYELOID - This change in bone marrow consists
of excess non-neoplastic proliferation of granulocytic
precursors. Erythroid precursors are present but usually
reduced in number. The myeloid proliferation may be
multifocal or diffuse. The change is coded as "Present."
3. MYELOFIBROSIS/OSTEOSCLEROSIS - All normal marrow elements
are greatly reduced in number and are replaced by
hypocellular loosely arranged fibrous tissue. The lesion is
coded as "Present."
4 . LARGE GRANULAR LYMPHOCYTE LEUKEMIA - See "General
Diagnoses" above.
SPINAL CORD
No gross or microscopic lesions were observed the the
spinal cords of rats used in Study GLP 83009.
ABRSHAL GLANDS
1. CORTICAL ADENOMA - A benign tumor of adrenal cortical
cells. The tumor cells are arranged in a discrete nodule
which compresses adjacent cortical tissue. Within the tumor,
the cells lack their normal orderly arrangement and
relationship to basement membrane and vasculature. They are
arranged in short cords, or nests separated by delicate
f ibrovascular stroma. Tumor cells may be either larger or
smaller than their non-neoplastic counterparts and the
tinctorial qualities of their cytoplasm vary considerably.
The presence of lipid vacuoles is quite common as is slight
granular basophilia. Mitotic figures are rare. Adenomas are
well-vascularized and irregular, blood-filled, endothelial-
lined spaces and hemorrhage are common findings.
2. LIPIDOSIS - Presence of intracytoplasmic lipid vacuoles in
cortical cells. This change may be uniform or multifocal.
Severity grade is based on the amount of the adrenal cortex
involved:
Brown et al. — 457
Appendix I (cont.) : GLOSSARY OF TERMS
FOR PATHOLOGY FINDINGS
1 * Less than 25% of the cortical cells are
vacuolated.
2 * 25% to 50% of the cells are affected.
3 = 50% to 75% of the cortex is affected.
4 = More than 75% of the cortex is affected.
3. FOCI OF CELLULAR ALTERATION - These are degenerative
lesions affecting cells of the adrenal cortex. The changes
are focal. Affected cells may be either larger or smaller
than normal and have different tinctorial qualities as
follows :
3A. FOCUS OF CELLULAR ALTERATION, EOSINOPHILIC - Degenerative
cortical cells are slightly larger than normal and their
cytoplasm is granular and eosinophilic. There is slight
compression of adjacent normal cortical cells.
3B. FOCUS OF CELLULAR ALTERATION, VACUOLATED - Degenerative
cortical cells may be slightly larger than normal and their
cytoplasm is vacuolated. There is usually slight compression
of adjacent cortical cells.
3C . FOCUS OF CELLULAR ALTERATION, BASOPHILIC - Degenerative
cortical cells may be slightly smaller than normal and their
cytoplasm has a slight basophilic granularity. Severity
grade criteria for foci of cellular alteration:
1 = One focus .
2 * Two or three foci .
3 * Four to six foci.
4 * More than six foci.
4. CORTICAL NODULAR HYPERPLASIA - Nodular proliferation of
adrenal cortical cells. Cells may be slightly larger than
normal and cytoplasm may be finely vacuolated. These small
nodules are usually located at the surface of the adrenal and
are surrounded by a thin extension of the adrenal capsule.
This change is coded as "Present."
5. FIBROSIS, CAPSULE - Proliferation of fibrous connective
tissue in the adrenal capsule. There are minimal numbers of
mononuclear inflammatory cells present. Severity grade
criteria are based on the proportion of the adrenal capsule
involved:
1 - Minimal capsular fibrosis; less than 10% of
capsule is involved.
Brown et al . — 458
Appendix I (cont.) : GLOSSARY Or TERMS
FOR PATHOLOGY FINDINGS
2 ** 10% to 25% cf the capsule is involved.
3 * 25% to 50% of the capsule is fibrotic.
4 = More than 50% of the capsule is fibrotic.
6. MEDULLARY CARCINOMA (MALIGNANT PHEOCHROMOCYTOMA) -
Malignant tumor of the adrenal medulla. The cells resemble
normal medullary cells but usually they have less cytoplasm
and the nuclei are hyperchromatic . The cells are arranged in
nests and sometimes in trabecular fashion. Usually the cells
are of one type although there are occasional small
basophilic cells, with transitions to larger cells having
abundant cytoplasm and large nuclei. The only criteria that
are used to differentiate malignant from benign tumors of the
adrenal medulla is invasion of the capsule and infiltration
of tissues outside the adrenal gland or metastasis.
7. PHEOCHROMOCYTOMA - Benign tumor of the adrenal medulla.
Morphologic characteristics are similar to that of medullary
carcinoma described above. The benign tumors may become
quite large but are confined to the adrenal gland.
8 . LARGE GRANULAR LYMPHOCYTE LEUKEMIA - See "General
Diagnoses" above.
9. EXTRAMEDULLARY HEMATOPOIESIS - Presence of erythrocytic
precursors within the adrenal gland. This change is coded as
"Present . "
10. NECROSIS - Coagulative or liquefactive necrosis in the
adrenal cortex or medulla. Severity grade criteria:
1 ■ Focus of necrosis less than the diameter of a
40X microscopic field.
2 = Necrosis of less than 25% of an adrenal gland.
3 = Necrosis of 25% to 50% of an adrenal gland.
4 = Necrosis of more than 50% of an adrenal gland.
PITUITARY GLAND
1. ADENOMA - A benign tumor of the anterior pituitary gland.
Proliferating cells of the anterior pituitary gland vary
considerably in their cytological characteristics and in
their tinctorial qualities. Using only hematoxylin and eosin
staining, it is not possible to identify cell types
accurately or to identify the type of hormone that may be
Brown et al. — 459
Appendix I (cont.): GLOSSARY OF TERMS
TOR PATHOLOGY FINDINGS
secreted. Pituitary tumor cells are usually arranged in
short cords or nests separated by very fine f ibrovascular
stroma. They are highly vascular and irregular, blood-
filled, endothelial-lined spaces occur frequently as does
hemorrhage. Metastases occur rarely but large tumors may
infiltrate adjacent tissue and compress overlying tissue of
the brain which undergoes compression atrophy.
2. CYST(S) - Presence of spaces within the pituitary that are
usually filled with pale eosinophilic fluid. The spaces may
be lined with endothelium or flattened epithelial cells.
Rarely, a ciliated cell may be observed. Cysts in the
pituitary may be single or multiple. They are coded as
"Present . "
3. ADENOCARCINOMA - A malignant tumor of the anterior
pituitary gland. Morphologically, malignant tumors of the
pituitary can be distinguished from their benign counterparts
only by their invasiveness. Metastases are very rare. If
the tumor cells infiltrate tissues outside the confines of
the pituitary gland, it is coded as an adenocarcinoma.
4. LARGE GRANULAR LYMPHOCYTE LEUKEMIA - See "General
Diagnoses" above.
EYES AND OPTIC NERVE
1. CORNEAL MINERALIZATION - Presence of small spicules of
mineral within the cornea. Usually this is accompanied by
vascularization and occasionally by infiltration of a few
inflammatory cells. Severity grade criteria:
1 * Presence of one focus of mineral.
2 = Presence of two or three mineralized foci.
3 = Four to six foci present.
4 = More than six mineralized foci present.
2. RETINAL ATROPHY AND/OR DEGENERATION - Consists of variable
reduction of cellular elements and disorganization of the
different layers of the retina. This is a progressive
condition that increases in severity as the animal ages . The
condition may be unilateral or bilateral. Severity grade
criteria:
1 ~ Perceptible reduction in the number of cells in
the retina.
Brown et al . — 460
Appendix I (cont.): GLOSSARY OF TERMS
FOR PATHOLOGY FINDINGS
2 * Multifocal disorganization of retinal layers.
3 = Diffuse disorganization of retinal layers.
Some parts of layers may be recognizable.
4 = No recognizable retinal tissue is present. The
retina consists of a band of fibrous tissue.
3. CORNEAL PIGMENTATION - Presence of pigment within the
cornea. Pigment may be hemosiderin or melanin. It is
present within histiocytic cells and usually accompanies
inflammatory lesions in the cornea. Such pigment
accumulations are usually focal. Severity grade criteria is
based on the number of pigmented foci present:
1 = One pigmented focus is present.
2 = Two or three pigmented foci are present .
3 = Four to six pigmented foci are present.
4 = More than six pigmented foci are present.
4 . CORNEAL VASCULARIZATION - Presence of endothelial-lined
vascular spaces beneath the epithelium or within the corneal
stroma. Severity grade criteria are based on the number of
vascular cross sections present:
1 = One vascular cross section.
2 * Two or three vascular cross sections.
3 = Four to six vascular cross sections.
4 = More than six vascular cross sections.
5 . CHRONIC KERATITIS - Chronic inflammation involving the
cornea. One or more of the following histologic findings may
be present: mononuclear inflammatory cell infiltration
beneath the epithelium and into the stroma, erosion or
ulceration of the epithelium, proliferation of vascular
structures (see corneal vascularization above) , presence of
pigment, necrosis of cellular elements, and presence of scar
tissue. Severity grade criteria are based on the degree of
corneal damage and the amount of the cornea involved:
1 - Minimal to mild mononuclear inflammatory cell
infiltration .
2 - Moderate inflammatory cell infiltrate with
vascular proliferation or pigment deposition.
3 = Similar to grade 2 plus minimal necrosis or
scar tissue proliferation.
4 = Marked chronic inflammatory changes involving
50% or more of the cornea.
Brown et al. — 461
Appendix I (cont.): GLOSSARY 07 TERMS
70R PATHOLOGY FINDINGS
6. IRIDOCYCLITIS - Inf lammation of the iris and/or ciliary
body. This was a very unusual lesion in this study. It
affected only three rats in which it consisted of mild
infiltration of the uveal tract with mononuclear inflammatory
cells. Severity grade criteria:
1 = Minimal infiltration of uveal tract with
mononuclear inflammatory cells.
2 = Mild mononuclear infiltration of uveal tract.
3 = Criteria not established.
4 = Criteria not established.
7. METAPLASTIC BONE FORMATION AND/OR MINERALIZATION, SCLERA -
This very common finding consists of focal proliferation of
plaques of metaplastic bone or deposition of mineral, or
both, in the dense fibrous tissue of the sclera. There are
no inflammatory lesions associated with these changes. These
changes are coded as "Present."
8. LENTICULAR DEGENERATIVE CHANGES COMPATIBLE WITH CATARACT -
A cataract is opacity of the lens that can be detected
grossly. Microscopically, this lesion may consist of some or
all of the following degenerative changes in the lens:
abnormal proliferation of lens epithelium which may become
redundant and disorganized, disorganization of lens fibers in
the cortex with aggregation into spherical masses or globules
of material which may become mineralized, increased density,
disorganization, and possibly liquefaction of nuclear fibers.
These changes are coded collectively under this diagnosis and
are designated as "Present.”
9. CHRONIC CONJUNCTIVITIS - Chronic inflammation of the
conjunctiva. This lesion is characterized primarily by the
infiltration of mononuclear inflammatory cells into the
conjunctival membrane. Fibrosis may be present. Severity
grade criteria are based on the amount of cellular
infiltration present:
1 * Minimal mononuclear cell infiltrate.
2 - Mild mononuclear cell infiltrate.
3 - Moderate mononuclear cell infiltrate.
4 = Marked mononuclear cell infiltrate.
EAR
1. OTITIS MEDIA, SUPPURATIVE OR NONSUPPURATIVE - Acute or
Brown et al. — 462
Appendix I (cont.): GLOSSARY OF TERMS
FOR PATHOLOGY FINDINGS
subacute inflammation of middle ear structures.
Microscopically, this lesion consists of infiltration of
neutrophils (suppurative) or mononuclear inflammatory cells
(nonsuppurative) into the structures of the middle ear.
Severity grade criteria:
1 = Minimal inflammatory cell infiltration.
2 = Mild inflammatory cell infiltration into
tissues surrounding the cavities of the middle
ear .
3 = Moderate inflammatory cell infiltrate; presence
of cellular exudate within the cavities of the
middle ear.
4 = As in Grade 3 above plus necrosis and
destruction of middle ear structures.
2. FIBROSARCOMA, SUBCUTANEOUS, EXTERNAL EAR, ADJACENT TO EAR
TAG - Histological characteristics of this tumor are similar
to fibrosarcomas described under the SKIN. There was one
such tumor adjacent to the ear tag in one animal.
3. PITUITARY TUMOR INVASION - There is an infiltration of
cells from a pituitary tumor within the cranial cavity
adjacent to the structures of the middle and inner ear near
the origin of the acoustic nerve. Cellular characteristics
and arrangement of tumor cells are similar to that described
for adenoma under the PITUITARY GLAND.
APPITQRX SEBACEOUS GLAND
No gross or microscopic lesions were recognized in the
auditory sebaceous glands of rats in Study GLP 83009.
ABPQMINAL WALL
1. INFECTION AND INFLAMMATION, SEVERE, INVOLVING MUSCULATURE
AND PERITONEAL SURFACE - Thl.3 diagnosis is self-explanatory.
This lesion was not observed in animals necropsied during the
second year of this study. This diagnosis is described in
the interim report of Study GLP 83009, which covers the
findings of the first year of this two-year study.
THORAX
1. PRESENCE OF METASTATIC SARCOMA IN THORACIC WALL - See
"General Diagnoses" above.
Brown et al . — 463
Appendix I (cont.): GLOSSARY 07 TERMS
FOR PATHOLOGY FINDINGS
HBSI1 BODX
1. LARGE GRANULAR LYMPHOCYTE LEUKEMIA - Since neoplastic
cells from this disease may occur in virtually every organ
and tissue of the body, the primary site for the lesion is
coded under WHOLE BODY. See "General Diagnoses" above for
microscopic description and criteria for coding metastases.
2. INFLAMMATION OF BROWN FAT - This lesion consists of
infiltration of inflammatory cells and proliferation of
fibrous connective tissue in brown fat. The lesion can occur
in brown fat deposits anywhere in the body. For this reason
it is coded under WHOLE BODY and its location is specified in
the special histologic comments section of the Xybion
program. The lesion is coded as "Present."
MEDIASTINUM
1. CHRONIC INFLAMMATION - The presence of lymphocytes,
macrophages, plasma cells, and the proliferation of fibrous
connective tissue within the mediastinal tissues. Severity
grade is based on a subjective impression of the intensity
and extent of the inflammatory lesion:
1 - Minimal detectable infiltration of inflammatory
cells .
2 = Mild inflammatory response limited to a small
focal area in the mediastinum.
3 - Moderate inflammatory response; not all tissues
in the mediastinum are involved.
4 = Marked inflammatory response involving most of
the tissues in the mediastinum.
2. REACTIVE HYPERPLASIA, LYMPH NODE - Lymph nodes in