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Nasal Diagrams: A Tool for Recording the Distribution of Nasal Lesions in Rats
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Nasal Diagrams: A Tool for Recording the Distribution of Nasal Lesions in Rats and Mice
Stéphane Mery, Elizabeth A. Gross, Donald R. Joyner, Matthew Godo and Kevin T. Morgan
Toxicol Pathol 1994 22: 353
DOI: 10.1177/019262339402200402

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immunoassay after oral administration of C~.4 ~ TCP
kg and 1.7 g BTP kg for 9 wk revealed that inhi.-
bition of steroidogenesis was not the mechanism of
toxicity (24).
Adrenocortical and 01 cells utilize an intracellular
storage pathway to conserve excess cholesterol as
cholesteryl ester stored in cytoplasmic lipid droplets
(14. ?8). As physiologic demands change in response
to trophic hormones. cytosolic neutral cholesterol
esterase is activated via cyclic adenosine mono-
phosphate-dependent phosphorylation to cleave
cholesterol from cholesterol esters forming free cho-
lesterol for steroid hormone biosynthesis (14. 15.
28).
Some triaryl phosphates have been reported to be
esterase inhibitors (8. 19). Another possible mech-
anism for the lipidosis observed in the adrenal cor-
tex and 01 cells in rats administered TCP and BTP
would be a defect in the storage pathway caused by
inhibition of neutral cholesterv ester hydrolase. An
inhibition of this enzyme would result in the ac-
cumulation of cholesteryl esters in the adrenocor-
tical and 01 cells. The progressive cholesteryl lipi-
dosis associated with increased duration of
xenobiotic exposure as seen in this study would be
consistent with this potential mechanism. Signifi-
cant decreases in neutral cholesteryl ester hydrolase
activity compared to controls found in adrenal gland
and ovaries of rats exposed to both BTP and TCP
in another study support this hypothesis (22).
The testicular lesions caused bv exposure to TCP
free of any detectable ortho isomer were consistent
with those described by Somkuti et al (33) for TOCP
in a 21-day time-course study where Sertoli’s cells
were shown to be the first cells affected and principal
target cells for the compound. Similarities in testic-
ular lesions reported suggests the possibility of a
common mechanism: however, the exposure inter-
val in the study reported here was up to 3 times as
long and the dose over 2 times greater. The testicular
degeneration caused by TOCP is mediated through
a reactive intermediate metabolite (saligenin cyclic-
o-tolyl phosphate) (8) after TOCP is metabolized by
P-450 in the testicular Leydig cells (9). Although the
TCP used in our study was free of any detectable
tri-o-cresyl-isomer. other mono- and dicresvl-sub-
stituted triaryl phosphates (ethylpheny1- xylyl-
substituted species) made up a substantial propor-
tion of the TCP fluid. No assignment of positional
isomers was done for the species containing x~,~l~-1
and ethylphenyl substitutions due to the lack of ref-
erence materials and the large number of possible
species. It is probable that the o-cresol moiety was
present in some of these more highly substituted
species. BB nether or not the Sertoli cell is specifically
targeted by any of these species is unknOBJ&dquo;l1. Further
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351
studies are needed to elucidate the mechanismis) of
testicular degeneration caused by the tricresyl phos-
phates.
A~~.~o~~-t_E~~~~
This research was supported by the Naval Medical
Research and Development Command. Department
of the Navy. Task No. 63706N-M0096.004.0006.
The opinions and assertions contained herein are
those of the authors and are not to be construed as
ofhcial or reflecting the views of the Nax-x, Depart-
ment or the Naval Servile at large. The experiments
conducted herein were performed according to the
principles set forth in the current edition of the Guide
for the Care and L’se of Laboratory Animals. Insti-
tute of Laboratory Animal Resources. National Re-
search Council.
The authors thank HM3 William Milbrandt, HM3
~3yan Baer. Ms. Lana Martin, and other Navy per-
sonnel of the Toxicology Detachment and also Owen
Kindig and Evelyn A. Handley of the Department
of Veterinary Pathobiology for their technical as-
sistance during this study.
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Annu. Rev. Phar-
induced delayed neuratoxicity.
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2. Bondy HF. Field EJ. Worden AN. and Hughes JPW
(1960). A study on the acute toxicity of the tri-aryl
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3. Carlton BD, Barlett PB, and Smith MK (1986). Re-
productive toxicity of tricresyl phosphate in Long
Evans rats. Toxicology 6: 292.
4. Carlton BD, Basaran AH. Mezza LE, and Smith MK
(1987). Examination of the reproductive effects of
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Toxicology 46: 32 1-328.
5. Carlton BD. Irwin R. Hejtmancik M. Deskin R. Ryan
M. and Peters AC(1986). Reproductive toxicity of
tricresyl phosphate in male rats and mice by two
dosing routes. Texicologist 6: 292.
6. Chamacho AM, Cash R. Brough AJ, and Wilroy RS
(1967). Inhibition of adrenal steroidogenesis by ami-
noglutethimide and the mechanism of action. J. Am.
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7. Chapin RE. George JD. and Lamb JC IV (1988).
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8. Chapin RE. Phelps JL, Burka LT. Abou-Donia MB.
and Heindel JJ (1991). The effects of tri- -cresyl
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in primary culture. Toxicol. Appl. Pharmacel. 108:
194-204.
9. Chapin RE. Phelps JL. Somkuti SG. Heindel JJ. and
Burka LT (1990). The interaction of Sertoli and Ley-
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dig cells in the testicular toxicity o
of
-cresyl
tri- phos-
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10. Cohen MP (1968). Aminoglutethimide inhibition of
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(1967). Inhibition of adrenal corticosteroid synthesis
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action. J. Clin. Endocrinol. 27: 473-480.
13. Environmental Protection Agency (1983). Aryl phos-
phates; response to the interagency testing commit-
tee. Fed. Reg. 48: 57452-57460.
14. Erickson GF (1987). The ovary: Basic principles and
concepts. In: Endocrinology and Metabolism, 2nd ed.,
P Felig, JD Baxter, AE Broadus, LA Frohman (eds).
McGraw-Hill, New York, pp. 905-950.
15. Erickson GF, Magoffen D, Dyer CA, and Hofeditz C
(1985). The ovarian androgen producing cells: A re-
view of structure/function relationships. Endocrinol.
Rev. 6: 371-399.
16. Eto M (1974). Organophosphorus Pesticides: Organic
and Biological Chemistry. CRC Press, Cleveland,
Ohio.
17. Hejtmancik M, Deskin R, Ryan M, Carlton B, Hag-
gerty G, Peters A, and Irwin R (1986). Comparative
dosed feed and gavage subchronic studies of tricresyl
phosphate (TCP) in F344 rats and B6C3F1 mice.
Toxicologist 6 : 207.
18. Hertz R, Tullner WW, Schricker JA, Dhyse FG, and
Hallman LF (1955). Studies on amphenone and re-
lated compounds. Rec. Prog. Horm. Res. 11: 119-
147.
19. Hollingshaus GJ (1984). Chemistry and metabolism
of delayed neurotoxic organophosphorus esters. Proc.
14th Ann. Conf. Environ. Toxicol. Wright-Patterson
AFB, Air Force Aerospace Medical Research Labo-
ratory Technical Report 83-099, p. 76.
20. Kovacs K, Bloscheck JA, Yeghiayan E, Hatakeyame
S, and Gardell C (1971). Adrenocortical lipid hyper-
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34.
21. Lamb JC IV (1985). Reproductive toxicity testing:
Evaluating and developing new testing systems. J.
Am. Coll. Toxicol. 4: 163-171.
22. Latendresse JR, Azhar S, Brooks CL, and Capen CC
(1993). Pathogenesis of cholesteryl lipidosis of ad-
renocortical and ovarian interstitial cells in F344 rats
caused by tricresyl phosphate and butylated triphenyl
phosphate. Toxieol. Appl. Pharmacol. 122: 281-289.
23. Latendresse JR, Brooks CL, and Capen CC (1994).
Reproductive toxicity of butylated triphenyl phos-
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phate and tricresyl phosphate fluids in F344 rats. Fund.
Appl. Toxicol. 22: 392-399.
24. Latendresse JR, Brooks CL, and Capen CC (1994).
Toxic effects of butylated triphenyl phosphate-based
hydraulic fluid and tricresyl phosphate in female F344
rats. Vet. Pathol. (in press).
25. Luse S (1967). Fine structure of the adrenal cortex.
In: The Adrenal Cortex, AB Esenstein (ed). Little,
Brown and Co., Boston, pp. 1-69.
26. Malendowicz LK (1972). Steatotic degeneration ofrat
adrenocortical cells after treatment with aminoglu-
tethemide. Acta Histochem. (Jena) 43: 350-360.
27. Maronpot RR (1987). Ovarian toxicity and carcin-
ogenicity in eight recent national toxicology program
studies. Environ. Health Perspect. 73: 125-130.
28. Payne AH, Quinn PG, and Stalvey JRD (1985). The
stimulation of steroid biosynthesis by luteinizing hor-
mone. In: Luteinizing Hormone Action and Recep-
tors, M Ascoli (ed). CRC Press, Boca Raton, Florida,
pp. 136-173.
29. Racela A Jr, Azarnoff D, and Svoboda D (1969).
Mitochondrial cavitation and hypertrophy in rat ad-
renal cortex due to aminoglutethemide. Lab. Invest.
21: 52-60.
30. Rossi GL and Bestetti G (1983). Technical aspects in
the study of pathologic lesions in the hypothalamus
of the rat. In: Endocrine System, TC Jones, U Mohr,
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308-316.
31. Sheehan DC and Hrapchak BB (1980). Digitonin re-
action. In: Theory and Practice of Histotechnology,
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pp. 212-213.
32. Smith MI, Elvove E, and Frazier WH (1930). The
pharmacological actions of certain phenol esters with
specific reference to the etiology of so-called ginger
paralysis. Pub. Health Rep. 45: 2509-2524.
33. Somkuti SG, Lapadula DM, Chapin RE, and Abou-
Donia MB (1991). Light and electron microscopic
evidence of tri-o-cresyl phosphate (TOCP)-mediated
testicular toxicity in Fischer 344 rats. Toxacol. Appl.
Pharmacol. 107: 35-46.
34. Temple TE and Liddle GW (1970). Inhibitors of ad-
renal steroid biosynthesis. Annu. Rev. Pharmacol. 10:
199-218.
35. Wall HG, Kinkead ER, Vinegar A, Bruner RH, and
Flemming CD (1990). Pathologic Effects in Animals
after Subchronic Inhalation Exposure to MIL-H-
19457C, MIL-H-19457B, or MIL-H-22072B. Toxic
Hazards Research Unit Annual Technical Report.
AAMRL-TR-90-063. Armstrong Aerospace Medical
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45433-6573, pp. 306-322.
 Nasal Diagrams: A Tool for Recording the
Distribution of Nasal Lesions in Rats and Mice*
STÉPHANE MERY, ELIZABETH A. GROSS. DONALD R. JOYNER,
MATTHEW GODO, AND KEVIN T. MORGAN
CIIT,
Research Triangle Park, North Carolina 27709

ABSTRACT
Knowledge of patterns of lesion distribution can provide insight into the relative roles played by regional
tissue dose and local tissue susceptibility in toxic responses to xenobiotics in the nose and assist assessment
of potential human risk. A consistent approach is needed for recording lesion distribution patterns in the
complex nasal airways of rats and mice. The present work provides a series of diagrams of the nasal passages
of the Fischer-344 rat and B6C3F1 mouse, designed for mapping nasal lesions. The diagrams present each
of the major cross-sectional airway profiles, provide adequate space for nasal mucosal lesion recording, and
are suitable for duplication in a commercial photocopier. Sagittal diagrams are also provided to permit
transfer oflesion location data observed in transverse sections onto the long axis of the nose. The distribution
of lesions induced by a selected range of xenobiotics is presented. Approaches to application of the diagrams
and interpretation of results obtained are discussed in relation to factors responsible for lesion distribution
in the nose and their relevance to interspecies extrapolation. A modified approach to anatomical classification
of the ethmoturbinates of the rodent is also presented.
Keywords. Pathology; dosimetry; anatomy; histology; toxicology; mapping lesions; olfaction

INTRODUCTION chemical reaching the affected area. site-specific tis-

The nasal passages are an important target site
for a wide range of toxic agents in rodent toxicology
studies ( 1, 8. 42)~ however, consistency in interpre-
tation oflesions is challenging in this complex struc-
ture (13, 28). The first description of a systematic
approach to sectioning the nose of laboratory ro-
dents for toxicology studies was reported by Young
(43), who proposed a set of 4 standard sections.
These sections included many of the major regions
of the nose in which lesions have been described.
A set of 3 sections has been used by the National
Toxicology Program (41 )_ while other workers pro-
posed more numerous section levels (28, 38). Sec-
tion level selection is a critical issue in nasal toxi-
cology. and availability of suitable sections is
essential for adequate assessment of nasal lesion ex-
tent,severity, and relevance.
Site specihcity of nasal lesions has been reported
for the 4 major epithelial (mucosal) types in the
nose, including the squamous 10). transitional (21).
respiratory (31). and olfactory (9) regions. Lesion
location may be attributable to local dose of the
.
Address correspondence to: Dr. ~~~-in T. Morgan CUT. P-0-
Box 12137. Research Triangle Park- North Carolina 17709.
353
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sue susceptibility, or a combination of these factors
(33). Adequate characterization of lesion location is
important during assessment of the mechanism of
action and for appropriate interspecies extrapola-
tions. The complex nature of the nasal ainvays con-
tributes to difficulties encountered during the re-
cording of the location of nasal lesions. Maps of the
nose have been used to assist this process 1 ~.. 19,
21. 23. 24. 31), but a consistent approach to this
mapping process is needed. The present work was
undertaken to simplify the process of recording le-
sion location in toxicology laboratories by providing
a comprehensive set of diagrams suitable for re-
cording the location of tissue responses for any
transverse section level of the nose of the Fischer-
344 (F-344) rat or B6C3Fl 1 mouse. The application
of these diagrams to nasal toxicology is discussed.
MATERIALS .~&dquo;D METHODS
Source of.-l fl.1:tÎJ}IlÙll and Hislological Jfaterial.
Maternal for these studies was obtained from the
available literature and Chemical Industry Institute
of Toxicology ~~‘11~I‘) research archives. These ar-
chives Included a set of serial step hematoxylin-and-
eosin-stained paraffin sections. 1 0D ~m apart and 5
~m thick, of the nose of a 3-mo-old male F=344 rat
354

TABLE 1.-Mapping of chemically induced nasal lesion.&dquo;

and a 3-mo-old male B6C3F1 mouse used for pre-
vious studies of nasal morphometry (12). A consid-
erable amount of detailed anatomical information
was also derived from nasal casts and other data
sets generated for previous investigations of nasal
airflow in the F-344 rat (22, 32).
special reference to the cross-sectional profile of the
airway. A separate diagram was prepared for each
level at which a characteristic, and essentially unique,
airway profile occurred. When examining the trans-
verse diagrams, it is important to note that our goal
was to design a working tool and not a precise copy

Preparation of Nasal Diagrams. Longitudinal di-
agrams were based on data derived from previous
studies of the nose of F-344 rats ( 12, 22, 29, 30, 32)
and B6C3F1 mice (12, 19). A diagram of a sagittal
section of the nose of a 3-mo-old male F-344 rat
(29) was optically scanned into Macintosh comput-
ers (LCIII, Powerbook 230) and modified using
MacDraw software (Claris Corporation) to include
cross-section levels (see below). These cross-sec-
tional levels were correlated with buccal landmarks
using information derived from rat nasal dissections
(Morgan and Gross, unpublished studies) and dia-
grams published by other researchers (41, 43).
Transverse nasal section levels were selected on
the basis of critical features of nasal anatomy with
of the nasal airway cross-sections. For instance, cer-
tain meatuses were enlarged slightly to provide space
for recording lesion location in these sites. The ma-
jor epithelial types lining the nose, squamous, tran-
sitional, respiratory, and olfactory, were identified
by light microscopy and their locations recorded on
the diagrams.
Mapping Selected Chemically Induced Nasal Le-
sions. A range of previously reported nasal lesions
(Table I) was recorded on both transverse and lon-
gitudinal diagrams of the nose. These lesions were
selected because they occur in diverse regions of the
nose, have characteristic patterns of distribution,
and exhibit clear concentration-response relation-
ships.

FIG. lea) Midsaggital section of the nasal passages of a F-344 rat with the septum removed to reveal the turbinates.
Major landmarks on dorsal buccal cavity used for section level identification are shown for comparison with Fig. 1B.
Straight verticle lines indicate section levels selected for transverse diagrams. Curving solid lines indicate the junction
of the squamous-transitional, respiratory epithelia (anterior line) and respiratory-olfactory epithelia (posterior line).
Arrows indicate direction in which all major airway shapes are maintained in cross-sections. All cross-sections are
numbered in sequence, and missing numbers reflect the lack of landmarks for their identification in this figure. For
labeling of major structures. see Fig. 5. Modified from Morgan et al (29). B) Dorsal buccal cavity to show major landmarks
used for section level identification. The short arrows indicate section levels recommended by Morgan (28). Modified
from Young (4~).

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 355

I
Upper incisor tooth First palatal ridge Firs, upper molar tooth
Incisive papilla Second palatal ridge

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356
FIG. 2.-Key to Figs. 3-6- Appropriate orientation of markers permits identification of distribution epithelial types.
All refer to isolated structures or regions covered by a single epithelial type. The nasolachrymal duct, teeth, and olfactory
bulbs are included in a simplified form as anatomical locators.
RESULTS AND DISCUSSION
The longitudinal and cross-sectional diagrams re-
sulting from this work are shown Figs. 1-6. The
levels at which cross-sectional diagrams occur for
the rat are shown for the midsagittal plane (Fig. 1 A),
and 6 selected sections, those used routinely in this
laboratory, are shown with respect to the major
landmarks of the buccal cavity (Fig. 1 B). These land-
marks are useful during tissue trimming (41, 43). A
key to the cross-sectional diagrams indicates the sys-
tem used to identify the location of the 4 major
epithelial types and other major structures (Fig. 2).
The cross-sectional diagrams are shown in sets of 6
(30 diagrams for each species) for the rat (Fig. 3a-
e) and the mouse (Fig. 4a-e). The figures are iden-
tified by plate number (3a, 3b, etc.) and by diagram
number on each plate (3a6, 3b9, etc.). A sagittal
diagram and 3 cross-sectional diagrams have been
reproduced in Fig. 5 to indicate the location of im-
portant anatomical landmarks, with special refer-
ence to the ethmoturbinates and the principal nasal
meatuses.
L~Tnd~rst~znding the Diagrams
The anatomy of the nasal passages of rats is sim-
ilar to that of mice, but not identical (Fig. 5). Ex-
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amination of the diagrams, especially in the more
posterior regions, illustrates these interspecies dif-
ferences. The diagrams provided here can act as a
framework for studying nasal anatomy, using the
airway outline as a landmark. For the anterior air-
ways or meatuses, we have used a system of clas-
sification based on inspiratcry airflow (32). A de-
tailed classification of the airways of the ethmoid
region has yet to be developed. The shape of the
airways is influenced by certain adjacent structures,
which were included in the diagrams. For instance,
the incisor teeth of the rat may play an important
role in shaping the anterior nasal airway of the rat
(34), especially with respect to the form of the lateral
recess of the lateral meatus (32). The nasolachrymal
duct is another structure that lies close to the nasal
airways of the rat and mouse. This association is
reflected by a recess on the medial surface of the
maxilloturbinate that is visible in both the longi-
tudinal (Fig. 5) and cross-sectional (Figs. 3a5, 4a4,
and 4a5) diagrams.
Knowledge of epithelial distribution in the nose
is critical for lesion mapping, especially at or near
the junctions of these epithelia in and adjacent to
the nasal vestibule and in the complex ethmoid re-
gion. The distribution of epithelial types was, there-
 357

FIG. 3a-e. - Cross- sectional diagrams of the nasal passages of the F-344 rat- Numbers in right-hand lower region of
each diagram indicate section level on Fig. 1. The key for these diagrams is presented in Fig- 2.

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358

F344 RAT

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 359

F344 RAT

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360

F344 RAT

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 361

F344 RAT

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362

FiG. 4a-~.-~ross-sectional diagrams of the nasal passages of the ~~C3F1 mouse. Numbers in right-hand lower region
of each diagram indicate section level on Fig. 1. The key for these diagrams is presented in Fig. 2.

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 363

B6C3F1 MOUSE

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364

B6C3F1 MOUSE

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 365

B6C3F1 MOUSE

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366

B6C3F1 MOUSE

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fore. recorded on the maps using specific icons for
each of the interepithelial junctions (Fig. 2). Dis-
tinction of the atrioturbinates (Fig. 5). which are
supported by cartilage. from other nasal turbinates.
which are generally supported by bore, is also of
value when interpreting responses in the most an-
terior regions of the nose. Other selected anatomical
features incorporated into the diagrams as &dquo;loca-
tors&dquo; included the incisor and molar teeth. naso-
lachrymal ducts. nasopalatine ducts, and olfactory
bulbs.
The anatomy of the anterior nose has been de-
scribed in some detail (13, 15, 32, 39): however, the
posterior nose is more complex and has been less
well defined. Examination of Figs. 3b9-3e30 and
4b9-4e30 will assist understanding of the shape of
the airways formed by the ethmoid turbinates. Rec-
ognition of these turbinates at their points of at-
tachment to the nasal wall and throughout their con-
voluted shapes within nasal sections cut at differing
levels and angles can be achieved with practice.
Copies of selected figures of the ethmoid region have
been duplicated in Fig. 5 with incorporation of la-
beling to assist this identification process.
Allen, in 1894 (39), was the first to subdivide these
turbinates into endo-/and ectoturbinates. This clas-
sification was apparently based on turbinate shape:
ecto meaning going toward the exterior, and endo
toward the interior. Using these definitions, we iden-
tified 3 ectoturbinates and 3 endoturbinates in both
the rat and the mouse. This observation differs from
the publication by Young (43), who reported the
presence of 2 ectoturbinates and 4 endoturbinates;
the second endoturbinate of Young has the form of
an ectoturbinate. In our opinion, the terminology
of Allen is too complex and could lead to unnec-
essary confusion. For instance, in cross-sectional
views the ventral scroll of the anterior region of
Young’s third endoturbinate transforms caudallv
into a structure resembling an ectoturbinate (cf. Fig.
3d24 and Fig. 3e28). The number ofturbinates seen
in cross-sections may also vary depending on the
orientation of the cross-sections.
A new system of classification of the ethmotur-
binates of rats and mice is proposed. The most dor-
sal turbinate is identified as the first ethmoturbinate,
and each subsequent turbinate, moving ventrally
along the lateral wall of the nasal cavity, is numbered
sequentially. The F-344 rat and B6C3Fl mouse.
using such an approach, have 6 ethmoturbinates. A
comparison of the system recommended here for
the ethmoturbinates with those of other workers is
shown in Table II. The majority of the ethmotur-
binates exhibits 2 scrolls at some point in cross-
sections. while elsewhere they appear to have only
I scroll. These scrolls mav be referred to as dorsal
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367
TABLE n.―Anatomical classification of ethmoturbi-
natesintherat.
and ventral scrolls, with the exception of the first
ethmoturbinate, which has I medial and I lateral
scroll anteriorly. The ethmoturbinates are seen to
fuse with each other or with the lateral nasal wall
in a complex manner that can readily lead to their
rnisidentification.
Finally, the nasoturbinate of the F-344 rat appears
to have only a single scroll. in addition to a ridge
lateral to this scroll [the lateral ridge reported by
Morgan et al (35)]. In certain strains of rats. how-
ever, this ridge mav be extended to for a clear
scroll. and the terms dorsal and ventral scroll may
be more appropriate for these portions of the na-
soturbinate. In addition to interstrain differences,
the internal structure of the rodent nose changes in
shape with age (11). Thus. minor modifications of
the diagrams may be needed.
Use of the Diagrams
The objective of the mapping procedure should
be considered before starting this potentially time-
consuming process. For instance, if nasal airflow or
local xenobiotic metabolism is of importance, cer-
tain lesion distribution patiems may be predicted.
Appropriate and adequate section levels can then
be planned for histopathologic examination and for
lesion mapping. Once section levels have been cho-
sen. they may be extracted from the full set of 30
diagrams provided here for photocopying onto a
single work sheet. This approach saves space and
time during lesion recording. I-Io~~e~-er. if the section
levels on slides do not match the diagrams exactlv,
lesion recording can be difficult. In the case of the
mouse. which has a very small nose. or in the eth-
moid region of the rat. where slight differences in
section location or angle dramatically influence the
368

FIG. 5.~_-~. top) Sagittal section of nasal passages of the F-344 rat to identify selected structures; inset shows the
ethmoid turbinates of the BbC3F 1 mouse. ~ A = ventral atrioturbinate. DA dorsal atrioturbinate; N nasoturbinate;
= =

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 369

airwav profile observed,. this approach may be prob-
lematic. An alternative procedure is to photocopy
all 30 diagrams. record lesion location for section
levels in the slide set. and leave all other diagrams
blank. This approach also permits lesion recording
where section angle varies, as several diagrams may
be required to incorporate all the regions seen in
histologic preparations. The appropriate choice will
be dictated by the degree of resolution required. As
the nose changes in shape with age ( 11 ) and between
strains of rats and mice (Morgan, unpublished ob-
servations). minor modifications may also be need-
ed prior to photocopying the diagrams to be incor-
porated into the study.
During lesion recording, transfer of information
from cross-sections onto a sagittal diagram is rec-
ommended, as this process may draw attention to
many other changes. are described in the references
listed in Table I.
Lesion distribution in the nose may be attribut-
able to local dose. regional tissue susceptibility, or
(probably more commonly) a combination of these
factors (33). Interpretation of patterns of lesion de-
velopment can be assisted by addressing these issues
consecutively. For instance. if airflow-driven dose
is responsible for lesion location. it would be rea-
sonable to expect responses in the major inspiratorv
airways, especially in the nasal vesibule and in the
anterior regions of the lateral and middle medial
meatuses. and in the anterior dorsal medial meatus.
This characteristic pattern has been observed for
formaldehyde and attributed to local airflow-driven
deposition of this gas (22). Similar factors could
account for the anterior-to-posterior severity gra-

patterns of lesion location. The location of the cross-
sectional diagrams in the long axis of the nose is
shown in Fig. 1 for all cross-sections having specific
anatomical landmarks visible in the midsagittal
view. Cross-sections not indicated in Fig. 1 lie be-
tween those indicated according to numerical se-
quence. A compilation of data from cross-sections
is transferred to the longitudinal diagram, to include
an assessment of the anterior-to-posterior extent of
the responses. For detailed localization of lesions in
the long axis of the nose, more detailed maps could
be developed to include structures that are masked
by the turbinates in Fig. 1. For an example of such
an approach, see Morgan et al (29).
Selected Examples and
Their Interpretation
The distribution of selected lesions induced by
inhalation and noninhalation exposure to a range
of chemicals, environmental cage contaminants, and
a rat-adapted influenza virus are shown in Fig. 6.
These lesions occurred in a site-specific manner and
involved a range of epithelial and subepithelial
structures. Histological details of these lesions, which
included squamous epithelial hyperplasia (glutar-
aldehyde), secretory (ozone) and squamous (form-
aldehyde) metaplasia, intraglandular accumulations
of proteinaceous material (dimeth~~lamine), olfac-
tory epithelial degeneration (dibasic esters), and
dient observed for many gaseous irritants in the
olfactory epithelium of the dorsal medial meatus
(5). However, lesion location in the anterior nose
will also be influenced by relative tissue or cellular
susceptibility. For instance, this could account for
the infrequency of lesions in the nasal vestibule.
which is lined by squamous epithelium, in the pres-
ence of severe changes in the transitional and re-
spiratory epithelial regions closely adjacent to the
vestibule. In the anatomically more complex pos-
terior nose, determination of mechanisms respon-
sible should include consideration of airflow-driven
local dose in relation to local metabolic capacity and
regional blood now (36). Table I lists factors corn-
sidered to be the most probable underlying cause of
lesion location for each of the examples cited.
CONCLUSIONS
The present work wasundertaken as a direct con-
sequence of previous studies of formaldehyde tox-
icity in this laboratory. Mapping approaches were
used to identify the principal target sites of form-
aldehyde in the nasal passages of rats. with respect
to nasal cancer ( 1) and inhibition of nasal muco-
ciliary function (35). This localization process per-
mitted subsequent studies of site-specific responses
to formaldehyde. including the induction of I~!v A~
protein cross-links (16) and epithelial cell replica-
tion (27). Mapping of formaldehyde-induced nasal

DS=
dorsal scroll of nasoturbinate: VS = central scroll of nasoturbinate: M maxilloturbinate: ~’~ _ ventral recess
=

of maxilloturbinate (see Fig. 3a51: ID ineisi~.-e duct: 2PR

=
second palatal ridge: NPD
=
nasopharp ngeal duct: ~~1~
= =

olfactory bulb. The labeling of the ethmoid turbinates is shown using a simplified system of nomenclature (Table II).
IE =
first ethmoturbinate: 3ED =
dorsal scroll of third ethmoturbinate: 3EV = centra! scroll of third ethmoturbinate,:
SED = dorsal scroll of f~fth ethmoturbinate: SEV ventral scroll of Iiftb ethmoturbinate. The venica) lines correspond
=

to section lemels shown in Fig. 5B. B. bottom) Cross-sections of the nose of the F-344 rat to show m:o’’’- -~n:!!Omical
features. including the meatuses. turbinates. and a proposed nomenclature for the ethmoturbinates (Ta;~ _&dquo;mpare
with Fig. 5A. ~.~eatuses: D~1 =
dorsal medial; ~1~1 medial media!: S’°Ni
=
superior entr-al medial: I> hi = mferior
=

ventral medial: DL =
dorsal lateral: ML middle lateral: B’L = central lateral.
=

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 370

Fm. 6.-Diagram to show distribution of lesions induced by selected agents (Table I) in both the cross-sectional (top)
and sagittal (bottom) planes.

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