            42nd Annual Pathology of Laboratory Animals Course
                            AFIP August 1995


                DISEASES AND NEOPLASMS OF THE AGING SD RAT

                 James B. Nold, DVM, PhD, Diplomate, ACVP
                       Corning Hazleton (Wisconsin)

                                    and

                  George A. Parker, DVM, Diplomate, ACVP
                   Biotechnics, Mountainside, New JerseyGeneral Comments

    1.  Limited to Sprague-Dawley (CD) and Fischer 344 (F344) rats.

    2.  Based on information from chemical safety tests:

        a.  Two-week repeated dose range-finding studies.

        b.  90-day to 120-day subchronic studies.

        c.  24-month to 30-month chronic toxicity/oncogenicity studies.

    3.  Rats

        a.  Hsd:Sprague Dawley SD  (Harlan Sprague Dawley, Inc.)

             Direct descendants of original SD colony

        b.  Crl:CD BR Rat (Charles River Laboratories)

             Originated from the outbred SD  40+ years ago.

        c.  Fischer 344 (F344)

        d.  Wistar
I.   Urinary System

     A.  Kidney

          1. Chronic progressive nephropathy
             Synonyms: Spontaneous degenerative nephropathy
                       Rat nephropathy
                       Chronic nephrosis
                       Glomerulonephrosis

             a. Most common renal disease of laboratory rats.

             b. Proteinaceous casts, interstitial inflammation, fibrosis, thickened
                basement membranes, glomerulosclerosis, crescent formation.

             c. Basophilic epithelium in early stages of disease.        Seen in animals as
                young as 3-4 months.

             d. Striking hyaline droplet degeneration.

             e. More common and more severe in males than females.
                Incidence in males is reduced if they are castrated.

             f. Incidence is elevated in rats on a high protein diet.

             g. Commonly associated systemic lesions in advance CPN include
                multifocal mineralization (vessels, heart, lung) and fibrous
                osteodystrophy.

          2. Acute hemorrhage in renal sinus

             a. Acute hemorrhage in renal sinus is relatively common in sacrificed
                animals.

             b. Rarely see hematuria in association with hemorrhage, therefore
                presumed to be an agonal change.

          3. Hydronephrosis

             a. Relatively common in subchronic studies.

             b. Reported incidence of 2% in Sprague-Dawley breeding colonies.

             c. Selective breeding resulted in incidence of 33.6% in two generations.

             d. Right kidney is more commonly involved.

             e. An anatomic basis has been proposed in one strain of rats 
                (Slonaker-Addis), but this was not confirmed by another study.

             f. Uroliths, pelvic inflammation, or pelvic mineralization may be present,
                but often the cause is not evident.

             g. Cortical tubular cysts commonly seen as a background lesion.

          4. Microlithiasis

             a. Microscopically similar to "dehydration salts" in other species.

             b. Typically located in a band at the corticomedullary   junction.

             c. More common in females.

             d. More common in animals that die.

          5.  Microcalculi in renal sinus

             a. Sometimes associated with hyperplasia of transitional epithelium of
                the renal sinus.

             b. Commonly associated with mild dilatation of the renal sinus.

          6. Pigmentation of renal cortical epithelium

             a. Diffuse, particulate to amorphous, light brown cytoplasmic pigment is
                compatible with lipofuscin ("aging pigment").

             b. Globular, greenish brown pigment in some cases is similar to
                hemosiderin.

          7. Hyaline droplets

             a. Alpha2  -globulin.

             b. More common in males.

             c. Typically indicative of protein reabsorbed from the glomerular filtrate. 
                Involves proximal convoluted tubule and/or pars recta, or collecting
                ducts.


             d. Hydrocarbon nephropathy (alpha2  -globulin), histiocytic sarcoma
                (lysozyme), or Bence Jones protein.

          8. Lipomatous foci

             a. Focal accumulation of lipocytes, typically in renal cortex.

             b. May be neoplasm or hamartoma.

          9. Nephroblastoma (embryonal nephroma)

             a. Low incidence.

         10. Tubular adenomas/adenocarcinomas

             a. Microscopically similar to other species.

             b. Associated with hydrocarbon exposure.

                (1) Tend to be located in the poles of the kidneys.

                (2) Probably dependent on presence of alpha-2u-         globulin.

       B.   Urinary bladder

          1. Papillary hyperplasia of urinary bladder epithelium.

             a. Commonly associated with cystic calculi.  Bladder may  have been
                described as thickened at necropsy.

             b. Calculi are not present in sections, therefore careful review of gross
                necropsy observations is critical in diagnosis.

             c. Hyperplasia typically is associated with some degree of inflammation,
                though often mild.

             d. Nearly normal polarity and orderly maturation of epithelial cells is
                present in hyperplasia, in contrast to transitional cell carcinoma.

          2. Lymphocytic infiltration in urinary bladder

             a. Must be differentiated from mononuclear cell leukemia infiltrates in
                F344 rats.


             b. The nonneoplastic infiltrates tend to be limited to the submucosa,
                whereas leukemic infiltrates are throughout the wall of the bladder.

             c. Cell morphology on standard H&E sections isn't particularly helpful in
                differentiating between lymphocytic and leukemic infiltrates.

             d. Multiple organs involvement is most important feature in
                distinguishing leukemia from inflammatory infiltrates.

          3. Calculi

             a. May be microscopic or macroscopic.

             b. Usually associated with microcalculi in the renal pelvis.

          4. Agonally, may see semen ejaculate in the urinary bladder or urethra.  Not
             to be mistaken for a calculus or occlusion.

II.  Respiratory System

     A.  Nasal cavity.

         1. Incisive fissures in nasal cavity.

            a. Normal anatomic structure.

            b. Provides direct communication between oral and nasal cavities.

            c. Must be distinguished from cleft palate, particularly in teratology
               studies.

         2.  Maxillary "sinusitis"

            a. Correct anatomic term is maxillary recess rather than maxillary sinus.

            b. Commonly the site of mild suppurative inflammation, sometimes in
               association with similar inflammation in other parts of the nasal cavity.

         3. Rhinitis

            a. Typically involves neutrophilic infiltration, and sometimes includes
               erosion or ulceration of the nasal epithelium.

            b.  Etiology unknown.

            c. Mycotic (aspergillus) rhinitis is seen sporadically.

     B.  Trachea

         1. Mineralization of tracheal cartilage.

            a. Very common as an aging change.

            b. May represent normal anatomic progression with age.

     C.  Lung

         1. Alveolar histiocytosis.

            a. Multifocal aggregations of alveolar macrophages within alveoli and
               terminal airways.

            b. May represent resolved inflammatory foci, or may represent a focal
               deficit in the pulmonary clearance mechanisms.

            c. Sialoadenodacryoadenitis virus infection has an associated
               pneumonitis.

         2. Mineralization of pulmonary arteries

            a. Seen more commonly in F344 than in Sprague-Dawley rats.

            b. Typically consists of focal or multifocal mineralization beneath the
               intima or within the muscular wall of the arteries.

         3. Hair shaft emboli in intravenous injection studies

         4. Murine respiratory mycoplasmosis (Mycoplasma pulmonis)

            Synonym:  Chronic respiratory disease (CRD)

            a. Used to be the most significant spontaneous lesion in most rat
               colonies.

            b. Principally an upper respiratory tract pathogen.  Severe lung
               involvement is common only in advanced cases and/or aged animals.

            c. Earliest lesions in nares, larynx, and middle ear.

               (1)  Epithelial hyperplasia and metaplasia.

               (2)  Subepithelial lymphoid infiltration.

               (3)  Purulent exudate.

            d. Lung involvement

               (1)  Lymphoid hyperplasia and infiltration -- considered a
                    characteristic lesion even in the absence of more advanced
                    pathological changes. Note: the rat lung does normally contain
                    some small bronchial associated lymphoid tissue.

               (2)  Bronchiectasis -- large, distended airways filled with large
                    quantities of purulent debris -- an advanced lesion.

            e. Urogenital

               (1)  Mycoplasmosis also may infect the genital system, producing
                    infertility and histologic changes in the ovaries and oviducts.

         5. Pulmonary neoplasms

            a. Primary pulmonary neoplasms are rare spontaneous neoplasms in the
               rat.

III. Cardiovascular System

     A.  Heart

         1. Cardiomyopathy

            a. Consists of myofiber atrophy and interstitial fibrosis,  most commonly
               beginning in the subintimal myocardium of the left ventricle.

            b. More common and more severe in males than females.

         2. Atrial thrombosis

            a. May be so severe as to be grossly visible.

            b. Typically has fibrosis and organization at the base, which continues
               into the atrial wall.

         3. Myocardial mineralization

            a. Most commonly is secondary to severe nephropathy.


         4. Chronic inflammation of base of heart (coronary arteritis)

            a. Is an uncommon lesion which usually is encountered as an incidental
               finding.

            b. Usually not associated with disseminated polyangiitis, and is
               morphologically different from polyangiitis.

         5. Coronary arteriosclerosis

            a. Uncommonly seen in the larger branches of the coronary arteries.

            b. Resembles amyloid, but special staining attempts have been
               unsuccessful.

         6. Endocardial hyperplasia/sarcoma (schwannoma)

            a. Was called fibroelastosis.

            b. Thickening and cellular proliferation in the subendocardium.

            c. Infiltrates into the myocardium and expands into the ventricular lumen.

            d. Size and extent of lesion will be a determining factor in whether to
               classify this as a hyperplasia or neoplasm.

     B.  Vasculature

         1. Polyangiitis (polyarteritis nodosa, panarteritis)

            a. Grossly visible nodular thickening of mesenteric arteries. But,
               frequently may be diagnosed microscopically in absence of gross
               lesions.

            b. Consists of fibrosis, inflammation and fibrinoid necrosis of muscular
               arteries in a variety of locations, including mesentery.

            c. Mesenteric polyangiitis is commonly seen in sections of pancreas.

            d. Commonly seen in testis and mesenteric arteries.

            e. Fibrinoid necrosis of the muscular wall of arterioles, with surrounding
               mixed inflammatory cell infiltration.

         2. Aortic mineralization

            a. Most commonly seen secondary to nephropathy.

            b. May be so severe as to be grossly noted ("brittle aorta").

         3. Portal vein thrombosis

            a. Occasional incidental finding.

IV.  Gastrointestinal System

     A.  Oral cavity

         1. General information

            a. Dental formula: I 1/1, M 3/3.

            b. Root of upper incisor extends nearly to eye.

            c. Incisors grow continuously throughout life.

         2. Broken teeth

            a. Incisors may be broken or trimmed to short by caretakers.

            b. Foreign material from feed may become impacted in pulp cavity and
               periodontal space.

            c. May result in endodontitis or periodontitis, sometimes with necrosis of
               tooth.

         3. Odontodystrophy

            a. May be odontoma but, if neoplastic, does not appear to be an
               aggressive neoplasm.

            b. Incidence may approach 10%, though more typically is much lower.

            c. Consists of a disorderly mass of tooth bud elements.

     B.  Salivary gland

         1. Rat salivary glands

            a. Submaxillary (submandibular) - mixed mucoserous.


            b. Sublingual - mucous.  Attached to anterior pole of submaxillary gland.

            c. Parotid - primary serous.  Plasmacytic infiltrates more common.

         2. Acinar atrophy of salivary gland

            a. Lobular atrophy of glandular cells with fibroplasia in the surrounding
               interstitium.

         3. Focal tinctorial alteration

     C.  Liver

          1. Hepatodiaphragmatic nodules in liver

             a. Nodular protrusion on anterior surface of liver associated with small
                diaphragmatic hernia.

             b. Microscopically consist of normal hepatic tissue, with a rounded outer
                contour.

             c. Diagnosis depends a great deal on necropsy observation, i.e.,
                location of the nodule on the anterior surface of the liver and in
                association with a diaphragmatic hernia.

             d. Must be carefully differentiated from true hepatic neoplasia.

          2.  Hepatic angiectasis

             a. Focal or multifocal sinusoidal dilatation.

             b. Subcapsular foci may be associated with a depression in the surface
                contour.

          3. Ito cell proliferation/hypertrophy

             a. Resemble angiectasis, except are filled with proteinic material rather
                than blood.

             b. Are perisinusoidal fat-storing cells ("Ito cells").

             c. Has been called cystic degeneration of hepatocytes.

          4. Mitotic figures and multinucleated hepatocytes

             a. Small number is normal.

             b. If elevated, may be test material induced.

          5. Focal or multifocal inflammation in liver

             a. Possibly due to bacterial showering from gut.

             b. Bacteria or overt suppurative inflammation are rarely seen.

             c. May be acute, subacute or granulomatous.

          6. Periportal fatty change in liver

             a. Spontaneous lesion in older rats.

             b. May be more common in Sprague-Dawley than F344.

             c. Must be carefully distinguished from compound-related fatty change.

          7. Bile ductule hyperplasia in the liver

             a. Very common in F344 and Sprague-Dawley rats.

             b. Consist of hyperplasia and proliferation of bile ductule epithelium,
                sometimes surrounded by fibroplasia.

             c. The fibrotic variant has been called cholangiofibrosis. Probably is a
                chronic form of the purely hyperplastic lesion.

          8. Paranuclear vacuoles in liver

             a. Usually subcapsular.

             b. Probably some type of artefact.

          9. Torsion of liver lobes

             a. May be seen in any lobe, though the papillary process of the caudate
                lobe seems to be most prone to torsion.

             b. Acute torsion has hemorrhagic necrosis with variable neutrophilic
                infiltration.

             c. Chronic torsion has fibrosis and a variable degree of necrosis and
                neutrophilic infiltration.  May also have nodular hepatocytic
                regeneration which must be distinguished from neoplasia.
         10. Streamlining in liver

             a. Blood from different areas of the gastrointestinal tract are
                concentrated in different lobes of the liver due the phenomenon of
                streamlining.

             b. Hepatotoxins which are primarily absorbed from one region of the gut
                may cause lesions primarily in one lobe of the liver, thus it is essential
                to take multiple sections of liver on toxicologic pathology studies.

         11. Tension lipidosis

             a. Grossly recognized as a circumscribed pale area.

             b. Usually occur at periphery of lobe near attachments to adjacent lobes
                or tissues.

         12. Foci of cellular alteration

             a. Basophilic, eosinophilic, clear cell and mixed foci.

             b. Omenclature based on tinctorial alteration of hepatocytic cytoplasm.

             c. Margins blend into the surrounding parenchyma.

             d. Some foci may compress adjacent parenchyma slightly.

             e. No disruption of hepatic lobular architecture.

             f. Hepatocytes within foci may be larger, smaller or same size as
                hepatocytes in surrounding parenchyma.

             g. Foci have been shown by special staining techniques to be
                metabolically different from the surrounding parenchyma.

             h. Areas of cytoplasmic alteration are same as foci of cytoplasmic
                alteration, except for size.

         13. Hepatocellular hyperplasia

             a. Usually multifocal nodular lesion associated with previous or
                concurrent hepatic damage.  Regenerative nodule.

             b. Often accompanies mononuclear cell leukemia in F344.

             c. Spherical proliferation of hepatocytes without nuclear atypism.

             d. May have cytoplasmic tinctorial variation, similar to altered foci.

             e. Hepatic lobular architecture is evident but may be distorted.  Portal
                triads often can be seen.

             f. May reach a large size, eg. several millimeters.

         14. Hepatocellular adenoma

             a. Nodular proliferations that are sharply demarcated by virtue of definite
                compression of surrounding parenchyma.

             b. Usually have distinct cytoplasmic tinctorial changes.

             c. Hepatic plates in adenoma are not continuous with plates of
                surrounding parenchyma, but impinge with them at a sharp angle.

             d. Loss of normal lobular architecture.

             e. May have increased mitotic rate or cellular atypism.

         15. Hepatocellular carcinoma

             a. Usually larger and more irregular than adenoma.

             b. Compress or invade surrounding parenchyma.

             c. Characterized by one or more of the following:  cellular atypism, local
                invasion, haphazard arrangement of cells, broad sheets of cells,
                trabecular patterns, or glandular patterns.

         16. Hepatoblastoma

         17. Cholangiocarcinoma

         18. Hemangiosarcoma

             a. Sinusoidal spaces lined by neoplastic endothelial cells.

             b. May entrap hepatocytes.

     D.  Tongue

          1. Papilloma


     E.  Pharynx

          1. Papilloma

          2. Squamous cell carcinoma

     F.  Stomach

          1. General information

             a. Nonglandular epithelium often is thickened at junction.

             b. There often is a mild eosinophil infiltration in the submucosa beneath
                the junction.

          2. Cystic dilatation of gastric glands

             a. Consists of dilatation of the crypts of gastric glands.

             b. No apparent inflammation or adverse effect is noted.

          3. Gastric ulceration and erosion

             a. Ulceration of the glandular or nonglandular mucosa is commonly
                seen in aged rats.

             b. More common in gavage studies, probably due to trauma.

             c. Edges of ulcers in nonglandular stomach have a variable degree of
                epithelial hyperplasia.

             d. Erosion must be differentiated from multifocal autolysis of superficial
                mucosa.  Inflammatory cell infiltration is critical feature of erosion.

     G.  Small intestine

          1. Adenocarcinoma

     H.  Large intestine

          1.  Adenomatous polyp

          2.  Adenocarcinoma 

     I.  Mesentery

          1. Mesenteric fat necrosis

             a. Consist of nodular masses of necrotic, inflamed mesenteric fat.  At
                necropsy is usually described as a mass in the peritoneal cavity or
                along the testes.

             b. Appears to be caused by torsion of mesenteric fat.

          2. Mesothelioma

             a. Seen with moderate frequency, especially in F344.

             b. May consist of very small foci on surface of testis.

             c. Consist of fibrous tags covered by mesothelial cells.

             d. May see implants on serosal surface of various abdominal organs.

             e. Microscopic appearance of benign mesothelioma is similar to
                malignant mesothelioma.  Presence of implants on abdominal organs
                is evidence of metastasis, therefore malignancy.

     J.  Pancreas

          1. Acinar atrophy of the pancreas

             a. Similar to acinar atrophy of salivary gland.

             b. Consists of atrophy of acinar elements with persistence of ducts and
                a variable degree of fibrosis.

             c. Islets are not affected.

          2. Pancreatic vacuoles

             a. Reported to be an early manifestation of autolysis.

             b. Consists of clear vacuoles in acinar cells.

          3. Hepatocytic islands in pancreas

             a. Typically located around islets.

             b. Consist of microscopically normal hepatocytes with Kupffer cells and
                bile ductules.

             c. Appears to be functional liver.  Toxic changes observed in the liver
                also are present in the hepatocytes in the pancreas.

          4. Acinar cell hyperplasia 

             a. Focal or multifocal hyperplasia is relatively common.

             b. Consists primarily of focus of tinctorial alteration.

          5. Acinar cell adenoma

             a. Less common than hyperplasia.

             b. May be associated with corn oil gavage.

          6. Tubular adenocarcinoma

V.   Endocrine System

     A.  Pancreatic islets

          1. Islet cell hyperplasia or giant islets

             a. Great variation in size of islets is commonly noted. 

             b. Probably is normal anatomic variation.

          2. Islet cell adenoma/carcinoma

             a. Adenomas are relatively common in laboratory rats.

             b. Cell morphology is slightly altered, therefore diagnosis is based on
                size of lesion and evidence of compression or infiltration.

     B.  Pituitary

          1. Pituitary cysts.

             a. Very common.

             b. Often have apical cilia on lining cells.

             c. Probably represent cystic remnants of Rathke's pouch.

          2. Focal hyperplasia of the pituitary

             a. Very common.

             b. Must be distinguished from adenoma.


          3. Pituitary adenoma

             a. Very common.

             b. Incidence is 60% in males; 70% in females.

             c. Chromophobe adenomas are most common.

             d. Often have bizarre cellular features.

             e. May cause compression of ventral aspect of brain. Incidence in lower
                in rats on low protein diet.

             f. 81/83 stained for prolactin.  14/83 also stained for growth hormone.

             g. Ovariectomy significantly decreases incidence of pituitary adenomas
                in female rats.

     C.  Adrenal gland

          1. Cortical vacuolation

             a.  Very common.

             b. Focal/multifocal aggregations of adrenocortical cells which have clear
                cytoplasmic vacuoles.

          2. Cystic degeneration, cortical

             a. May be part of a continuum from cellular vacuolation to degeneration
                to large clear- or blood-filled spaces.

             b. Focal to multifocal areas of degenerative, vacuolated                    cortical cells
                being replaced by larger clear-filled or blood-filled spaces.

             c. More common in females.

             d. Severely affected glands may grossly appear swollen, soft, dark red,
                or mass-like.

          3. Angiectasis

             a. Very common.

             b. More common in cortex, but may also be in medulla.

             c. Dilatation or coalescence of vascular spaces.

             d. May be sequelae of cystic degeneration.

             e. Combinations of cortical vacuolation, angiectasis, and cystic
                degeneration are very common.  Consistency of diagnostic criteria
                and terminology is critical for purposes of tabulating these changes.

          4. Extramedullary hematopoiesis

             a. Focal or multifocal aggregates of hematopoietic cells.

          5. Ectopic adrenocortical tissue

             a. Most often present outside adrenal capsule.  May be seen in kidney.

          6. Adrenal medullary and cortical mixing

             a. Common to see clusters of cortical cells within the medulla.

             b. Depending on section, medullary tissue may extend out to the
                capsule.  This must be differentiated from medullary hyperplasia.

          7. Hyperplasia, cortical

             a. Distinct cortical foci, usually within the zona fasciculata and zona
                reticularis.  Focal or multifocal.

             b. Cells may be variably sized, but are well-differentiated.  May be
                vacuolated.

             c. May be associated with aforementioned degenerative changes.

             d. Common lesion, but not clear progression to neoplasm.

             e. Some call these foci of cellular hypertrophy or cellular alteration.

          8. Adenoma, cortical

             a. Well-differentiated, but clearly expansile and compressive.

          9. Carcinoma, cortical

             a. Frequently metastasize.

         10. Hyperplasia, medullary

             a. Must be distinguished from pheochromocytoma.

             b. Criteria for differentiation based on compression and size. 
                Consistency within a study is important.

             c. More common in males.

             d. Basophilic clusters of medullary cells.

         11. Pheochromocytoma

             a. Common in aged rats, particularly males.

         12. Ganglioneuroma of adrenal medulla

             a. Have well differentiated ganglion cells surrounded by well
                differentiated neuropil.

             b. Usually (always?) associated with a pheochromocytoma.

             c. Not common, 28 in 60048 F344 rats from NTP program.

     D.  Thyroid

          1. Ultimobranchial cysts or remnants

             a. Cyst lined by squamous epithelial cells, filled with keratin and cellular
                debris.

             b. May be very small, follicle-sized remnants with no cystic dilatation.

             c. Most commonly seen in the central area of the thyroid.

          2. Thyroid colloid concretions

             a. Basophilic globules in colloid.

          3. C-cell hyperplasia

          4. C-cell adenoma

             a. C-cell masses greater than 5 average follicular diameters are
                classified as adenomas.



          5. C-cell carcinoma

             a. Criteria for malignancy may include size, invasion, cellular
                pleomorphism, etc.

             b. May metastasize to lung.

          6. Hyperplasia, follicular

          7. Adenoma/carcinoma, follicular

     E.  Parathyroid

          1. Fibrosis, parathyroid

             a. Thickening of fibrous trabeculae.

          2. Ectopic parathyroid

             a. Common in mediastinum.

          3. Hyperplasia

                a.  Commonly secondary to spontaneous nephropathy.

             b.  Usually diffuse within the gland.

              4.  Adenoma

             a. Uncommon.

             b. Distinguish from hyperplasia by unilateral distribution  and remnants
                of normal parathyroid tissue around the adenoma.

VI.  Reproductive System and Mammary Gland

     A.  Testis

          1. Hypospermatogenesis or tubular atrophy

             a. May occur as a primary (idiopathic) change or secondary to
                polyangiitis.  Also seen near interstitial cell tumors.

          2. Giant cell degeneration

             a. Multinucleated giant cells in seminiferous tubules.


             b. Often not associated with tubular atrophy, thus appears to be a
                distinct pathologic process.

          3. Mineralization

             a. May affect seminiferous tubules or blood vessels.

             b. Appears grossly as white fibers visible from surface of testis.

          4. Sperm granuloma

             a. Tubule distended by a mass of spermatozoa.

             b. Usually no associated inflammation.

             c. May result in secondary tubular atrophy or hypospermatogenesis.

          5. Interstitial cell hyperplasia

             a. Very common in F344, where it is a precursor to interstitial cell tumor.

             b. Difficult to establish criteria for differentiation between small
                interstitial cell tumors and large focal hyperplasia. Cellular
                morphology is similar in both lesions.

             c. In USA, hyperplasia is no greater than one seminiferous tubule
                diameter.  In Europe, hyperplasia may be up to diameters.

          6. Interstitial cell tumor (ICT)

             a. Up to 95% incidence in 24-month-old F344 rats.  Much  lower
                incidence in Sprague-Dawley rats.

             b. White to yellow foci visible through the tunica vaginalis of the testis.

             c. Microscopically similar to ICT in other species.

     B.  Prostate

          1. Senile atrophy and concretions

             a. Epithelium is cuboidal or squamoid rather than columnar.

             b. Lumina contains small, deeply basophilic concretions which are
                microscopically similar to the "corpora amylacia" of other species.

          2. Chronic prostatitis

             a. Very common in old rats.

             b. Primarily an interstitial process, though some lumina may be filled
                with inflammatory cells and cellular debris.

          3. Epithelial hyperplasia.

             a. Seen with moderate frequency.

             b. Focal or multifocal proliferation of epithelial cells, sometimes filling
                glandular lumen.

          4. Prostatic neoplasms

             a. Uncommon as spontaneous entity in laboratory rats.

     C.  Preputial and clitoral gland

          1. General information

             a. Are large organs in the rat, eg. 10 mm long x 5 mm wide.

             b. Consist of a large central duct surrounded by modified sebaceous
                cells.

             c. Located on either side of prepuce or vulva.

          2. Adenomas may be acinar or squamous

          3. Preputial/clitoral gland adenocarcinomas

             a. Occur in a low incidence as spontaneous entity.

             b. A few are malignant, and metastasize to the lungs.

             c. Must be distinguished from inguinal mammary gland neoplasms.

             d. Most characteristic microscopic feature of acinar preputial/clitoral
                gland neoplasms is brightly eosinophilic cytoplasmic granules.


          4. Duct ectasia

             a. Consists of dilatation of the central lumen, sometimes with impacted
                secretory material.  May be seen grossly as a discolored focus in the
                center of the gland.

             b. Inflammation is variable.

     D.  Ovary

          1. Atrophy

             a. Present in virtually all rats at terminal sacrifice on chronic study.

             b. Consists of reduction in number of follicles and corpora lutea with a
                variable amount of intracellular pigment in stromal cells.

          2. Hyperplasia, interstitial gland (stromal)

             a. Frequently in combination with atrophy will see hyperplasia of the
                interstitial glands.

          3. Cysts

             a. Parovarian cysts consist of dilatation of the ovarian bursa.  May be
                difficult to detect on microscopic examination.

             b. Intraovarian cysts.  Exact genesis unknown.  Are present in the
                ovarian parenchyma, therefore are microscopically distinct from
                parovarian cysts.

          4. Papilloma of ovarian rete

             a. Uncommon, but not rare.

             b. Seen in the hilar region of the ovary.

             c. Typical papilloma contained with a dilated tubular structure.

          5. Teratoma

             a. Uncommon, but not rare.



             b. All three germ layers present.  Epithelium and neural tissue are
                usually most prominent.  The mesodermal element may be muscle,
                fat or other elements

          6. Granulosa/theca cell tumors

             a. Occur in low incidence.

             b. Microscopically similar to other species.

          7. Cystadenomas/adenocarcinomas

             a. Uncommon.

          8. Dysgerminoma

             a. Not reported in the rat.

     E.  Uterus

          1. Wall of uterus and cervix commonly has eosinophil infiltration

          2. Mild dilatation is common in young rats

          3. Cystic endometrial hyperplasia

             a. Not as common in rat as in mouse.

             b. In the rat is primarily cyst formation.  The rat has less epithelial
                proliferation than the mouse.

          4. Endometrial fibrosis

             a. May be normal for old rats.

          5. Endometrial stromal polyp

             a. Very common in old rats.

             b. Consists of a polypoid mass of endometrial stroma and capillaries
                covered by epithelium.

             c. May be infarcted by torsion or other disruption of the stalk.

          6. Endometrial stromal sarcoma

             a. The malignant counterpart of endometrial stroma polyp.

             b. Some degree of invasiveness is an important criterion in diagnosis.

          7. Cystic dilatation of vaginal fornix

             a. Gross observation of mass near body of uterus or in cervix.

             b. Lined by stratified squamous epithelium and filled with keratinaceous
                debris.  May contain a neutrophilic infiltration, to the degree that they
                resemble abscess.

     F.  Mammary gland

          1. Sexual dimorphism

             a. Mammary glands of males and females are microscopically similar at
                birth.

             b. By 19 weeks, males and females are markedly different: 

                (1)  Females have widely scattered tubuloacinar
                    units.

                (2) Males have more prominent glandular tissue, but                       not organized
                    into ductular units.

          2. Senescent atrophy

             a. Decrease in glandular elements with intraluminal concretions and
                accumulations of pigment-laden cells.

          3. Duct dilatation

             a. Moderately common in aged females.

             b. Cystic mammary ducts often called galactoceles.

          4. Lobular hyperplasia

             a. Enlarged lobules with relatively normal appearing alveoli.

             b. Cystic alveoli and dilated ducts may be present.

             c. Lack a prominent collagenous stroma, which early fibroadenomas
                have.




          4. Fibroadenoma

             a. Very common neoplasms in aged females, with a lower incidence in
                aged males.

             b. May be multiple, and may be nearly as large as the rat.

             c. Rats have mammary tissue on nearly the entire body, with the
                exception of the head, tail and distal extremities. Any subcutaneous
                neoplasm on the trunk of a rat may be a mammary neoplasm.

             d. Consist of epithelial elements surrounded by proliferating fibrous
                connective tissue.

             e. Some neoplasms consist almost entirely of fibrous connective tissue.

             f. Ovariectomy significantly decreases the incidence of mammary
                fibroadenomas in female rats.

VII. Lymphoreticular and Hematopoietic Systems

     A.  Spleen

         1.  Increased hemosiderin

             a. Rat spleen normally has a moderate amount of hemosiderin.  More in
                females than males.

             b. May be markedly increased in some animals, due to diverse causes.

             c. Difficult to establish criteria for distinguishing between normal and
                excessive hemosiderin.

          2. Increased extramedullary hematopoiesis

             a. Rat spleen normally has a small amount of EMH.

             b. Chronic disease process, eg. neoplasms, commonly are associated
                with an increase in the level of splenic EMH.

             c. Difficult to establish criteria for distinguishing between normal and
                excessive EMH.

          3. Mesothelial cyst

             a. Not uncommon.

             b. Usually disrupted in processing, with only fibrous tags remaining on
                surface of spleen.

     B.  Lymph nodes

          1. Cystic degeneration

             a. Consists of cystic dilatation of sinusoids.

             b. Often so prominent as to be noted at necropsy.

          2. Plasmacytosis

             a. Commonly seen in mandibular lymph nodes.

             b. May be so prominent as to be noted grossly.

             c. Medullary region consists of sheets of mature plasma cells.

             d. Etiology and significance unknown.  Seem to be more prominent in
                association with oral cavity lesions.

          3. Senescent atrophy

             a. Nearly ubiquitous in chronic studies.

             b. Consist of reduction in lymphoid follicles with a moderate amount of
                intracellular pigment in medullary area.

          4. Mast cells

             a. Rats have numerous mast cells in many organs.

             b. Are very obvious when in lymph nodes.

          5. Mesenteric lymph node hemangioma

             a. Uncommon, but not rare in mesenteric lymph nodes.

             b. Rare in other lymph nodes.

     C.  Thymus

          1. Epithelial remnants 

             a. Epithelial tubules or nests in medullary region of thymus of old rats.

             b. Occasionally see neoplasms of these epithelial elements.

          2. Thymic cysts

             a. May be lined by squamoid cells or tall columnar cells with cilia.

          3. Ectopic thymus in thyroid

             a. Relatively common within or adjacent to the thyroid.

          4. Atrophy/involution

             a. Thymus often difficult to identify at necropsy in aged animals.

          5. Thymoma

             a. Consist of a mixture of "epithelial" and lymphoid elements, similar to
                other species.

             b. May have epithelial tubules.

             c. Often have a moderate population of eosinophils.

     D.  Systemic

         1.  Large Granular Lymphocyte (LGL) Lymphoma/Leukemia

             a. Formerly called mononuclear cell leukemia.

             b. Very common neoplasm in F344 rat.  Rare, but occurs in
                Sprague-Dawley.  Reported in Wistar and                         Wistar-Furth.

             c. Splenic architecture is effaced by sheets of individualized neoplastic
                cells.

             d. Cell morphology is not specific on H&E sections.

             e. Can involve virtually any organ in the body.

             f. Early leukemic infiltrates are in the spleen and liver. Are more easily
                detected in the liver.

             g. 30-50% of early deaths in 2-year F344 study are due to this disease.

             h. Death apparently due to hemolytic anemia.  Also thrombocytopenic.

             i. Bone marrow involvement results in reduced bone formation.

             j. Large granule lymphocytes are NK (natural killer) cells.  Constitute
                1-5% of normal rat peripheral leukocyte count.

             k. Large granule lymphocytic leukemia has been reported in man and a
                cat.

          2. Granulocytic leukemia (myelogenous leukemia)

             a. Uncommon, incidence < 5%.

             b. Distinct myelogenous differentiation of neoplastic cells. Granulocytic
                differentiation more common than erythroid or basophilic.

             c. May be induced by ionizing radiation or some chemical agents.

          3. Lymphoma (lymphosarcoma)

             a. May be classified as follicular center cell, immunoblastic, plasma cell,
                or lymphoblastic, but usually not typed in routine carcinogenicity
                studies.   Most are
                B cell origin.

             b. Slight higher incidence than LGL or granulocytic leukemia,
                approximately .5-.9% in our laboratory.

VIII.    Sense Organs

     A.  Eyes and Harderian glands

          1. Cataracts and retinal degeneration

             a. Common in older rats.

             b. Retinal degeneration may be due to excessive light in animal rooms.

             c. Careful cage rotation schedule is necessary to prevent excessive
                incidence in one group.

             d.  Microscopically similar to other species.

             e. Retinal degeneration often is secondary to cataract, but can occur
                independently.


          2. Phthisis bulbi

             a. Rupture of the eye due to trauma from cage wire or retrobulbar
                bleeding.

          3. Scleral osseous metaplasia

             a. Common, more in F344 than in SD.

             b. Linear or ovoid foci of mineralization or ossification in the middle
                layers of the sclera, most commonly in the middle or posterior thirds
                of the eyeball.

          4. Keratitis

             a. Common in rats kept in wire cages and in gang-caged rats.

          5. Corneal dystrophy/mineralization

             a. Common in F344.

          6. Porphyrin accumulation in Harderian gland

             a. Cause of "red tears".

             b. Nonspecific change, indicating a sick rat.

          7. Exorbital lacrimal gland

             a. Cellular pleomorphism is normal.

             b. Often get differentiation of Harderian gland type acini.

IX.  Central Nervous System

     A.  Brain

         1.  Vacuoles and mucocytes

             a. Vacuoles commonly seen in otherwise normal brains.

             b. Mucocytes are vacuoles that contain amorphous gray material.

             c. Etiology and significance unknown.  Probably both are artifacts.

             d. Mucocytes are reported to be more common in brains that are
                immersed in alcohol.

          2. Lipofuscin pigmentation of neurons

             a. Microscopically similar to other species.

          3. Compression of the brain stem

             a. Results from expansion of pituitary adenoma.

          4. Astrocytoma

             a. Astrocytomas are fairly common in brain, and rarely occur in spinal
                cord.

          5. Granular cell tumor

             a. Usually in the superficial cortex, near the meninges.

             b. Distinctly bounded, as opposed to gliomas.

             c. Distinctly granular cytoplasm in polygonal neoplastic cells. 
                Granularity is enhanced by PAS stain.

     B.  Spinal cord

          1. Degenerative myelopathy

             a. Posterior paresis or ataxia.

             b. Lesions in the spinal cord and nerve roots, principally the ventral and
                lateral white tracts from T4 - L4 region and the ventral spinal roots
                from mid-thoracic area posteriorly.  

             c. May occasionally see degenerative changes in the sciatic nerve.

             d. Characterized by demyelination, distended axon sheaths, swollen or
                absent axons, lipid filled macrophages, and reactive glial cells.

          2. Chordoma

             a. Neoplasm derived from primitive notochord elements.

             b. Characterized by large vacuolated "physaliphorous"                                 cells.



X.   Musculoskeletal System

     A.  Skeletal muscle

          1. Atrophy of skeletal muscle

             a. Relatively common, often secondary to degenerative myelopathy.

             b. Reduction in cross-sectional area of myofibers, with apparent or real
                increase in endomysial connective tissue.

     B.  Bone

         1.  Fibrous osteodystrophy

             a. Common in association with spontaneous nephropathy.

         2.  Degeneration of sternebral cartilage

             a. Degenerative cleft formation in intersternebral cartilage is commonly
                seen.

             b. Similar changes are reported in vertebra, but these bones are not as
                commonly sectioned in chronic studies.

XI.  Integumentary System

     A.  Skin

         1.  Tarsal granulomas

             a. Common in rats that are kept in wire cages, and especially in heavier
                animals.  So, more common in males.

             b. May be very large.

         2.  Keratoacanthoma

             a. Common.

             b. Must be differentiated from squamous papillomas and epidermal
                inclusion cysts.

         3.  Amelanotic melanoma

             a. Probably more common than incidence summaries show.


             b. Solid sheets of spindled and interlacing cells, usually diagnosed as a
                neurofibroma/sarcoma or fibroma/sarcoma.

             c. Electron microscopy shows characteristic premelanosomes.

         4.  Epidermal inclusion cyst

             a. Very common, particularly on tail.

             b. Consist of a cystic space filled with keratinaceous debris and lined by
                maturing stratified squamous epithelial cells.

             c. Some may have a neck-like connection to the surface.

         5.  Chronic inflammation, tail

             a. Focal to multifocal crusty lesions.

             b. Chronic inflammation with acanthosis and hyperkeratosis.

             c. Some lesions may be epidermal inclusion cysts or
                keratoacanthomas.

         6.  Auricular chondritis

             a. Distortion and mineralization of the auricular cartilage.

             b. Possibly associated with trauma.

             c. Reported to be a heritable collagen disease in some strains.

     B.  Zymbal's gland

         1.  Large gland that lies around the external ear canal

         2.  Very susceptible to carcinogenic influence

         3.  Carcinomas may be very large.  May have both sebaceous and squamous
             elements, or either element alone

         4.  Rarely invade into the brain, presumably along cranial nerve tracts
                  DISEASES AND NEOPLASMS OF THE AGING RAT
                    JAMES B. NOLD and GEORGE A. PARKER

                                AUGUST 1995

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Sellers, AL, HC Goodman, J Marmorston and M Smith:  Sex difference in proteinuria in the rat.  Am. J. Physiol.
163:  662-667, 1950.

Solleveld, HA and GA Boorman:  Spontaneous renal lesions in five rat strains.  Toxicol. Pathol. 14:  168-174,
1986.

Tapp, DC, WG Wortham, JF Addison, DN Hammonds, JL Barnes and MA Venkatachalam:  Food restriction
retards body growth and prevents end-stage renal pathology in remnant kidneys of rats regardless of protein
intake.  Lab. Invest. 60: 184-195, 1989.

Thamavit, W, S Sahaphong, S Angsubhakorn and T Glinsukon:  Spontaneous teratoid nephroma in a rat.  Vet.
Pathol. 16: 130-131, 1979.

Weaver, RN, JE Gray and JR Schultz:  Urinary proteins in Sprague-Dawley rats with chronic progressive
nephrosis.  Lab. An. Sci. 25:  705-710, 1975.

Zwicker, GM et al:  Spontaneous renal neoplasms in aged Crl:CD BR rats.  Toxicol. Pathol. 20: 125-130, 1992.


                               MAMMARY GLAND

Barsoum, NJ, AW Gough, JM Sturgess and FA de la Iglesia:  Morphologic features and incidence of
spontaneous hyperplastic and neoplastic mammary gland lesions in Wistar rats.  Toxicol. Pathol. 12:  26-38,
1984.

Cardy, RH:  Sexual dimorphism of the normal rat mammary gland.  Vet. Pathol. 28:  139-145, 1991.

Noble, RL and JH Cutts:  Mammary tumors of the rat:  a review.  Cancer Res. 19:  1125-1139, 1959.


                            REPRODUCTIVE SYSTEM

Alison, RH and KT Morgan:  Ovarian neoplasms in F344 rats and B6C3F1 mice.  Environ. Health Perspectives
73:  91-106, 1987.

Gopinath, C and WA Gibson:  Mesovarian leiomyomas in the rat.  Environ. Health Perspectives 73:  107-113,
1987.

James, RW and R Heywood:  Age-related variations in the testes of Sprague- Dawley rats.  Toxicology Letters
4:  257-261, 1979.

Kanno, J, C Matsuoka, K Furuta, H Onodera, A Maekawa and Y Hayashi:  Glandular changes associated with
the spontaneous interstitial cell tumor of the rat testes.  Toxicol. Pathol. 15: 439-443, 1987.

Lewis, DJ:  Ovarian neoplasia in the Sprague-Dawley rat.  Environ. Health Perspectives 73:  77-90, 1987.

Lutzen, L and H Uebergerg:  A study on morphological changes in the testes of old albino rats.  Beitr. Path.
Bd. 149:  377-385, 1973.



                        REPRODUCTIVE SYSTEM CON'T

Montgomery, CA and RH Alison:  Nonneoplastic lesions of the ovary in Fischer 344 and B6C3F1 mice. 
Environ. Health Perspectives 73:  53-75, 1987.

Padykula, HA and AG Campbell:  Cellular mechanisms involved in cyclic stromal renewal of the uterus.  II.  The
albino rat.  Anat. Rec. 184:  27- 48, 1976.

Selye, H:  Studies on the physiology of the maternal placenta in the rat.  Proc. Royal Soc. Biol. 119:  1-31,
1935.

Tanigawa, H, H Onodera and A Maekawa:  Spontaneous mesotheliomas in Fischer rats- a histological and
electron microscopic study.  Toxicol. Pathol. 15: 157-163, 1987.

Tchernitchin, A, J Roorijck, X Tchernitchin, J Vandenhende and P Galand:  Dramatic early increase in uterine
eosinophils after oestrogen administration.  Nature 248:  142-143, 1974.

Turek, FW and C Desjardins:  Development of Leydig cell tumors and onset of changes in the reproductive and
endocrine systems of aging F344 rats.  J. Natl. Cancer Inst. 63:  969-975, 1979. 

Yoshitomi, K.:  Cystic dilatation of the vaginal fornix in aged female Crj:F344/Du rats.  Vet. Pathol. 27: 282-284,
1990.


                          MUSCULOSKELETAL SYSTEM

Berg, BN:  Muscular dystrophy in aging rats.  J. Gerontology 11:  134-139, 1956.

Kato, M and T Onodera:  Early changes of osteochondrosis in medial femoral condyles from rats.  Vet. Pathol.
24:  80-86, 1987.

Yamasaki, K, and S Inui:  Lesions of articular, sternal and growth plate cartilage in rats.  Vet. Pathol. 22:  46-50,
1985.

Yamasaki, K, and S Anai:  Kinked tail in Sprague-Dawley rats.  Lab. Anim. Sci. 39: 77-78, 1989.


                           SPECIAL SENSES SYSTEM

Bruner, RH et al:  Spontaneous corneal dystrophy and generalized basement membrane changes in Fischer-
344 rats.  Toxicol. Pathol. 20: 357-366, 1992.

Bellhorn, RW, GE Korte and D Abrutyn:  Spontaneous corneal degeneration in the rat.  Lab. An. Sci. 38:  46-
50, 1988.

Dowling, JE and RL Sidman:  Inherited retinal dystrophy in the rat.  J. Neuropathol. 22:  349-350, 1963.

Gaertner, DJ, JR Lindsey and JO Stevens:  Cytomegalic changes and "inclusions" in lacrimal glands of
laboratory rats.  Lab. An. Sci. 38:  79-82, 1988.

Heywood, R:  Glaucoma in the rat.  Brit. Vet. J. 131:  213-221, 1975.

Lee, EW et al:  Unilateral degeneration of retina and optic nerve in Fischer-344 rats.  Vet. Pathol. 27: 439-444,
1990.

Lin, W-L and E Essner:  An electron microscopic study of retinal degeneration in Sprague-Dawley rats.  Lab.
An. Sci. 37:  180-186, 1987.

Noell, WK, VS Walker, BS Kaag, et al:  Retinal damage by light in rats.  Invest. Ophthalmol. 5:  450-473, 1966.

Nyska, A, et al:  Retinal atrophy in albino rats associated with Pituranthos triradiatus (Umbelliferae)-induced
photosensitization.  Vet. Pathol. 21:  551-552, 1984.

Rao, GN:  Light intensity-associated eye lesions of Fischer 344 rats in long-term studies.  Toxicol. Pathol. 19: 
148-155, 1991.

Schardein, JL, JA Lucas and JE Fitzgerald:  Retinal dystrophy in Sprague- Dawley rats.  Lab. An. Sci. 25: 
323-326, 1975.

Semple-Rowland, S and WW Dawson:  Retinal cyclic light damage threshold for albino rats.  Lab. An. Sci. 37: 
289-298, 1987.


                              NERVOUS SYSTEM

Burek, JD, AJ van der Kogel and CF Hollander:  Degenerative myelopathy in three strains of aging rats.  Vet.
Pathol. 13:  321-331, 1976.

Cotard-Bartley, MP, J Secchi, R Glomot and JB Cavanagh:  Spontaneous degenerative lesions of peripheral
nerves in aging rats.  Vet. Pathol. 18:  110-113, 1981.

Eisenbrandt, DL, JL Mattsson, RR Albee, PJ Spencer and KA Johnson:  Spontaneous lesions in subchronic
neurotoxicity testing of rats.  Toxicol. Pathol. 18: 154-164, 1990.

Krinke, G. J Suter and R Hess:  Radicular myelinopathy in aging rats.  Vet. Pathol. 18:  335-341, 1981.

Mitsumori, K, RR Maronpot and GA Boorman:  Spontaneous tumors of the meninges in rats.  Vet. Pathol. 24: 
50-58, 1987.

Reuber, MD, and HM Reznik-Schuller:  Benign chordoma (sacrococcygeal) in the rat:  a light and electron
microscopic study.  Vet. Pathol. 21:  536- 538, 1984.

Vaughan, DW:  Membranous bodies in the cerebral cortex of aging rats:  an electron microscopic review.  J.
Neuropathol. Exp. Neurol. 35:  152-166, 1976.

Verg, BN, A Wolf and HS Simms:  Degenerative lesions of spinal roots and peripheral nerves in aging rats. 
Gerontologia 6:  72-80, 1962.

van Steenis, G and R Kroes:  Changes in the nervous system and musculature of old rats.  Vet. Pathol. 8: 
320-332, 1971.

Wisneiwski, HM and RD Terry:  Morphology of the aging brain, human and animal.  Prog. Brain Res.  167-186,
1973.

Zwicker, GM et al:  Spontaneous brain and spinal cord/nerve neoplasms in aged Sprague-Dawley rats.  Toxicol.
Pathol.  20:  576-584, 1992.



                 HEMATOPOIETIC AND LYMPHORETICULAR SYSTEMS

Abbott, DP, and CP Cherry:  Malignant mixed thymic tumor with metastases in a rat.  Vet. Pathol. 19:  721-723,
1982.

Abbott, DP, DE Prentice and CP Cherry:  Mononuclear cell leukemia in aged Sprague-Dawley rats.  Vet.
Pathol. 434-439, 1983.

Bellanti, J. A.:  Immunology II.  W. B. Saunders Co., Philadelphia, 1978.  pp747-748.

Cherry, CP, R Eisenstein and A Glucksmann:  Epithelial cords and tubules of the rat thymus:  effects of age,
sex, castration of sex, thyroid and other hormones on their incidence and secretory activity.  Br. J. Exp. Pathol.
48:  90, 1967

Cline, JM and RR Maronpot:  Variations in the histologic distribution of rat bone marrow cells with respect to
age and anatomic site.  Toxicol. Pathol. 13:  349-355, 1985.

Frith, CH:  Morphologic classification and incidence of hematopoietic neoplasms in the Sprague-Dawley rat. 
Toxicol. Pathol. 16:  451-457, 1988.

Giroud, JP, JM Papadimitriou, C Dunn and DA Willoughby:  Thymic anomalies in the rat after various neonatal
treatments.  J. Pathol. 108:  335, 1972.

Harada, T., RR Maronpot, RW Morris and GA Boorman:  Effects of mononuclear cell leukemia on altered
hepatocellular foci in Fischer 344 rats.  Vet. Pathol. 27: 110-116, 1990.

Kuper, CF, RB Beems, and VMH Hollanders:  Spontaneous pathology of the thymus in aging Wistar (Cpb:WU)
rats.  Vet. Pathol. 23:  270-277, 1986.

Losco, PE, and JM Ward:  The early stage of large granular lymphocyte leukemia in the F344 rat.  Vet. Pathol.
21:  286-291, 1984.

Meihuizen, SP and JD Burek:  The epithelial cell component of the thymuses of aged female BN/Bi rats.  Lab.
Invest. 39:  613-622, 1978. 

Moloney, WC, M Batata, and V King:  Leukemogenesis in the rat:  further observations.  J. Natl. Cancer Inst.
46:  1139-1143, 1971.

Moloney, WC, AE Boschetti, and V King:  Observations on leukemia in Wistar- Furth rats.  Cancer Res. 29: 
938-946, 1969.

Moloney, WC, AE Boschetti, and V King:  Spontaneous leukemia in Fischer rats.  Cancer Res. 30:  41-43,
1970.

Moloney, WC and VP King:  Reduction in leukemia incidence following splenectomy in the rat.  Cancer Res.
33: 573-574, 1973.

Rosol, TJ, and PC Stromberg:  Effects of large granular lymphocyte leukemia on bone in F344 rats.  Vet.
Pathol. 27: 391-396, 1990.

Stromberg, PC, and LM Vogtsberger:  Pathology of the mononuclear cell leukemia of Fischer rats.  I. 
Morphologic studies.  Vet. Pathol. 20:  698- 708, 1983.

Stromberg, PC, LM Vogtsberger, LR Marsh, and FD Wilson:  Pathology of the mononuclear cell leukemia of
Fischer rats.  II.  Hematology.  Vet. Pathol. 20:  709-717, 1983.

Stromberg, PC, LM Vogtsberger, and LR Marsh:  Pathology of the mononuclear cell leukemia of Fischer rats. 
III.  Clinical chemistry.  Vet. Pathol. 20:  718-726, 1983.

Stromberg, PC, et al:  Spleen cell population changes and hemolytic anemia in F344 rats with large granular
lymphocyte leukemia.  Vet. Pathol. 27: 397-403, 1990.

Stromberg, PC, et al:  SErial syngeneic transplantation of large granular lymphocyte leukemia in F344 rats. 
Vet. Pathol. 27: 404-410, 1990.

Ward JM, and CW Reynold:  Large granular lymphocytic leukemia, a heterogeneous lymphocytic leukemia in
F344 rats.  Am. J. Pathol. 111:  1- 10, 1983.


                          GASTROINTESTINAL SYSTEM

Boorman, GA and SL Eustis:  Proliferative lesions of the exocrine pancreas in male F344/N rats.  Environ.
Health Perspect. 56:  213-217, 1984.

Chiu, T:  Spontaneous hypertrophic foci of pancreatic acinar cells in CD rats.  Toxicol. Pathol. 11:  115-119,
1983.

Chiu, T and HC Chen:  Spontaneous basophilic hypertrophic foci of the parotid gland in rats and mice.  Vet.
Pathol. 24:  606-609, 1987.

Dillberger, JE: Age-related pancreatic changes in Sprague-Dawley rats. Toxicol. Pathol., 22(1):48-55, 1994.

Dominick, MA, WF Bobrowski, and AL Metz:  Proliferative exocrine pancreatic lesions in aged Wistar rats. 
Toxicol. Pathol. 18: 423-426, 1990.

Eustis, SL and GA Boorman:  Proliferative lesions of the exocrine pancreas:  Relationship to corn oil gavage
in the National Toxicology Program.  J. Natl. Cancer Instit. 75:  1067-1073, 1985.

Farber, E:  The biology of carcinogen-induced hepatocyte nodules and related liver lesions in the rats.  Toxicol.
Pathol. 10:  197-205, 1982.

Farber, E and DSR Sarma:  Biology of Disease. Hepatocarcinogenesis:  a dynamic cellular perspective.  Lab.
Invest. 56:  4-22, 1987.

Fitzgerald, J:  Ameloblastic odontoma in the Wistar rat.  Toxicol. Pathol. 15: 479-481, 1987.

Hacker, HJ, MA Moore, D Mayer and P Bannasch:  Correlative histochemistry of some enzymes of carbohydrate
metabolism in preneoplastic and neoplastic lesions in the rat liver.  Carcinogenesis 3:  1265, 1982.

Harada, T., RR Maronpot, RW Morris and GA Boorman:  Effects of mononuclear cell leukemia on altered
hepatocellular foci in Fischer 344 rats.  Vet. Pathol. 27: 110-116, 1990.

Institute of Laboratory Animal Resources:  Histologic typing of liver tumors of the rat.  J. Natl. Cancer Inst. 64: 
179-206, 1980.

Lee, KP:  Peliosis hepatis-like lesion in aging rats.  Vet. Pathol. 20:  410-423, 1983.

Maronpot, RR, CA Montgomery, GA Boorman and EE McConnell:  National Toxicology Program Nomenclature
for hepatoproliferative lesions of rats.  Toxicol. Pathol. 14:  263-273, 1986.

McDonald, M and GA Boorman:  Pancreatic hepatocytes associated with chronic 2,6-dichloro-p-
phenylenediamine administration in Fischer 344 rats.  Toxicol. Pathol. 17:  1-6, 1989.

Newsholme, SJ, and Fish, CJ:  Morphology and incidence of hepatic foci of cellular alteration in Sprague-
Dawley rats. Toxicol. Pathol., 22(5):524-527, 1994.

Peraino, C, WL Richards and FJ Stevens:  Multistage hepatocarcinogenesis.  In Mechanisms of Tumor
Promotion, Vol 1, edited by TJ Slaga, CRC Press, Boca Raton, 1983.

Pretlow, TP, RW Grane, PL Goehring, AS Lapinsky and TG Pretlow II:  Examination of enzyme-altered foci with
gamma-glutamyl transpeptidase, aldehyde dehydrogenase, glucose-6-phosphate dehydrogenase, and other
markers in methacrylate-embedded liver.  Lab. Invest. 56:  96-100, 1987.

Reddy, JK, MS Rao, SA Qureshi, MK Reddy, DG Scarpelli and ND Lalwani:  Induction and origin of
hepatocytes in rat pancreas.  J. Cell Biol. 98:  2082-2090, 1984.

Rinde, E, R Hill, A Chiu and B Haberman:  Proliferative hepatocellular lesions of the rat:  Review and future use
in risk assessment.  Risk Assessment Forum, U.S. Environmental Protection Agency, Washington, DC, 20460. 
February, 1986.

Scarpelli, DG and MS Rao:  Differentiation of regenerating pancreatic cells into hepatocyte-like cells.  Proc. Natl.
Acad. Sci. USA 78:  2577-2581, 1981.

Squire, RA and MH Levitt:  Report of a workshop on classification of specific hepatocellular lesions in rats. 
Cancer Res. 35:  3214-3215, 1975.

Walsh, KM, and Razmpour, A: Stereological evaluation of altered hepatocellular foci in control Wistar rats. 
Toxicol. Pathol., 20(1):27-31, 1992.

Yoshitomi, K, HR Brown and S Eustis:  Fordyce's granules of the incisor and molar gingiva in F344 rats.  Vet.
Pathol. 27:  432-438, 1990.

Zwicker, GM et al:  Naturally occurring intestinal epithelial neoplasms in aged CRL:CD BR rats.  Toxicol. Pathol.
20: 253-259, 1992.


                           INTEGUMENTARY SYSTEM

Chiu, T, and KP Lee:  Auricular chondropathy in aging rats.  Vet. Pathol. 21:  500-504, 1984.

Greaves, P, and JM Faccini:  Fibrous histiocytic neoplasms spontaneously arising in rats.  Br. J. Cancer 43: 
402-411, 1981.

Greaves, P, J-M Martin, and M-T Masson:  Spontaneous rat malignant tumors of fibrohistiocytic origin:  an
ultrastructural study.  Vet. Pathol. 19:  497-505, 1982.

Reznik, G and JM Ward:  Morphology of hyperplastic and neoplastic lesions in the clitoral and preputial gland
of the F344 rat.  Vet. Pathol. 18:228- 238, 1981.

Squire, RA, et al:  Histiocytic sarcoma with a granuloma-like component occurring in a large colony of
Sprague-Dawley rats.  Am. J. Pathol. 105:  21-30.  1981.  


Ward, JM, et al:  Malignant fibrous histiocytoma.  An unusual neoplasm of soft tissue origin in the rat that is
different from the human counterpart.  Arch. Pathol. Lab. Med. 105:  313-316, 1981.

Yoshitomi K and Boorman GA:  Palpebral amelanotic melanomas in F344 rats.  Vet. Pathol. 30:280-286, 1993.

Yoshitomi, K, et al.: Pathology and incidence of amelanotic melanomas of the skin in F-344/N rats.  Toxicol.
Pathol., 23(1):16-25, 1995.

Zwicker, GM et al:  Spontaneous skin neoplasms in aged Sprague-Dawley rats.  Toxicol. Pathol. 20: 327-340,
1992.


                             CONNECTIVE TISSUE

Coleman, GL:  Four intrathoracic hibernomas in rats.  Vet. Pathol. 17:  634-637, 1980.

Kerry, PJ, et al.: Identification of a spontaneous pleomorphic rhabdomyosarcoma in the thoracic and abdominal
cavities of a female Wistar rat.  Vet. Pathol. 32:76-78, 1995.

Stefanski, SA, MR Elwell and K Yoshitomi:  Malignant hibernoma in a Fischer 344 rat.  Lab. An. Sci. 37:  347-
349, 1987.


                          HISTORICAL CONTROL DATA

Chandra, M, and Frith, C H:  Spontaneous neoplasms in B6C3F1 mice. Toxicol. Lett. (Amst), 60:91-98, 1992.

Dixon D, et al.:  Incidence of nonneoplastic lesions in historical control male and female Fischerr-344 rats from
90-day toxicity studies. Toxicol. Pathol. 23(3):338-348, 1995.

Haseman, J K:  Value of historical controls in the interpretation of rodent tumor data.  Drug Information Journal,
26:191-200, 1992.

Haseman, J K, et al.:  Use of dual control groups to estimate false positive rates in laboratory animal
carcinogenicity studies.  Fundamental and Applied Toxicology, 7:573-584, 1986.

Haseman, J K, et al.:  Use of historical control data in carcinogenicity studies in rodents.  Toxicol. Pathol.,
12:126-135, 1984.

Haseman JK, et al.:  Neoplasms observed in untreated and corn oil gavage control groups of F344/N rats and
(C57BL/6N x C3H/HEN)F, (B6C3F1) mice.  J. Natl. Cancer Instit. 75: 975-984, 1985.

Haseman, J K:  Issues in carcinogenicity testing: Dose selection. Fundam. Appl. Toxicol. 5:66-78, 1985.

Haseman, J K:  Use of statistical decision rules for evaluating laboratory animal carcinogenicity studies. 
Fundam. Appl. Toxicol., 14:637-648, 1990.

Iwata, H, et al.:  Historical control data of organ weight and gross findings in F344/DuCrj rats and B6C3F1 mice. 
Jikken Dobutsu (Japan) 42:383-396, 1993.

Lang, Patricia L:  Spontaneous Neoplastic Lesions and Selected Non-neoplastic Lesions in the Crl:CD BR
Rat.  Charles River Laboratories, 1992.

Lang, Patricia L:  CD-1 Mouse Liver Tumors in 24 Month Studies, from Charles River Historical Database, 1993
(personal communication), unpublished.

Lin K K, and Ali, W A:  Statistical review and evaluation of animal tumorigenicity studies, Chpt. 2, In: Statistics
in the Pharmaceutical Industry, 2nd Ed.,  C. R. Buncher and J-Y Tsay, eds., 1994.

Lijinsky, W, et al.:  Lack of effect of carcinogen treatment on development of tumors arising spontaneously in
Fischer 344 rats.  Journal of Toxicology and Environmental Health, 39:527-538, 1993.

McConnell, E E, et al.:  Guidelines for combining neoplasms for evaluation of rodent carcinogenesis studies.
JNCI, 76:283-289, 1986.

McMartin, D N, et al.:  Neoplasms and related proliferative lesions in control Sprague-Dawley rats from
carcinogenicity studies. Historical data and diagnostic considerations.  Toxicol. Pathol., 20:212-225, 1992.

Morawietz, G, et al.:  RITA registry of industrial toxicology animal - data progress of the working group.  Exp.
Toxicol. Pathol., 44:301-309, 1992.

NTP Data.  Tumor Incidence in Control Animals by Route and Vehicle of Administration - F344/N Rats. 
Toxicology Data Management System. National Institute of Environmental Health Sciences, POB 12233,
Research Triangle Park, NC  27709, July 6, 1993.

NTP Data.  Tumor Incidence in Control Animals by Route and Vehicle of Administration - B6C3F1 Mice. 
Toxicology Data Management System. National Institute of Environmental Health Sciences, POB 12233,
Research Triangle Park, NC  27709, April 27, 1993.

Prentice, R L, et al.:  On the use of historical control data to estimate dose response trends in quantal bioassay. 
Biometrics, 48:459-478, 1992.

Vater, S T, et al.:  Biological considerations for combining carcinogenicity data for quantitative risk assessment. 
Regulatory Toxicology and Pharmacology, 18:403-418, 1993.

Walsh, K M, and Poteracki, J:  Spontaneous neoplasms in control Wistar rats.  Fundamental and Applied
Toxicology, 22:65-72, 1994.

Woutersen, R A:  Incidence of tumors in CPB:WU Wistar random rats.  Data of control animals from long-term
studies.  TNO-report V 92.087.  POB 360, 3700 AJ Zeist, Utrechtseweg 48, 3704 HE Zeist, The Netherlands. 
February 1992.

Yamamoto, T, et al.  Mortality body weight food and water consumptions and clinical signs in SLC B6C3F-1
C57BL-6XC3H mice utilized in chronic toxicity and carcinogenicity studies.  Exp. Anim. (Tokyo), 42:397-404,
1993.


Clinical Pathology Historical Control Data

Galen, R S:  The normal range: a concept in transition.  Arch Pathol Lab Med, 101:561-565, 1977.

Watare, N, et al.:  Age-associated historical data of the hematology and blood biochemistry in F344 rats and
B6C3F1 mice.  J. Toxicool. Sci., 15:223 (abstract), 1990.

Wolford, S T, et al.:  Age-related changes in serum chemistry and hematology values in normal Sprague-
Dawley rats.  Fundamental and Applied Toxicology, 8:80-88, 1987.