Cancer Letters, 62 (1992)
49
49 - 56
Elsevier Scientific Publishers Ireland Ltd.
Spontaneous M. Chandra”
(U.S.A.)
in aged control Fischer 344 rats
and C.F. Frithb
Pathology
“Experimental
20965
neoplasms
Medical
Deportment,
bToxicofogy
Pathology
Research
Associates,
Division,
Briar Creek
American
Road,
Cyanamid
Little Rock.
Company,
AR 72211
Pearl River,
NY
(U.S.A.)
(Received 23 September 1991) (Revision received 11 October 1991) (Accepted 14 October 1991)
Keywords: spontaneous; F-344; rat; rodent
Summary Neoplastic lesions in untreated F-344 rats (740 males and 740 females) used as controls in carcinogenicity studies were evaluated and tabulated. The incidence of spontaneous tumors was 84.3% in the males and 76.2% in the females. In males, the most common were testicular interstitial cell neoplasms tumors (79.5 %) followed by mononuclear cell IeukemiaAymphomas (30.5 W), pituitary adenomas (20.5 W), pancreatic islet cell adenomas (6.5 %), thyroid c-cell adenomas (5.7%), pheochromocytomas (5.7%), skin fibromas (3.2%), keratoacanthomas (1.9%), and thyroid follicular cell adenomas (1.9%). In females, the most common neoplasms were pituitary adenomas (30.3%) foitowed by mononuclear cell leukemia/lymphomas (20.5%), endometrial polyps (14.1 W), mammary fibroadenomas (11.1 W), thyroid c-cell adenomas (5.1 W), mammary adenomas s k in fbi romas (1 .l W), and clitoral (1.9%), carcinomas (1.1%). A variety of less common neoplasms were also observed in various other organs.
Correspondence Department, Company,
to:
M.
Chandra,
Medical Research Pearl River, NY
0304-3835/92/$05.00
0
10965,
1992
Printed and Published in Ireland
Experimental
Division, U.S.A.
American
Pathology Cyanamid
neoplasm; tumor;
Introduction An adequate pathology review, knowledge of background data, and variations in the tumor incidence in species and strains of control animals available for use, are essential for the evaluation of rodent carcinogenicity bioassays. Data on the incidence of spontaneous neoplasms from a total of 1480 F-344 rats (740 males and 740 females) from 12 carcinogenicity studies over a period of the last 6 years were evaluated and tabulated. The types of neoplasms and their incidences in male and female rats based on organ/system are described and discussed. Materials
and Methods
This paper includes data from a total of 1480 control F-344 rats used in 12 oncogenicity studies in the last 7 years. All animals were individually housed in hanging wire mesh cages. For the duration of studies, the temperature was 71 f 2’F, the humidity was 50 f 10%) and room lighting was on a 12/12 h (light/dark) cycle. All animals used in this study were obtained from Charles River Breeding Laboratories. Humane care was
El sevier Scientific Publishers Ireland Ltd
50
taken in accordance with NIH guideline (Guidelines for the Care and Use of Laboratory Animals). The rats reported in this study were maintained in commercial testing houses. Food (Ralson Purina Certified Rodent Chow) and water were provided ad libitum. Each animal was identified individually at the beginning of the study with a metal ear tag bearing an identification number. The rats were routinely observed for morbidity and mortality twice daily, 7 days a week, throughout the studies. Detailed observations of appearance, behavior, and disease conditions including palpable masses were conducted at least weekly for each of the studies. All animals that died or that were killed in a moribund condition received a complete necropsy examination. Survivors and animals killed in extremis were euthanized by carbon dioxide aspiration. After a thorough external examination, each animal was opened and the contents of the abdominal, thoracic, and cranial cavities were examined both in situ and after removal and dissection. A full complement of tissue was collected from all animals and fixed in 10% neutral buffered formalin. The following tissues were collected: adrenals, brain, eyes with contiguos Harderian glands, gastrointestinal tract, gonads, heart, kidneys, liver, lungs with mainstem bronchi, lymph nodes, mammary glands, pancreas, pituitary, prostate and seminal vesicles, salivary glands, scitic nerve, skeletal muscles, skin, spinal cord, spleen, sternum (bone and bone marrow), tissue from the thymic region, thyroid/parathyroid, trachea, urinary bladder, uterus, all gross lesions and all tissue masses. Tissues were routinely trimmed, processed, and stained with hematoxylin and eosin for microscopic examination. Whenever required special techniques were used. Results The total number of neoplastic events in male and female rats were 1252 and 709, respectively. In males, out of 1252 neoplasms 269 (21.5%) were malignant and 983
were benign. (78.5%) In females, 194 (27.4%) were malignant and 515 (72.6%) were benign. The overall incidences of spontaneous tumors in male and female rats were 84.3% and 76.2 % , respectively. The mortality rates in male and female rats in 12 studies ranged from 19 to 24% for the males and 23 to 28% for the females (Table I). The types and incidences of spontaneous neoplasms observed in 1480 F-344 rats (male and female) from 12 carcinogenicity studies are provided in Table II. System-wise tumor incidence is presented in Table III. Neoplasms occurring with more than 1% incidence are listed in Table IV and Table V presents tumors which had metastasized to various organs. Endocrine system Endocrine tumors were observed in 43.2% males and 41.4% females. In males, pituitary adenomas were the most commonly occurring endocrine neoplasms (20.5%) followed by pancreatic islet cell adenomas (6.5%)) thyroid c-cell adenomas (5.7%)) pheochromocytomas (5.7 %) , thyroid follicular cell adenomas and adrenal cortical adenomas (1.9%) (1.6%). In females, most frequent tumors were pituitary adenomas (30.3%) followed by adrenal cortical adenomas (1.2%) and thyroid follicular cell adenomas (1.2%). Other endocrine neoplasms occurred in low incidence.
Table 1. Overall incidences F-344 rats in 12 carcinogenicity
Overall tumor incidence (W) Mortality rate ( W) Survival rate (W) Total number of tumors No. of benign tumors (%) No. of malignant tumors (W)
and mortality studies.
rates
Male
Female
84.3 19-24 76-81 1223
76.2 23-28 72-77 719
983 (78.5)
515 (72.6)
269 (21.5)
194 (27.4)
in
5:
Table II. rats.
System
Site
and organ-wise
incidence
of neoplasms
in 1480 (740 males and 740 females)
Tumor type
No. of rats with tumor (W) Male (740)
Endocrine
aged control F-344
Female (740)
system
Adrenal
Thyroid
Parathyroid Pancreas Pituitary
Respiratory
Cortical adenoma Cortical adenocarcinoma Pheochromocytoma, benign Pheochromocytoma, malignant Follicular cell adenoma Follicular cell carcinoma C-cell adenoma C-cell carcinoma Adenoma
-
Acinar adenoma Islet cell adenoma Adenoma. anterior Ganglioneuroma
4 48 152 1
lobe
12 1 42 2 14 1 42 1
(1.6) (0.1) (5.7) (0.3) (1.9) (0.1) (5.7) (0.1)
9 2 2 1 8 1 38
(1.2) (0.3) (0.3) (0.1) (1.2) (0.1) (5.1)
2 (0.3) (0.6) (6.5) (20.5) (0.1)
1 (0.1) 224 (30.3)
system
Lung
Alveolar-brochiolar
Digestioe system Oral tissue Cecum Salivary gland Liver
carcinoma
Chondrosarcoma Leiomyosarcoma Adenocarcinoma Squamous cell carcinoma Hepatocellular adenoma Hepatocellular carcinoma
-
2 (0.3)
1 (0.1) 1 (0.1) 2 (0.3) 4 (0.6) 2 (0.3)
1 (0.1) 2 (0.3)
Urinary system
Kidney
Urinary bladder Reproductive
Uterus
6 1 3 1 1 -
(0.8) (0.1) (0.4) (0.1) (0.1)
2 (0.3) 1 (0.1) 1 (0.1) 1 (0.1)
system
Testis Prostate Seminal
Lipoma Liposarcoma Renal cell adenoma Renal cell carcinoma Transitional cell carcinoma Papilloma
vesicle
Interstitial cell tumor Mesothelioma Adenoma Adenoma Adenoma Adenocarcinoma Leiomyoma Leiomyosarcoma Endometrial Polyp
588 6 16 1
-
(79.5) (0.8) (2.2) (0.1)
-
1 4 2 1 104
(0.1) (0.6) (0.3) (0.1) (14.1)
52 Table 11. (continued) Site
Tumor type
Cervix
No. of rats with tumor
Adenocarcinoma Leiomyosarcoma
(W)
Male
Female
(740)
(740)
-
2 1 2 2 8 14 82 12
-
(0.3) (0.1) (0.3) (0.3) (1.1) (1.9) (11.1) (1.6)
Polyp Granulosa cell tumor Adenocarcinoma Adenoma Fibroadenoma Adenocarcinoma
1 (0.1) 2 (0.3) 1 (0.1)
Skeletal muscle Bone
Rabdomyosarcoma Osteosarcoma
1 (0.1) 1 (0.1)
4 (0.5)
Nervous
Astrocytoma
2 (0.3)
1 (0.1)
Ovary Clitoral gland Mammary gland
Musculo-skeletal system
system
Hemolymphoreticular All sites
Special sense Eye Harderian
-
system Mononuclear cell leukemia/lymphoma Histiocytic sarcoma
226 (30.5) 3 (0.4)
152 (20.5) -
organ
gland
Integumentary system Skin/subcutaneous
Neurofibrosarcoma Adenoma
1 (0.1) 4 (0.5)
Fibroma Papilloma Keratoacanthoma Basal cell tumor Squamous cell carcinoma Sebaceous adenoma Sebaceous carcinoma
24 6 14 4 7 1 6
(3.2) (0.8) (1.9) (0.5) (0.9) (0.1) (0.8)
3 (0.4)
8 (1.1) 2 (0.3) 4 (0.5) -
-
Metastases from pheochomocytomas were observed in 1 male and 2 females. Thyroid follicular carcinoma had lung metastasis in 1 male.
Digestive
Respiratory system Tumors of the respiratory tract were rare. Alveolar-bronchiolar carcinomas were the only
Hepatocellular neoplasms (adenomas/carcinemas) were observed in 6 males and 2 females. In the digestive tract, leiomyosarcoma was the only tumor which occurred in the ce-
neoplasms and were observed of 1480 rats.
in 2 females out
system
53 Table
111. System-wise incidence of neoplasms in 1480 (740 males and 740 females) aged control F-344 rats.
No. of rats with tumors
System
(%)
Endocrine Respiratory Digestive Urinary Reproductive Musculo-skeletal Nervous Hemolymphoreticular Special sense lntegumentary
Male
Female
320 (43.2) -
306 2 5 4 227 5 1 152 3 14
8 12 581 4 2 229 5 62
(1.1) (1.6) (78.5) (0.5) (0.3) (30.1) (0.7) (8.4)
(41.4) (0.3) (0.7) (0.5) (30.7) (0.7) (0.1) (20.5) (0.4) (1.9)
cum of a female. Other observed neoplasms were adenocarcinomas and squamous cell carcinomas in the salivary gland and chondrosarcoma which were observed in the hard palate (mouth) of a female. From hepatocellular car-
Table
IV.
Neoplasms
Organ
occurring
cinemas lung metastases were observed male and 1 female. Salivary carcinoma lung metastasis in 1 female.
Urinary system Lipomas/liposarcomas were the most common renal neoplasms and were observed in 7 males and 3 females. Renal cell adenomas/carcinomas were observed in 4 males and 1 female. Transitional cell carcinoma was observed in 1 male. Urinary bladder papilloma was observed in 1 female. Reproductive system Reproductive tract tumors were the most common neoplasms and were observed in 78.5% males and 30.7% females. In males, testicular interstitial cell tumors were the most common neoplasms (79.5%) followed by prostate adenomas (2.2%) and testicular mesotheliomas (0.6%). A seminal vesicle adenoma was observed in 1 case. Lung metastases were observed from 7 interstitial cell tumors. In females, the most common neoplasms were endometrial stromal polyps
with more than 1% incidence.
Tumor type
Percentage
Adrenal
Cortical adenoma
Thyroid Pancreas
Pheochromocytoma, benign Follicular cell adenoma C-cell adenoma Islet cell adenoma
Pituitary Testis Prostate Uterus Clitoral gland
Adenoma, anterior lobe Interstitial cell tumor Adenoma Endometrial polyp Adenocarcinoma
Mammary
Adenoma Fibroadenoma Adenocarcinoma
gland
Hemolymphoreticular Skin
Mononuclear Fibroma
cell leukemia/lymphoma
Keratoacanthoma
in 1 had
Male
Female
1.6 5.7 1.9 5.7 6.5 20.5 79.5 2.2 -
1.2 1.2 5.1 30.3 14.1 1.1 1.9 11.1 1.6 20.5 1.1
30.5 3.2 1.9
54
Table V.
Tumors
Organ
with metastasis Tumor type
No. with metastasis
Leukemia/lymphoma Cortical carcinoma Pheochromocytoma Follicular carcinoma Adenocarcinoma Hepatocellular carcinoma Interstitial cell tumor Adenocarcinoma
Multiple sites Adrenal Thyroid Salivary Liver Testis Mammary
Squamous Sebaceous
Skin
cell carcinoma carcinoma
(14.1%) followed by mammary tumors (14.6%)) clitoral adenocarcinomas (1.1%) and uterine adenomas (0.6%). Other neoplasms were observed in low incidence. Lung or liver metastases were observed from 10 mammary carcinomas. Musculo-skeletal system Musculo-skeletal neoplasms were rare. Rabdomyosarcoma was observed in 1 male. Osteosarcomas were observed in 1 male and 4 females. Nervous system Astrocytomas were the only neoplasms observed in this system. These tumors occurred in 2 males and 1 female. Hemolymphoreticular system ceil leukemia/lymphomas Mononuclear were observed in 30.5% (226 out of 740) males and 20.5% (152 out of 740) females. Histiocytic sarcomas were observed in 3 males. Integumentary
system
the males, common (3.2%) keratoacanthomas In
fibromas were the most neoplasms followed by (1.9%)) squamous cell car-
Organ with metastasis
Male
Female
226 1 1
152
.
Multiple organs lung lung lung lung lung lung lung liver lung lung
2
1
-
1 1
1 7 6
4
2 -
1 2
cinemas (0.7%)) squamous cell papillomas (0.8%) and sebaceous carcinomas (0.8%). In the females, fibromas occurred in 1.1% cases, followed by keratoacanthomas (0.5%) and squamous cell papillomas (0.3%). Lung metastases from the squamous cell carcinomas were observed in 2 males and 1 female. Lung metastses were also found in 2 out of 6 sebaceous carcinomas. Special
sense
Neurofibrosarcoma was observed in the eye of 1 male. It appeared to arise from the nerve ending in the cornea. Harderian adenomas were observed in 4 males and 3 females. Discussion Since the National Cancer Institute recommended guidelines for the use of F-344 rats, this strain has become the most commonly used rat for carcinogenicity bioassays and biomedical research. The reasons for its popularity are its relatively small size, longevity, resistance to infectious disease when maintained under proper conditions, and quite low incidence of most of the spontaneously occurring neoplasms in various organs [lo]. How-
ever, a high incidence of a few neoplasms including testicular, mammary, uterine, hemopoietic and endocrine neoplasms in F-344 rats has been reported [3]. It is important to have historical control data on the types and incidences of spontaneous tumors in the animals available at a particular facility. Historical controls should only serve as guidelines for evaluating incidence patterns. Matched control group which minimizes variability between control and treated animals are essential for accurate assessment of each experiment [l]. Considering the extensive use of this strain of rat, there are few comprehensive reports on background tumor incidence from long term studies [V,lO]. The definite cause of spontaneous neoplasms is not known. The role of microorganisms in the development of spontaneous tumors has been suggested [8]. In the incidence of a particular present study, neoplasm is calculated for 740 males and 740 females. This incidence may vary greatly in smaller groups of 50 - 60 animals used in carcinogenicity studies. In the present study, 84.3% and 76.2% overall incidences of neoplasms in male and female rats are in agreement with a previous report ill]. Historical findings and organ distributions of neoplasms are characteristic for F-344 rats and are similar to those reported previously [ 1,2,8 - lo]. This paper includes data from studies conducted in the last 6 years. There were no significant differences in the incidences of various neoplasms in different studies. At the end of a 2-year period, the mortality rates ranged from 19% to 24% and from 23% to 28% for males and females, respectively, which is comparable to those reported previously [ll] . There were no significant differences in the mortality patterns in different studies. In this study few tumors metastasized to the lung or liver which is in accordance with previous reports [3,7]. In our study, besides leukemia/lymphomas, the most commonly metastasizing tumors were testicular interstitial cell tumors and mammary neoplasms. Isolated cases of metastases were also observed from the adrenal, skin, liver,
thyroid and salivary neoplasms. Maekawa et al. [7] reported that besides leukemia the most common metastatic tumors were malignant uterine adenocarcinofibrous histiocytomas, mas and osteosarcomas. Goodman et al. [3] reported c-cell carcinomas and malignant pheochromocytomas as the most frequently metastasizing neoplasms. Reproductive tract neoplasms were the most commonly observed tumors followed by endocrine tumors and leukemia. Most frequently observed tumors in male and female reproductive systems were testicular interstitial cell tumor (79.5%) and endometrial polyps (14.1%) , respectively which are comparable to previous reports [6,9]. The higher incidence of endocrine tumor in males was due to pheochromocytomas, thyroid c-cell adenomas, pancreatic islet cell adenomas and pituitary adenomas. In females, pituitary adenomas were the most commonly observed neoplasms followed by thyroid c-cell adenoma. Our reported 20.5% and 30.3% incidences of pituitary adenomas in male and female rats are quite comparable to 23.9% and 35.9% in males and females reported by Sass et al. [VI. Mononuclear cell leukemia, a quite characteristic neoplasm for this strain of rat, was observed in 30.5% males and 20.5% females which is quite comparable to reports by Maekawa et al. [7] and Sass et al [VI, but is higher than that reported by Coleman et al. [l]. The incidences of various tumors may be reflected by sex, genetic variations, source of animals, diet, age at death, environmental conditions, and pathological criteria used by the pathologist [5,12].
References S.W.,
Osbaldiston,
Foster, S.J. and Jones, A.M.
Coleman,
G.L.,
Barthold,
(1977)
Pathological changes
G.W..
during aging in barrier-reared
Fischer male rats. J. Geron-
tol.. 32, 258-278. Davey,
F.R.
observations
and
Maloney,
on Fischer
disorders. Lab. Invest., Goodman, and Linhart,
D.G., M.S.
W.C.
rats with
(1970) leukemia
Postmortem and
other
Chu,
K.C.
23, 327 - 334.
Ward, (1979)
J.M.,
Squire,
Neoplastic
R.A.,
and non-neoplastic
56
4
5
6
lesions in aging F-344 rats. Toxicol. Appl. Pharmacol., 48, 237 - 248. Guidelines for carcinogen bioassay in small rodents. Carcinogenesis Bioassay Program, Division of Cancer Control and Prevention (1974). Nat]. Cancer Inst., Bethesda, MD, U.S.A. Haseman, J.K., Huff, J. and Boorman, G.A. of historical control data in carcinogenicity rodents. Toxicol. Pathol., 12, 126 - 135. Jacobs,
(1984) Use studies in
R.A. (1967) Neoplasms occurrto testicular, tumors. J. Natl. Cancer Inst., 39,
uterine and 303 - 309.
8
10
B.B. and Huseby,
ing in aged Fischer rats, with special reference
7
9
thyroid
Maekawa, A., Kurokawa, Y., Takahashi, M. et al. (1983) Spontaneous tumors in F-344/DuCrj rats. G.A.N.N., 74, 365 - 372. Sacksteder, M.R. (1976) Occurrence of spontaneous
11
12
tumors in germ-free F-344 rats. J. Nat]. Cancer Inst., 57, 1371- 1373. Sass, B., Rabstein, L.S., Madison, R. et al. (1975) Incidence of spontaneous neoplasms in F-344 rats throughout the natural life-span. J. Nat]. Cancer Inst., 54, 1449 - 1456. Stinson, F.S. (1990) Spontaneous tumors in Fischer rats. In: Atlas of Tumor Pathology of the Fischer Rat, pp. 1 - 18. Editors: S.F. Stinson, H.M. Schuller and G.K. Reznik. CRC Press, Boca Ratin, FL, U.S.A. Takaki, Y., Kitamura, S., Uekusa, T. et al. (1989) Spontaneous tumors in F-344/Jcl rats. J. Toxicol. Sci., 14, 181-195. Ward, J.M. (1983) Background data and tumor rates of control rats and mice. Prog. Res., 26, 241- 258.
variations in Exp. Tumor
49
49 - 56
Elsevier Scientific Publishers Ireland Ltd.
Spontaneous M. Chandra”
(U.S.A.)
in aged control Fischer 344 rats
and C.F. Frithb
Pathology
“Experimental
20965
neoplasms
Medical
Deportment,
bToxicofogy
Pathology
Research
Associates,
Division,
Briar Creek
American
Road,
Cyanamid
Little Rock.
Company,
AR 72211
Pearl River,
NY
(U.S.A.)
(Received 23 September 1991) (Revision received 11 October 1991) (Accepted 14 October 1991)
Keywords: spontaneous; F-344; rat; rodent
Summary Neoplastic lesions in untreated F-344 rats (740 males and 740 females) used as controls in carcinogenicity studies were evaluated and tabulated. The incidence of spontaneous tumors was 84.3% in the males and 76.2% in the females. In males, the most common were testicular interstitial cell neoplasms tumors (79.5 %) followed by mononuclear cell IeukemiaAymphomas (30.5 W), pituitary adenomas (20.5 W), pancreatic islet cell adenomas (6.5 %), thyroid c-cell adenomas (5.7%), pheochromocytomas (5.7%), skin fibromas (3.2%), keratoacanthomas (1.9%), and thyroid follicular cell adenomas (1.9%). In females, the most common neoplasms were pituitary adenomas (30.3%) foitowed by mononuclear cell leukemia/lymphomas (20.5%), endometrial polyps (14.1 W), mammary fibroadenomas (11.1 W), thyroid c-cell adenomas (5.1 W), mammary adenomas s k in fbi romas (1 .l W), and clitoral (1.9%), carcinomas (1.1%). A variety of less common neoplasms were also observed in various other organs.
Correspondence Department, Company,
to:
M.
Chandra,
Medical Research Pearl River, NY
0304-3835/92/$05.00
0
10965,
1992
Printed and Published in Ireland
Experimental
Division, U.S.A.
American
Pathology Cyanamid
neoplasm; tumor;
Introduction An adequate pathology review, knowledge of background data, and variations in the tumor incidence in species and strains of control animals available for use, are essential for the evaluation of rodent carcinogenicity bioassays. Data on the incidence of spontaneous neoplasms from a total of 1480 F-344 rats (740 males and 740 females) from 12 carcinogenicity studies over a period of the last 6 years were evaluated and tabulated. The types of neoplasms and their incidences in male and female rats based on organ/system are described and discussed. Materials
and Methods
This paper includes data from a total of 1480 control F-344 rats used in 12 oncogenicity studies in the last 7 years. All animals were individually housed in hanging wire mesh cages. For the duration of studies, the temperature was 71 f 2’F, the humidity was 50 f 10%) and room lighting was on a 12/12 h (light/dark) cycle. All animals used in this study were obtained from Charles River Breeding Laboratories. Humane care was
El sevier Scientific Publishers Ireland Ltd
50
taken in accordance with NIH guideline (Guidelines for the Care and Use of Laboratory Animals). The rats reported in this study were maintained in commercial testing houses. Food (Ralson Purina Certified Rodent Chow) and water were provided ad libitum. Each animal was identified individually at the beginning of the study with a metal ear tag bearing an identification number. The rats were routinely observed for morbidity and mortality twice daily, 7 days a week, throughout the studies. Detailed observations of appearance, behavior, and disease conditions including palpable masses were conducted at least weekly for each of the studies. All animals that died or that were killed in a moribund condition received a complete necropsy examination. Survivors and animals killed in extremis were euthanized by carbon dioxide aspiration. After a thorough external examination, each animal was opened and the contents of the abdominal, thoracic, and cranial cavities were examined both in situ and after removal and dissection. A full complement of tissue was collected from all animals and fixed in 10% neutral buffered formalin. The following tissues were collected: adrenals, brain, eyes with contiguos Harderian glands, gastrointestinal tract, gonads, heart, kidneys, liver, lungs with mainstem bronchi, lymph nodes, mammary glands, pancreas, pituitary, prostate and seminal vesicles, salivary glands, scitic nerve, skeletal muscles, skin, spinal cord, spleen, sternum (bone and bone marrow), tissue from the thymic region, thyroid/parathyroid, trachea, urinary bladder, uterus, all gross lesions and all tissue masses. Tissues were routinely trimmed, processed, and stained with hematoxylin and eosin for microscopic examination. Whenever required special techniques were used. Results The total number of neoplastic events in male and female rats were 1252 and 709, respectively. In males, out of 1252 neoplasms 269 (21.5%) were malignant and 983
were benign. (78.5%) In females, 194 (27.4%) were malignant and 515 (72.6%) were benign. The overall incidences of spontaneous tumors in male and female rats were 84.3% and 76.2 % , respectively. The mortality rates in male and female rats in 12 studies ranged from 19 to 24% for the males and 23 to 28% for the females (Table I). The types and incidences of spontaneous neoplasms observed in 1480 F-344 rats (male and female) from 12 carcinogenicity studies are provided in Table II. System-wise tumor incidence is presented in Table III. Neoplasms occurring with more than 1% incidence are listed in Table IV and Table V presents tumors which had metastasized to various organs. Endocrine system Endocrine tumors were observed in 43.2% males and 41.4% females. In males, pituitary adenomas were the most commonly occurring endocrine neoplasms (20.5%) followed by pancreatic islet cell adenomas (6.5%)) thyroid c-cell adenomas (5.7%)) pheochromocytomas (5.7 %) , thyroid follicular cell adenomas and adrenal cortical adenomas (1.9%) (1.6%). In females, most frequent tumors were pituitary adenomas (30.3%) followed by adrenal cortical adenomas (1.2%) and thyroid follicular cell adenomas (1.2%). Other endocrine neoplasms occurred in low incidence.
Table 1. Overall incidences F-344 rats in 12 carcinogenicity
Overall tumor incidence (W) Mortality rate ( W) Survival rate (W) Total number of tumors No. of benign tumors (%) No. of malignant tumors (W)
and mortality studies.
rates
Male
Female
84.3 19-24 76-81 1223
76.2 23-28 72-77 719
983 (78.5)
515 (72.6)
269 (21.5)
194 (27.4)
in
5:
Table II. rats.
System
Site
and organ-wise
incidence
of neoplasms
in 1480 (740 males and 740 females)
Tumor type
No. of rats with tumor (W) Male (740)
Endocrine
aged control F-344
Female (740)
system
Adrenal
Thyroid
Parathyroid Pancreas Pituitary
Respiratory
Cortical adenoma Cortical adenocarcinoma Pheochromocytoma, benign Pheochromocytoma, malignant Follicular cell adenoma Follicular cell carcinoma C-cell adenoma C-cell carcinoma Adenoma
-
Acinar adenoma Islet cell adenoma Adenoma. anterior Ganglioneuroma
4 48 152 1
lobe
12 1 42 2 14 1 42 1
(1.6) (0.1) (5.7) (0.3) (1.9) (0.1) (5.7) (0.1)
9 2 2 1 8 1 38
(1.2) (0.3) (0.3) (0.1) (1.2) (0.1) (5.1)
2 (0.3) (0.6) (6.5) (20.5) (0.1)
1 (0.1) 224 (30.3)
system
Lung
Alveolar-brochiolar
Digestioe system Oral tissue Cecum Salivary gland Liver
carcinoma
Chondrosarcoma Leiomyosarcoma Adenocarcinoma Squamous cell carcinoma Hepatocellular adenoma Hepatocellular carcinoma
-
2 (0.3)
1 (0.1) 1 (0.1) 2 (0.3) 4 (0.6) 2 (0.3)
1 (0.1) 2 (0.3)
Urinary system
Kidney
Urinary bladder Reproductive
Uterus
6 1 3 1 1 -
(0.8) (0.1) (0.4) (0.1) (0.1)
2 (0.3) 1 (0.1) 1 (0.1) 1 (0.1)
system
Testis Prostate Seminal
Lipoma Liposarcoma Renal cell adenoma Renal cell carcinoma Transitional cell carcinoma Papilloma
vesicle
Interstitial cell tumor Mesothelioma Adenoma Adenoma Adenoma Adenocarcinoma Leiomyoma Leiomyosarcoma Endometrial Polyp
588 6 16 1
-
(79.5) (0.8) (2.2) (0.1)
-
1 4 2 1 104
(0.1) (0.6) (0.3) (0.1) (14.1)
52 Table 11. (continued) Site
Tumor type
Cervix
No. of rats with tumor
Adenocarcinoma Leiomyosarcoma
(W)
Male
Female
(740)
(740)
-
2 1 2 2 8 14 82 12
-
(0.3) (0.1) (0.3) (0.3) (1.1) (1.9) (11.1) (1.6)
Polyp Granulosa cell tumor Adenocarcinoma Adenoma Fibroadenoma Adenocarcinoma
1 (0.1) 2 (0.3) 1 (0.1)
Skeletal muscle Bone
Rabdomyosarcoma Osteosarcoma
1 (0.1) 1 (0.1)
4 (0.5)
Nervous
Astrocytoma
2 (0.3)
1 (0.1)
Ovary Clitoral gland Mammary gland
Musculo-skeletal system
system
Hemolymphoreticular All sites
Special sense Eye Harderian
-
system Mononuclear cell leukemia/lymphoma Histiocytic sarcoma
226 (30.5) 3 (0.4)
152 (20.5) -
organ
gland
Integumentary system Skin/subcutaneous
Neurofibrosarcoma Adenoma
1 (0.1) 4 (0.5)
Fibroma Papilloma Keratoacanthoma Basal cell tumor Squamous cell carcinoma Sebaceous adenoma Sebaceous carcinoma
24 6 14 4 7 1 6
(3.2) (0.8) (1.9) (0.5) (0.9) (0.1) (0.8)
3 (0.4)
8 (1.1) 2 (0.3) 4 (0.5) -
-
Metastases from pheochomocytomas were observed in 1 male and 2 females. Thyroid follicular carcinoma had lung metastasis in 1 male.
Digestive
Respiratory system Tumors of the respiratory tract were rare. Alveolar-bronchiolar carcinomas were the only
Hepatocellular neoplasms (adenomas/carcinemas) were observed in 6 males and 2 females. In the digestive tract, leiomyosarcoma was the only tumor which occurred in the ce-
neoplasms and were observed of 1480 rats.
in 2 females out
system
53 Table
111. System-wise incidence of neoplasms in 1480 (740 males and 740 females) aged control F-344 rats.
No. of rats with tumors
System
(%)
Endocrine Respiratory Digestive Urinary Reproductive Musculo-skeletal Nervous Hemolymphoreticular Special sense lntegumentary
Male
Female
320 (43.2) -
306 2 5 4 227 5 1 152 3 14
8 12 581 4 2 229 5 62
(1.1) (1.6) (78.5) (0.5) (0.3) (30.1) (0.7) (8.4)
(41.4) (0.3) (0.7) (0.5) (30.7) (0.7) (0.1) (20.5) (0.4) (1.9)
cum of a female. Other observed neoplasms were adenocarcinomas and squamous cell carcinomas in the salivary gland and chondrosarcoma which were observed in the hard palate (mouth) of a female. From hepatocellular car-
Table
IV.
Neoplasms
Organ
occurring
cinemas lung metastases were observed male and 1 female. Salivary carcinoma lung metastasis in 1 female.
Urinary system Lipomas/liposarcomas were the most common renal neoplasms and were observed in 7 males and 3 females. Renal cell adenomas/carcinomas were observed in 4 males and 1 female. Transitional cell carcinoma was observed in 1 male. Urinary bladder papilloma was observed in 1 female. Reproductive system Reproductive tract tumors were the most common neoplasms and were observed in 78.5% males and 30.7% females. In males, testicular interstitial cell tumors were the most common neoplasms (79.5%) followed by prostate adenomas (2.2%) and testicular mesotheliomas (0.6%). A seminal vesicle adenoma was observed in 1 case. Lung metastases were observed from 7 interstitial cell tumors. In females, the most common neoplasms were endometrial stromal polyps
with more than 1% incidence.
Tumor type
Percentage
Adrenal
Cortical adenoma
Thyroid Pancreas
Pheochromocytoma, benign Follicular cell adenoma C-cell adenoma Islet cell adenoma
Pituitary Testis Prostate Uterus Clitoral gland
Adenoma, anterior lobe Interstitial cell tumor Adenoma Endometrial polyp Adenocarcinoma
Mammary
Adenoma Fibroadenoma Adenocarcinoma
gland
Hemolymphoreticular Skin
Mononuclear Fibroma
cell leukemia/lymphoma
Keratoacanthoma
in 1 had
Male
Female
1.6 5.7 1.9 5.7 6.5 20.5 79.5 2.2 -
1.2 1.2 5.1 30.3 14.1 1.1 1.9 11.1 1.6 20.5 1.1
30.5 3.2 1.9
54
Table V.
Tumors
Organ
with metastasis Tumor type
No. with metastasis
Leukemia/lymphoma Cortical carcinoma Pheochromocytoma Follicular carcinoma Adenocarcinoma Hepatocellular carcinoma Interstitial cell tumor Adenocarcinoma
Multiple sites Adrenal Thyroid Salivary Liver Testis Mammary
Squamous Sebaceous
Skin
cell carcinoma carcinoma
(14.1%) followed by mammary tumors (14.6%)) clitoral adenocarcinomas (1.1%) and uterine adenomas (0.6%). Other neoplasms were observed in low incidence. Lung or liver metastases were observed from 10 mammary carcinomas. Musculo-skeletal system Musculo-skeletal neoplasms were rare. Rabdomyosarcoma was observed in 1 male. Osteosarcomas were observed in 1 male and 4 females. Nervous system Astrocytomas were the only neoplasms observed in this system. These tumors occurred in 2 males and 1 female. Hemolymphoreticular system ceil leukemia/lymphomas Mononuclear were observed in 30.5% (226 out of 740) males and 20.5% (152 out of 740) females. Histiocytic sarcomas were observed in 3 males. Integumentary
system
the males, common (3.2%) keratoacanthomas In
fibromas were the most neoplasms followed by (1.9%)) squamous cell car-
Organ with metastasis
Male
Female
226 1 1
152
.
Multiple organs lung lung lung lung lung lung lung liver lung lung
2
1
-
1 1
1 7 6
4
2 -
1 2
cinemas (0.7%)) squamous cell papillomas (0.8%) and sebaceous carcinomas (0.8%). In the females, fibromas occurred in 1.1% cases, followed by keratoacanthomas (0.5%) and squamous cell papillomas (0.3%). Lung metastases from the squamous cell carcinomas were observed in 2 males and 1 female. Lung metastses were also found in 2 out of 6 sebaceous carcinomas. Special
sense
Neurofibrosarcoma was observed in the eye of 1 male. It appeared to arise from the nerve ending in the cornea. Harderian adenomas were observed in 4 males and 3 females. Discussion Since the National Cancer Institute recommended guidelines for the use of F-344 rats, this strain has become the most commonly used rat for carcinogenicity bioassays and biomedical research. The reasons for its popularity are its relatively small size, longevity, resistance to infectious disease when maintained under proper conditions, and quite low incidence of most of the spontaneously occurring neoplasms in various organs [lo]. How-
ever, a high incidence of a few neoplasms including testicular, mammary, uterine, hemopoietic and endocrine neoplasms in F-344 rats has been reported [3]. It is important to have historical control data on the types and incidences of spontaneous tumors in the animals available at a particular facility. Historical controls should only serve as guidelines for evaluating incidence patterns. Matched control group which minimizes variability between control and treated animals are essential for accurate assessment of each experiment [l]. Considering the extensive use of this strain of rat, there are few comprehensive reports on background tumor incidence from long term studies [V,lO]. The definite cause of spontaneous neoplasms is not known. The role of microorganisms in the development of spontaneous tumors has been suggested [8]. In the incidence of a particular present study, neoplasm is calculated for 740 males and 740 females. This incidence may vary greatly in smaller groups of 50 - 60 animals used in carcinogenicity studies. In the present study, 84.3% and 76.2% overall incidences of neoplasms in male and female rats are in agreement with a previous report ill]. Historical findings and organ distributions of neoplasms are characteristic for F-344 rats and are similar to those reported previously [ 1,2,8 - lo]. This paper includes data from studies conducted in the last 6 years. There were no significant differences in the incidences of various neoplasms in different studies. At the end of a 2-year period, the mortality rates ranged from 19% to 24% and from 23% to 28% for males and females, respectively, which is comparable to those reported previously [ll] . There were no significant differences in the mortality patterns in different studies. In this study few tumors metastasized to the lung or liver which is in accordance with previous reports [3,7]. In our study, besides leukemia/lymphomas, the most commonly metastasizing tumors were testicular interstitial cell tumors and mammary neoplasms. Isolated cases of metastases were also observed from the adrenal, skin, liver,
thyroid and salivary neoplasms. Maekawa et al. [7] reported that besides leukemia the most common metastatic tumors were malignant uterine adenocarcinofibrous histiocytomas, mas and osteosarcomas. Goodman et al. [3] reported c-cell carcinomas and malignant pheochromocytomas as the most frequently metastasizing neoplasms. Reproductive tract neoplasms were the most commonly observed tumors followed by endocrine tumors and leukemia. Most frequently observed tumors in male and female reproductive systems were testicular interstitial cell tumor (79.5%) and endometrial polyps (14.1%) , respectively which are comparable to previous reports [6,9]. The higher incidence of endocrine tumor in males was due to pheochromocytomas, thyroid c-cell adenomas, pancreatic islet cell adenomas and pituitary adenomas. In females, pituitary adenomas were the most commonly observed neoplasms followed by thyroid c-cell adenoma. Our reported 20.5% and 30.3% incidences of pituitary adenomas in male and female rats are quite comparable to 23.9% and 35.9% in males and females reported by Sass et al. [VI. Mononuclear cell leukemia, a quite characteristic neoplasm for this strain of rat, was observed in 30.5% males and 20.5% females which is quite comparable to reports by Maekawa et al. [7] and Sass et al [VI, but is higher than that reported by Coleman et al. [l]. The incidences of various tumors may be reflected by sex, genetic variations, source of animals, diet, age at death, environmental conditions, and pathological criteria used by the pathologist [5,12].
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