Growth,Body Weight,Survival,and Tumor Trends in F344/N Rats during an Eleven-Year Period

Abstract

Time trends for growth, body weight, survival and tumor prevalences in 144 diet control groups with a total of 5,184 male F344/N rats and 146 diet control groups with a total of 5,289 female rats of NCI-NTP 2-yr chemical carcinogenicity studies started during an 11-yr period (1971 to 1981) in 11 toxicology testing laboratories were evaluated. Male and female rats in more recent studies grew faster and attained a higher body weight than rats from earlier studies. Survival of males showed a significantly decreasing trend over time, which may have been related to diseases associated with increasing body weight, prevalence of leukemia and changes in criteria for euthanasia of moribund animals. The time trend for survival of females was not significant. There were highly significant (p < 0.001) positive time trends for prevalences of leukemia, anterior pituitary tumors and thyroid C-cell tumors in both sexes, adrenal pheochromocytomas in males and mammary tumors and endometrial stromal polyps in females. The prevalence of mammary tumors in females and pituitary tumors in males had a highly significant (p < 0.01) positive association with body weight. Histological reevaluation of tumor prevalences in approximately 250 rats of each sex at each of 4 different time periods indicated that changes in diagnostic criteria may have contributed to but could not totally explain the increased prevalence of leukemia. Changes in diagnostic criteria and the amount of tissue examined may have contributed to the increased prevalence of anterior pituitary tumors in both sexes and adrenal pheochromocytomas in males. Interlaboratory variability and changes in diet may also have contributed to the time-related trends.

Keywords

Time trends carcinogenicity studies leukemia mammary tumors pituitary tumors adrenal pheochromocytomas thryoid C-cell tumors endometrial polyps

References

Amato

Lagakos

, (1988). Analysis of agreement among findings of pathologists in ED₀₁ experiment. J. Natl. Cancer Inst. 80: 919–925.

American Institute of Nutrition (1977). AIN Ad Hoc Committee on Standards for Nutritional Studies. J. Nutr. 107: 1340–1348.

Cameron

Hickman

Kornreich

Tarone

, (1985). History, survival, and growth of B6C3F1 mice and F344 rats in the National Cancer Institute carcinogenesis testing program. Fundam. Appl. Toxicol. 5: 526–538 and 1188.

Doll

Peto

, (1981). The causes of cancer; quantitative estimates of avoidable risks of cancer in the United States today. J. Natl. Cancer Inst. 66: 1191–1308.

Grice

, (1980). Age associated (geriatric) pathology: Its impact on long-term toxicity studies. In: Current Issues in Toxicology. Springer-Verlag, New York, p. 59.

Goldstein

Tarloff

Hook

, (1988). Age-related nephropathy in laboratory rats. FASEB. J. 2: 2241–2251.

Haseman

Huff

Rao

Arnold

Boorman

McConnell

, (1985). Neoplasms observed in untreated and corn oil gavage control groups of F344/N rats and (C57BL/6N × C3H/HeN) F1 (B6C3F1) mice. J. Natl. Cancer Inst. 75: 975–984.

Haseman

Huff

Rao

Eustis

, (1989). Sources of variability in rodent carcinogenicity studies. Fundam. Appl. Toxicol. 12: 793–804.

Haseman

, (1983). Patterns of tumor incidence in two-year cancer bioassay feeding studies in Fischer 344 rats. Fundam. Appl. Toxicol. 3: 1–9.

10.

Montesano

Bartsch

Vanio

Willbourn

Yamasaki

, (1986). Long-Term and Short-Term Assays for Carcinogens: A Critical Appraisal. IARC Publication No. 83, p. 23.

11.

National Research Council (1978). Guide for the Care and Use of Laboratory Animals. DHEW (NIH) publication 74-23, 1974 and NIH publication 78-23. Washington, DC.

12.

Rao

Knapka

, (1987). Contaminant and nutrient concentrations of natural ingredient rat and mouse diet used in chemical toxicity studies. Fundam. Appl. Toxicol. 9: 329–338.

13.

Rao

Piegorsch

Haseman

, (1987). Influence of body weight on the incidence of spontaneous tumors in rats and mice of long-term studies. Am. J. Clin. Nutr. 45: 252–260.

14.

Rao

Haseman

Grumbein

Crawford

Eustis

, (1990). Growth, body weight, survival, and tumor trends in (C57BL/6 × C3H/HeN) F1 (B6C3F1) mice during a nine-year period. Toxicol. Pathol. 18: 71–77.

15.

Roe

FJC

, (1987). Problems of pseudocarcinogenicity in rodent bioassays. In: Banbury Report 25, Ghoshal

Ruschmore

Farber

, (eds). Cold Spring Harbor Laboratory, Cold Spring Harbor, NY, pp. 189–200.

16.

Roe

FJC

, (1983). Testing for carcinogenicity and problems of pseudocarcinogenicity. Nature 303: 657–658.

17.

Roe

FJC

, (1981). Are nutritionists worried about the epidemic of tumors in laboratory animals?. Proc. Nutr. Soc. 40: 57–65.

18.

Ross

Bras

, (1973). Influence of protein under- and overnutrition on spontaneous tumor prevalence in the rat. J. Nutr. 103: 944–963.

19.

SAS Institute, Inc. (1985). SAS^(R) User's Guide: Statistics (5th ed.). SAS Institute, Inc., Cary, NC.

20.

Snedecor

Cochran

, (1980). Statistical Methods (7th ed.). Iowa State University Press, Ames, IA, pp. 258–339.

21.

Tucker

, (1987). Factors influencing carcinogenicity testing in rodents. Hum. Toxicol. 6: 107–109.

22.

Tucker

, (1979). The effect of long-term food restriction on tumors in rodents. Int. J. Cancer 23: 803–807.

23.

United States Food and Drug Administration (1978). Nonclinical laboratory studies, good laboratory practices regulations. Federal Register 43: 59986–60025.

24.

Weisburger

, (1983). History of the bioassay program of the National Cancer Institute. In: Progress in Experimental Tumor Research. Vol. 26. Skin painting techniques and in vivo carcinogenesis bioassays, Homburger

, (ed). S. Karger, Basel, pp. 187–201.