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Annual Ramazzini Days

Explore the suitability of Sprague Dawley rats as an animal model for studying various endpoints in experimental toxicology. This includes consistency of the animal model, housing conditions, diet analysis, experiment duration, biophase and histopathology phases, and more.

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Annual Ramazzini Days

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  1. Sprague Dawley rats from the CMCRC/RI: a suitable model for studying different endpoints in experimental toxicology Eva Tibaldi Cesare Maltoni CancerResearch Center Annual Ramazzini Days Carpi, October 28th, 2016

  2. 40 YEARS OF EXPERIENCE IN CARCINOGENICITY BIOASSAYS 2

  3. Consistency of the animal model and experimental conditions • Animal model: family tree of SD rats from the 1970’…..until now (more than 200.000) • Housing conditions (cages, conventional room) • Diet (periodically analyzed for nutritional components and determination of contaminants) • Start and duration of the experiment (for carcinogenicity at least 130 weeks or more) • Conduct of the biophase(measurements of water and food consumption, body weight, behaviour and clinical control • Conduct of the histopathology phase (complete necropsy, fixation, embedding, cutting and staining) • Microscopic examination (harmonization of the diagnoses with international classificationcriteria) • Final report (biophase and histopathologytables, statistics) 3

  4. BODY WEIGHT and SURVIVAL 4

  5. HISTORICAL CONTROL: data at 104 weeks • control groups of 158 experiments from 1969 to 2011 N. of animals Mean body weight Mean survival 7,854 45.7 % Males 533.2 g 8,202 Females 376.4 g 51.1 % Total (M+F) 16,056 47.8 %

  6. MEAN BODY WEIGHT (g) IN MALE AND FEMALE RATS

  7. MEAN SURVIVAL (%) IN MALE AND FEMALE RATS

  8. Comparison: Body weight and survival at 104 weeks (I) (II) NTP data: ToxicolPathol. 2003 Nov-Dec;31(6):674-81. Haseman JK et al. Effect of diet and animal care/housing protocols on body weight, survival, tumor incidences, and nephropathy severity of F344 rats in chronic studies. Charles River data: (I) HumExpToxicol. 1993 Mar;12(2):87-98. Nohynek GJ, et al. Fat, frail and dying young: survival, body weight and pathology of the Charles River Sprague-Dawley-derived rat prior to and since the introduction of the VAFR variant in 1988 France laboratory; (II): Report on several studies dated 2004;Charles River Japan: Report on biological reference data on CD SD IGS rats 2001, Yokohama; Harlan: Fundamental and Applied Toxicol 1996; 33, 196-211, Pettersen JC et al. A 2-Year Comparison Study of Crl:CD BR and Hsd:Sprague-Dawley SD Rats

  9. INCIDENCE AND TYPE OF TUMORS 1984-1994 versus 1995-2004 9

  10. ANIMAL BEARING BENIGN TUMOR IN MALE AND FEMALE Males Females 1984-1994 1995-2004 1984-19941995-2004 Male (%) 60.75 58.13 Female (%) 76.74 75.49 1984-1994 N. of animal: 2265 ; 1995-2004 N. of animal: 1428

  11. INCIDENCE OF BENIGN TUMORIN MALE AND FEMALE RATS (%) 1984-19941995-2004 M F M F Fibroma and Fa of the mammary gland Adenoma of the pituitary gland Pheocromocytoma of the adrenal gland Polyp of the uterus Islet cell adenoma of the pancreas Interstitial cell adenoma of the testis 4.47 49.37 28.60 30.25 20.30 21.36 - 21.50 8.94 3.43 3.90 - 4.24 44.50 24.33 41.91 33.86 24.98 - 15.57 8.43 3.96 7.28 -

  12. INCIDENCE (%) OF MAIN BENIGN TUMORS IN MALES %

  13. INCIDENCE (%) OF MAIN BENIGN TUMORS IN FEMALES %

  14. ANIMAL BEARING MALIGNANT TUMOR IN MALE AND FEMALE 1984-1994 Males Females 1995-2004 1984-19941995-2004 Male (%) 41.24 38.33 Female (%) 40.06 44.89 1984-1994 N. of animal: 2265 ; 1995-2004 N. of animal: 1428

  15. INCIDENCE OF MALIGNANT TUMOR IN MALE AND FEMALE RATS (%) 1984-19941995-2004 M F M F Haemolymphoreticular neoplasia Carcinoma of the mammary gland Carcinoma of the ear ducts Osteosarcoma of the head Malignant tumor of the uterus 20.44 13.10 0.49 9.94 5.21 6.02 4.86 2.90 - 6.47 18.95 14.36 0.35 9.73 3.19 6.09 6.60 4.97 - 6.93

  16. INCIDENCE (%) OF MAIN MALIGNANT TUMORS IN MALES %

  17. INCIDENCE (%) OF MAIN MALIGNANT TUMORS IN FEMALES %

  18. COMPARISON: INCIDENCE (%) OF MAIN BENIGN TUMORS IN MALES % For NTP F344 data: Haseman et al 1985, “Neoplasmsobserved in untreated and cornoilgavage control groups of F344/N rats and B6C3F1 mice”, JNCI and data from the book Pathology of the Fischer Rat: Reference and Atlas For CRC SD data: data on historical control from experimentsconducted in 1984-1994 For CH RIV SD data: Mc Martin et al 1992, “Neoplasms and related proliferative lesions in control Sprague-DawleyRats from Carcinogenicitystudies. Historical data and diagnosticconsiderations” ToxicolPathol and from Charles River “Compilation of SpontaneousNeoplasticLesions and Survival in Crl:CD (SD) Rats from Control Groups” March 2004

  19. COMPARISON: INCIDENCE (%) OF MAIN BENIGN TUMORS IN FEMALES % For NTP F344 data: Haseman et al 1985, “Neoplasms observed in untreated and corn oil gavage control groups of F344/N rats and B6C3F1 mice”, JNCI and data from the book Pathology of the Fischer Rat: Reference and Atlas For CRC SD data: data on historical control from experiments conducted in 1984-1994 For CH RIV SD data: Mc Martin et al 1992, “Neoplasms and related proliferative lesions in control Sprague-Dawley Rats from Carcinogenicity studies. Historical data and diagnostic considerations” Toxicol Pathol and from Charles River “Compilation of Spontaneous Neoplastic Lesions and Survival in Crl:CD (SD) Rats from Control Groups” March 2004

  20. COMPARISON: INCIDENCE (%) OF MAIN MALIGNANT TUMORS IN MALES % For NTP F344 data: Haseman et al 1985, “Neoplasmsobserved in untreated and cornoilgavage control groups of F344/N rats and B6C3F1 mice”, JNCI and data from the book Pathology of the Fischer Rat: Reference and Atlas For CRC SD data: data on historical control from experimentsconducted in 1984-1994 For CH RIV SD data: Mc Martin et al 1992, “Neoplasms and related proliferative lesions in control Sprague-DawleyRats from Carcinogenicitystudies. Historical data and diagnosticconsiderations” ToxicolPathol and from Charles River “Compilation of SpontaneousNeoplasticLesions and Survival in Crl:CD (SD) Rats from Control Groups” March 2004

  21. COMPARISON: INCIDENCE (%) OF MAIN MALIGNANT TUMORS IN FEMALES % For NTP F344 data: Haseman et al 1985, “Neoplasmsobserved in untreated and cornoilgavage control groups of F344/N rats and B6C3F1 mice”, JNCI and data from the book Pathology of the Fischer Rat: Reference and Atlas For CRC SD data: data on historical control from experimentsconducted in 1984-1994 For CH RIV SD data: Mc Martin et al 1992, “Neoplasms and related proliferative lesions in control Sprague-DawleyRats from Carcinogenicitystudies. Historical data and diagnosticconsiderations” ToxicolPathol and from Charles River “Compilation of SpontaneousNeoplasticLesions and Survival in Crl:CD (SD) Rats from Control Groups” March 2004

  22. A HUMAN-EQUIVALENT MODEL 22

  23. HUMAN-EQUIVALENT MODEL: CUMULATIVE PREVALENCE BY AGE AT DEATH • 1,114 people with malignant tumors (out of 2,560 autopsied men and women deceased at the Hospital of Trieste, in 1989) • 1,212 Sprague-Dawley rats with malignant tumor (out of 3,051 necropsied male and female untreated rats (from control groups) 80% of tumors occur in humans after 65 years, corresponding to 104 weeks of age in rats

  24. CONCLUSIONS • The RI colony of SD rats has consistent biological characteristics over time. • Our animal model represents a "human-equivalent" model in terms of incidence, natural history and age distribution of various types of cancer. • Our strain has a low background of spontaneous hormonally-induced tumor incidence (ovary, thyroid, testis, mammary gland). Therefore this model is able to provide important information on non-neoplastic and neoplastic waiting and is suitable for studying different types of endpoints in experimental toxicology.

  25. “The reward of great men is that, long after they have died, one is not quite sure that they are dead” Jules Renard , 1864 -1910 25

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