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1 Lab. Anim. Res. 2010: 26(2), Reference Data of the Main Physiological Parameters in Control Sprague-Dawley Rats from Pre-clinical Toxicity Studies Zhong-Ze Han, Hong-De Xu, Kwang-Ho Kim, Tae-Hwan Ahn, Jin-Sook Bae, Ji-Young Lee, Ki-Hyun Gil, Joo-Young Lee, Su-Jung Woo, Hyun-Jung Yoo, Hyun-Kul Lee, Kap-Ho Kim, Chan-Koo Park, Hu-Song Zhang and Si-Whan Song* Preclinical Research Center, ChemOn Inc., Yongin, Korea The purpose of this paper is to provide reference data related to the body weight, food & water consumptions, urinalysis, hematology and serum biochemistry parameters and absolute & relative organ weights obtained from control Sprague-Dawley rats, used in the 4-week and 13-week repeated-dose toxicity studies conducted in our laboratory between 2005 and The mean, standard deviation, minimum and maximum range values for hematology and serum biochemistry parameters, data of absolute & relative organ weights, and the difference between sexes and study duration of week 4 versus 13 week are presented. The studies were conducted according to the standards of Toxicity Study for Medicinal Products (2005) and The KFDA Notification No Good Laboratory Practice (GLP) (2000) issued by KFDA. These data could be used as reference material of Sprague-Dawley rats by conducting the studies to evaluate the toxicological profile of pre-clinical toxicity studies. Key words: Hematology, reference data, Sprague-Dawley rat, pre-clinical toxicity studies. Received 16 February 2010; Revised version received 17 May 2010; Accepted 10 June 2010 x w w, w» w x w x w š, w x w w y š. z w x sƒ w x x x y y w» w w w x v w, x w w» y w (Yamada, 1989; Alemán et al., 1998; Kitagaki et al., 2005; Petterino and Argentino-Storino, 2006; Ando et al., 2008). p, x x w w sƒ w w (No-Observed-Effect Level, NOEL) (No-Observed-Advese-Effect Level, NOAEL) y w w x x w mw ƒ w. x *Corresponding author: Si-Whan Song, Preclinical Research Center, ChemOn Inc., 334 Jeil-ri, Yangji-myeon, Cheoin-gu, Yongin-si, Gyeonggi-do , Korea Tel: Fax: swansong@chemon.co.kr x x w w w (Leonard and Ruben, 1986; Wolford et al., 1986; Roe, 1991; Matsuzawa et al., 1995; Alemán et al., 2000). x ü GLP» w x w» y w xsƒ w y wš (Song et al., 1990; Kang et al., 1995; Kang et al., 2004). [( )f l,» ] 2005 l 2008 ww Sprague-Dawley w 4 13 n x ³ n w,,, x w, x yw,» w» ww SD m w» l x z xsƒ» œwš ww. w t t (KFDA) t x» ( t t š y, 2005) x» ( t t š y, 2005) w ww. w, x ( ) f x ³ w w. 153

2 154 Zhong-Ze Han et al. lò x w x g l(» sk ) l w p ³ Sprague-Dawley (Hsd: Sprague Dawley TM SD TM ) 2005 l 2008 ww 4 13 n x» w. ³ n w w ü 1z n w š, n 5-20 ml/kg/day (10 ml/kg/day ). n 4 13 x 6. w, 4 x n f g, f g, 13 x n f g, f g. m 23±3 o C, 55±15%, y»z 10-20z/hr, 12», Lux KGLP» ( )f l x w, 4 n x l (W 215 L 355 H 200 mm), 13 n x s e p (235 W 380 L 175H mm) 3 w/ w. ³ x šx (Harlan Co. Ltd., USA. TEKLAD CERTIFIED GLOBAL 18% PROTEIN RODENT DIET, 2918C) s lü ú l œ w w, w ³» e w z w g. n x» 1z, š z d w. n x» 1z w š, w z, ú d w w, s³ (g/rat/day) w. d» w š, w ú d w w, s³ (g/ rat/day) w. á Multistix 10SG x (Bayer Corp., Elkhart, IN, USA) e(clinitek 100, Bayer Corp., Elkhart, IN, USA) w (glucose), (bilirubin), fm (ketone body), (specific gravity), x(occult blood), ph, (protein), (urobilinogen), (nitrite) x (leukocyte) w w. l j á x 16 k z, l w w z l xw x w š EDTA-2Kƒ CBC x w z x d e(advia 2120, SIEMENS, USA or Cell dyn 3700, Abbot, USA) w x (white blood cell count, WBC), x (red blood cell count, RBC), x (hemoglobin), x (hematocrit), s ³ x (mean corpuscular volume, MCV), s³ x x (mean corpuscular hemoglobin, MCH), s³ x x (mean corpuscular hemoglobin concentration, MCHC),x q (platelet), x [y (neutrophil), y (eosinophil), y» (basophil), v (lymphocyte), w (monocyte)] d w. x š prothrombin time (PT) activated partial thromboplastin time (APTT) x š e(acl 100, Instrumentation Laboratory, USA or CA-50, Sysmex, Japan) w d w. x š w š 3.2% sodium citrate w. d w d Table 1 ùkü. l mj á z l xw x 30 ew š k z (3000 rpm, 10 )w x w aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase (ALP), blood urea nitrogen (BUN), creatinine, glucose, total cholesterol (TC), total protein (TP), creatine phosphokinase (CPK), albumin, total bilirubin (TB), albumin/globulin (A/G) ratio, triglyceride, inorganic phosphorus (IP) Ca w yw» ++ (AU400, Olympus, Japan) w d w š Na +, K +, Cl w e(644, Na + /K + /Cl Analyzer, Ciba-corning, Medfield, MA, USA) w d w. d w d Table 1 ù kü.

3 Reference database of Sprague-Dawley rats 155 Table 1. Parameters, units and methods of analysis used in hematological and serum chemistry examinations Parameters (abbreviation) Units Methods White blood cell count (WBC) 10 3 /µl Laser optical flowcytometry or electric resistance method* Red blood cell count (RBC) 10 6 /µl Laser optical flowcytometry or electric resistance method* Hemoglobin concentration (HGB) g/dl Cyanmethemoglobin method* Hematocrit % Calculated from RBC and MCV Mean corpuscular volume (MCV) fl Histogram or electric resistance method* Mean corpuscular hemoglobin (MCH) pg Calculated from HGB and RBC Mean corpuscular hemoglobin concentration (MCHC) g/dl Calculated from HGB, RBC and MCV Red cell distribution width (RDW) % Histogram* Hemoglobin concentration distribution width (HDW) g/dl Histogram* Platelet 10 3 /µl Laser optical flowcytometry or electric resistance method* Mean platelet volume (MPV) fl Histogram* prothrombin time (PT) sec Nephelometric analysis # Activated partial thromboplastin time (APTT) sec Nephelometric analysis # Neutrophil % Peroxidase cytometric flowcytometry or scatter photocoagulation method* Lymphocyte % Peroxidase cytometric flowcytometry or scatter photocoagulation method* Monocyte % Peroxidase cytometric flowcytometry or scatter photocoagulation method* Eosinophil % Peroxidase cytometric flowcytometry or scatter photocoagulation method* Basophil % Peroxidase cytometric flowcytometry or scatter photocoagulation method* Large unstained cells (LUC) % Noise-Lymph Histogram* Aspartate aminotransferase (AST) U/L IFCC method & Alanine aminotransferase (ALT) U/L IFCC method & Alkaline phosphatase (ALP) U/L P-NPP method & Blood urea nitrogen (BUN) mg/dl Urease-UV method & Creatinine mg/dl Jaffe method & Glucose mg/dl UV method & Total cholesterol (TC) mg/dl Enzyme method & Total protein (TP) g/dl Biuret method & Creatine phosphokinase (CPK) U/L UV-Rate method & Albumin g/dl BCG method & Albumin/Globulin (A/G) ratio ratio Calculated from PRO, ALB Total bilirubin (TB) mg/dl Evelyn-Malloy method & Triglyceride mg/dl Enzyme method & Inorganic phosphorus (IP) mg/dl UV method & Calcium ion (Ca ++ ) mg/dl O-CPC method & Sodium ion (Na + ) mmol/l Electrode method $ Potassium ion (K + ) mmol/l Electrode method $ Chloride ion (Cl - ) mmol/l Electrode method $ *ADVIA 2120 (Simens, USA) or Cell dyn 3700 (Abbot, USA); & AU400 (Olympus, Japan); # CA-50 (Sysmex, Japan) or ACL 100 (Instrumentation Laboratory, Spain); $ 644 Na/K/Cl Analyzer (Simens, USA). á 4 x 10, 13 x k z d w.» d x w x óù w z w x e k z w., w,, ƒ, s,,,,,,, šy, šy, ù, ª w (BP221S and CP153, Sartorius AG, Germany) d w ( d» d» ƒƒ d ), d» w w w. f l t (Standard Operating Procedures, SOPs) w w.

4 156 Zhong-Ze Han et al. Figure 1. Reference data of mean body weights from 4- and 13-week toxicity studies in male and female Sprague-Dawley rats Figure 3. Reference data of water consumption from 4- and 13-week toxicity studies in male and female Sprague-Dawley rats y w, 1 s³ 4 x 13 x w s³ 2g (P<0.01). 13 x 1 s³ x» f g, f g ùkü. Figure 2. Reference data of food consumption from 4- and 13- week toxicity studies in male and female Sprague-Dawley rats j m w š m q j SPSS 10.1 w n x x w x yw w ƒƒ Student s t-test w w š,,,» w m w š wq w. w y w z, Wilcoxson-Mann-Whitney rank-sum test w y w. x 99% (a= 0.01) w. y Figure 1 ùkü. 4 y w, p»w w y. Figure 2 ùkü. 4 Figure 3 ùkü. 4 y w, p»w w. 13 x 1 s³ x» f g, f g ùkü. á Table 2 ùkü x, 4 x fm,, x, 13 x fm,, x, x, phƒ m w w ù kü (P<0.01) x, f, x ph, f fm m w w ùkü (P<0.01). l j á x w Table 3 ùkü x x w, 4 x RBC, hemoglobin, hematocrit, MCV, MCHC, WBC eosinophil, 13 x RBC, hemoglobin, hematocrit, MCV, MCH, RDW, HDW, WBC, neutrophil, lymphocyte, monocyte, eosinophil, platelet APTTƒ m w w ùkü (P<0.01) x x w, f RBC, hemoglobin, hematocrit, MCV, MCH,

5 Reference database of Sprague-Dawley rats 157 Table 2. Reference data of urinalysis from 4- and 13-week toxicity studies in male and female Sprague-Dawley rats Parameters Result Grade 4 weeks-group 13 weeks-group Males Females Males Females Glucose (mg/dl) Bilirubin Ketone body (mg/dl) Specific gravity ph Protein (mg/dl) Urobilinogen (Ehrlich unit/dl) Nitrite Occult blood Leukocyte Negative (Trace) Negative Small Negative (Trace) * 0 0 #$ * 1 $ * 0 # Negative (Trace) * 22 2 # Negative Positive Negative Trace Small Moderate Large * 1 # Negative Trace Small Moderate Large 4 2 0* 4 0 # Number of animals *: P<0.01, vs. 4 weeks male group; $ : P<0.01, vs. 4 weeks female group; # : P<0.01, vs. 13 weeks male group. WBC, neutrophil, lymphocyte, monocyte, eosinophil, platelet, PT APTT, f WBC, neutrophil, lymphocyte, monocyte, eosinophil, basophil, platelet, PT APTTƒ m w w ùkü (P<0.01). l mj á x yw Table 4 ùkü x x yw, 4 x ALT, ALP, TB, TP, A/G ratio, glucose, TC, triglyceride, BUN, IP, Ca ++, Na +, K +

6 158 Zhong-Ze Han et al. Table 3. Reference data of hematology from 4- and 13 week toxicity studies in male and female Sprague-Dawley rats Parameters 4 weeks-group 13 weeks-group N Mean±SD Range N Mean±SD Range Males RBC (10 6 /µl) ± ±0.39* Hemoglobin (g/dl) ± ±0.65* Hematocrit (%) ± ±3.53* MCV (fl) ± ±2.99* MCH (pg) ± ±0.64* MCHC (g/dl) ± ± RDW (%) ± ± HDW (g/dl) ± ± WBC (10 3 /µl) ± ±2.35* Neutrophil (%) ± ±8.60* Lymphocyte (%) ± ±8.97* Monocyte (%) ± ±1.46* Eosinophil (%) ± ±0.50* Basophil (%) ± ± LUC (%) ± ± Platelet (10 3 /µl) ± ±126.77* MPV (fl) ± ± PT (sec) ± ±3.63* APTT (sec) ± ±1.27* Females RBC (10 6 /µl) ±0.45* ±0.43 # Hemoglobin (g/ dl) ±0.83* ±0.65 # Hematocrit (%) ±2.91* ±3.26 # MCV (fl) ±2.34* ±3.06 # MCH (pg) ± ±0.82 # MCHC (g/dl) ±1.22* ± RDW (%) ± ±0.43 # HDW (g/dl) ± ±0.20 # WBC (10 3 /µl) ±1.93* ±1.78 #$ Neutrophil (%) ± ±6.69 #$ Lymphocyte (%) ± ±6.85 #$ Monocyte (%) ± ±1.03 #$ Eosinophil (%) ±0.49* ±1.14 #$ Basophil (%) ± ±1.13 $ LUC (%) ± ± Platelet (10 3 /µl) ± ± #$ MPV (fl) ± ± PT (sec) ± ±4.12 $ APTT (sec) ± ±1.51 #$ WBC: white blood cell count, RBC: red blood cell count, MCV: mean corpuscular volume, MCH: mean corpuscular hemoglobin, MCHC: mean corpuscular hemoglobin concentration. RDW: Red cell distribution width, HDW: Hemoglobin concentration distribution width, LUC: large unstained cells, PT: prothrombin time, APTT: Activated partial thromboplastin time. *: P<0.01, vs. 4 weeks male group; $ : P<0.01, vs. 4 weeks female group; # : P<0.01, vs. 13 weeks male group. Cl, 13 x ALT, ALP, TB, TP, A/G ratio, glucose, triglyceride, BUN, creatinine, IP, K + Cl m w w ùkü (P<0.01) x x yw, f ALT, ALP, TP, albumin, A/G ratio, TC, creatine, IP K +, f ALT, ALP, TP, A/G ratio, TC, triglyceride, BUN, creatinine, IP, Na +, K + Cl m w w ùkü (P<0.01).» w Table 5( f)

7 Reference database of Sprague-Dawley rats 159 Table 4. Reference data of blood biochemistry from 4- and 13 week toxicity studies in male and female Sprague-Dawley rats Parameters 4 weeks-group 13 weeks-group N Mean±SD Range N Mean±SD Range Males AST (IU/L) ± ± ALT (IU/L) ± ±9.19* ALP (IU/L) ± ±19.92* TB (mg/dl) ± ± Glucose (mg/dl) ± ± TC (mg/dl) ± ±18.72* Triglyceride (mg/dl) ± ± TP (g/dl) ± ±0.52* Albumin (g/dl) ± ±0.21* A/G ratio ± ±0.07* CPK (IU/L) ± ± BUN (mg/dl) ± ± Creatinine (mg/dl) ± ±0.07* IP (mg/dl) ± ±1.09* Ca ++ (mg/dl) ± ± Na + (mmol/l) ± ± K + (mmol/l) ± ±0.38* Cl - (mmol/l) ± ± Females AST (IU/L) ± ± ALT (IU/L) ±4.94* ±5.13 #$ ALP (IU/L) ±26.47* ±17.71 #$ TB (mg/dl) ±0.07* ±0.04 # Glucose (mg/dl) ±11.26* ±12.24 # TC (mg/dl) ±16.76* ±20.84 $ Triglyceride (mg/dl) ±11.36* ±7.92 #$ TP (g/dl) ±0.30* ±0.33 #$ Albumin (g/dl) ± ± A/G ratio ±0.24* ±0.08 #$ CPK (IU/L) ± ± BUN (mg/dl) ±3.08* ±2.59 #$ Creatinine (mg/dl) ± ±0.07 #$ IP (mg/dl) ±0.78* ±1.27 #$ Ca ++ (mg/dl) ±0.51* ± Na + (mmol/l) ±1.83* ±2.66 $ K + (mmol/l) ±0.31* ±0.46 #$ Cl - (mmol/l) ±1.85* ±2.39 #$ AST: aspartate aminotransferase, ALT: alanine aminotransferase, ALP: alkaline phosphatase, TB: total bilirubin, TP: total protein, A/G: albumin/globulin, CPK: creatine phosphokinase, TC: total cholesterol, BUN: blood urea nitrogen, IP: inorganic phosphorus. *: P<0.01, vs. 4 weeks male group; $ : P<0.01, vs. 4 weeks female group; # : P<0.01, vs. 13 weeks male group. Table 6( f) ùkü x», 4 x,, ƒ,, s,,, w, 13 x,, w,, ƒ,, s,, ùkü x», f, ƒ,, s,,,,, š y šy, f, w, ƒ,, s,,,, ª ù ùkü. x x w š 4 13 n x ³

8 160 Zhong-Ze Han et al. Table 5. Reference data of absolute and relative organ weights from 4- and 13 week toxicity studies in male Sprague-Dawley rats Males Organs 4 weeks-group 13 weeks-group N Mean±SD Range N Mean±SD Range Body weights (g) a) ± ± Brain (g) ± ± (%) ± ± Pituitary gland (g) ± ± (%) ± ± Thyroid gland-left+right (g) ± ± (%) ± ± Thyroid gland-left (g) ± ± (%) ± ± Thyroid gland-right (g) ± ± (%) ± ± Heart (g) ± ± (%) ± ± Lung (g) ± ± (%) ± ± Thymus (g) ± ± (%) ± ± Spleen (g) ± ± (%) ± ± Liver (g) ± ± (%) ± ± Kidney-left+right (g) ± ± (%) ± ± Kidney-left (g) ± ± (%) ± ± Kidney-right (g) ± ± (%) ± ± Adrenal gland-left+right (g) ± ± (%) ± ± Adrenal gland-left (g) ± ± (%) ± ± Adrenal gland-right (g) ± ± (%) ± ± Testis-left+right (g) ± ± (%) ± ± Testis-left (g) ± ± (%) ± ± Testis-right (g) ± ± (%) ± ± Epididymis-left+right (g) ± ± (%) ± ± Epididymis-left (g) ± ± (%) ± ± Epididymis-right (g) ± ± (%) ± ± Prostate (g) ± ± (%) ± ± a)the body weights were measured right before necropsy after overnight fasting.

9 Reference database of Sprague-Dawley rats 161 Table 6. Reference data of absolute and relative organ weights from 4- and 13 week toxicity studies in female Sprague-Dawley rats Females Organs 4 weeks-group 13 weeks-group N Mean±SD Range N Mean±SD Range Body weights (g) a) ± ± Brain (g) ± ± (%) ± ± Pituitary gland (g) ± ± (%) ± ± Thyroid gland-left+right (g) ± ± (%) ± ± Thyroid gland-left (g) ± ± (%) ± ± Thyroid gland-right (g) ± ± (%) ± ± Heart (g) ± ± (%) ± ± Lung (g) ± ± (%) ± ± Thymus (g) ± ± (%) ± ± Spleen (g) ± ± (%) ± ± Liver (g) ± ± (%) ± ± Kidney-left+right (g) ± ± (%) ± ± Kidney-left (g) ± ± (%) ± ± Kidney-right (g) ± ± (%) ± ± Adrenal gland-left+rigt (g) ± ± (%) ± ± Adrenal gland-left (g) ± ± (%) ± ± Adrenal gland-right (g) ± ± (%) ± ± Ovary-left+right (g) ± ± (%) ± ± Ovary-left (g) ± ± (%) ± ± Ovary-right (g) ± ± (%) ± ± Uterus (g) ± ± (%) ± ± a) The body weights were measured right before necropsy after overnight fasting. n w» ww x 4 x» ( z 6-10 ) d w, j ù 4 x 13 x w 1 s³ 2g ùkû. x 4 x l w š, 13 x s e p w» w l, ƒ w ƒ, s e p w w, l,

10 162 Zhong-Ze Han et al. s e p w w w w w w, y 4 13 x j ƒ ƒ x e w j q w. wr, Sauer (2006) l s e p 4 w z,, x w x yw cytochrome P450 z d w, w šw. yw,, x fm ƒ 4 13 x f f w ùkü š, ph 4 x 13 x w û, ùkù ùkü k»» w (Song et al., 1990 and 1992). x, wš 30 mg/dl 4 13 x f ƒƒ 48.3% 30.8%, f ƒƒ 88.3% 96.9% ùkü, f f w ùk û. w w k, ù w w. y ƒ w, f f w w j š (Snell, 1967; Bolton et al., 1976; Alt et al., 1980; Verhagen et al., 2000; Kohn and Clifford, 2002; Baylis, 2005; Loria et al., 2007). p, w ù p w ƒ (Tanimoto, 1988)ƒ w w.»k,,, 4 13 x (negative) (trace) w j ùkû. x x w x yw x w x sƒ w» š, y (, m,,,, y, y, ) y p y ùkü (Roe, 1993; Matsuzawa et al., 1995; Sharp et al., 2003; Gonder and Laber, 2007). d ƒ e q w» w ƒ w y w v ƒ. x, x x yw, 4 13 x m w w y. w w» š (Williams and Weirburger, 1991). x RBC t(hemoglobin, hematocrit, MCV, MCH ) (Seki et al., 1981; Petterino and Argentino-Storino, 2006). w, WBC lymphocyte 13 x 4 x w m w w, neutrophil, monocyte eosinophil ƒ ùkü w WBC e y x l» j (Petterino and Argentino-Storino, 2006). wr, Kang (1995) WBCƒ 13 x 4 x w f û e, f e ùkü. WBC e, ùküš, x x e y,»» d (Bounous et al., 1995; Lipman and Perkins, 2002). PLT x š w ƒ š d»» w y ùkù PLT d PT APTT m w š ƒ (Dodds, 1980; Weingand et al., 1992). x 13 x 4 x w PLT, PT APTT ƒ ùkü y. Wolford (1987) PLT w e ù ƒ f f w û w šw. x yw, w ALP eƒ j ùkü, 13 x 4 x w j w š, f f w û e ùk ü š ew ùkü (Wolford et al., 1986; Loeb and Carakostas, 1992; Alemán et al., 1998). x IP e w 13 x 4 x w w š, f f w û e ùkü y. z y,,»k y w (Uchida et al., 1990; Braun et al., 1993; Loeb et al., 1996; Kaneko, 1997; Gonder and Laber,

11 2007). x ALT, TP, TC, triglyceride 13 x 4 x w e, albumin A/ G ratio û e ùkü y. Petterino Argentino-Storino(2006) SD w 4 13 x w yw AST, ALT, TPƒ 13 x 4 x w e, albumin, A/G ratio triglyceride û e, TC w e ùkü AST, triglyceride, TC w»k d w x w w ùkü. wr, ü» (Kang et al., 1995) x AST, glucose, TC, TP, triglyceride, albumin 13 x 4 x w e ùk ü glucose, albumin A/G ratioƒ x w ùkü x y,» w. x» sƒ w ƒ Ÿ w š w x BUN creatinine. p, x creatinine w w» nephropathy y w w w (Bauck and Stefkovic, 1986; Ragan and Weller, 1999). w x y w w š (Owen and Haywood, 1986; Abrass, 2000). x x creatinine 13 x 4 x w ù kù y ùkü.» d, ƒ» w» ƒ ƒwš, w w, ƒ ƒ (Stevens and Gallo, 1989; Iwata et al., 1993; Alemán et al., 1998). wr,» ƒ ƒ w ùkû Song (1990) SD» ƒ 5 ƒ š z ƒ w š, ƒ ƒ» ny w (Elcüman and Akay, 1998; Elmore, 2006).»k ù w»» w y w. x w sƒ x ww w wù x Reference database of Sprague-Dawley rats 163 k p š ƒ w» y x w w v wù. x w w, w š, y, k, x d (Wolford et al., 1986; Yamada et al., 1989; Braun et al., 1993; kang et al., 1995; Petterino and Argentino-Storino, 2006). x» ww» y x w y y sƒw w.» ww x w w š Sprague-Dawley w p w ƒ. k Abrass, C.K. (2000) The nature of chronic progressive nephropathy in aging rats. Adv. Ren. Replace. Ther. 7(1), Alemán, C.L., Más, R.M., Rodeiro, I., Noa, M., Hernández, C., Menéndez, R. and Gámez, R. (1998) Reference database of the main physiological parameters in Sprague Dawley rats from 6 to 32 months. Lab. Anim. 32(4), Alemán, C.L., Noa, M., Más, R., Rodeiro, I., Mesa, R., Menéndez, R., Gámez, R. and Hernández, C. (2000) Reference data for the principal physiological indicators in three species of laboratory animals. Lab. Anim. 34(4), Alt, J.M., Deerberg, F., Hackbarth, H.J. and Stolte, H. (1980) The study of urinary protein excretion in male rats as compared with human proteinuria. Contrib. Nephrol. 19, Ando, R., Nakamura, A., Nagatani, M., Yamakawa, S., Ohira, T., Takagi, M., Matsushima, K., Aoki, A., Fujita, Y. and Tamura, K. (2008) Comparison of Past and Recent Historical Control Data in Relation to Spontaneous Tumors During Carcinogenicity Testing in Fischer 344 Rats. J. Toxicol. Pathol. 21, Bauck, L. and Stefkovic, G. (1986) Searching the records for clues about kidney disease in guineapigs. Vet. Med. 81, Baylis, C. (2005) Changes in renal hemodynamics and structure in the aging kidney; sexual dimorphism and the nitric oxide system. Exp. Gerontol. 40(4), Bolton, W.K., Benton, F.R., Maclay, J.G. and Sturgill, B.C. (1976) Spontaneous glomerular sclerosis in aging Sprague-Dawley rats. I. Lesions associated with mesangial IgM deposits. Am. J. Pathol. 85(2), Bounous, D., Bourdeaux, M.K. and Hoskins, J.D. (1995) Hematology of normal dogs and cats and responses to diseases. pp. 337Æ353, WB Saunders Co, Philadelphia. Braun, J.P., Aktas, M., Lefebvre, H., Rico, A.G. and Toutain, P.L. (1993) Clinical enzymology for the assessment of organ damage: interspecific differences. Comp. Haematol. Int. 3, 27Æ32. Dodds, W.J. (1980) Hemostasis and coagulation. pp , Academic Press, New York. Elcüman, E.A. and Akay, M.T. (1998) Age-Dependent Immunolocalization of Fibronectin and Histological Changes in the Thymus of Rats. Vet. Res. Comm. 22(8), Elmore, S.A. (2006) Enhanced Histopathology of the Thymus. Toxicol. Pathol. 34(5),

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