Lab. Anim. Res. 2010: 26(2), 153-164 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 2008. 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. 2000-63 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 449-826, Korea Tel: +82-31-329-9977 Fax: +82-31-329-9901 E-mail: 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 2005-60y, 2005) x» ( t t š 2005-79y, 2005) w ww. w, x ( ) f x ³ w w. 153
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 157.46-202.88 g, f 123.08-164.49 g, 13 x n f 162.37-213.81 g, f 125.57-163.59 g. m 23±3 o C, 55±15%, y»z 10-20z/hr, 12», 150-300 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.
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 19. 16 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.
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 19.86-22.09 g, f 13.67-15.41 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. 4 13 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 25.68-29.18 g, f 20.27-25.17 g ùkü. á Table 2 ùkü. 4 13 x, 4 x fm,, x, 13 x fm,, x, x, phƒ m w w ù kü (P<0.01). 4 13 x, f, x ph, f fm m w w ùkü (P<0.01). l j á x w Table 3 ùkü. 4 13 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). 4 13 x x w, f RBC, hemoglobin, hematocrit, MCV, MCH,
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 0 56 60 58 63 100 (Trace) 1 4 0 7 2 Negative 0 55 59 64 65 Small 1 5 1 1 0 Negative 0 29 47 43 65 5 (Trace) 1 23 12 17 0 15 2 7 1 5 0 40 3 1 0* 0 0 #$ 1.005 0 0 3 6 15 1.0100 1 6 3 9 11 1.0150 2 2 9 18 12 1.0200 3 10 8 15 18 1.0250 4 12 15 11 8 1.030 5 30 22 6* 1 $ 5.5 0 0 2 0 0 6.0 1 0 8 0 0 6.5 2 2 4 0 1 7.0 3 9 3 0 7 7.5 4 11 13 5 13 8.0 5 26 20 43 33 8.5 6 12 9 15 11 9.0 7 0 1 2* 0 # Negative 0 3 26 0 37 15 (Trace) 1 4 5 2 8 30 2 10 10 7 9 100 3 25 7 34 9 300 4 18 12* 22 2 # 0.1 0 60 60 65 65 Negative 0 58 60 65 65 Positive 1 2 0 0 0 Negative 0 53 54 29 60 Trace 1 2 4 14 3 Small 2 5 1 21 1 Moderate 3 0 0 1 0 Large 4 0 1 0* 1 # Negative 0 9 41 3 33 Trace 1 5 14 3 18 Small 2 22 4 26 10 Moderate 3 22 1 29 4 Large 4 2 0* 4 0 # Number of animals 60 65 60 65 *: 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. 4 13 x x yw, 4 x ALT, ALP, TB, TP, A/G ratio, glucose, TC, triglyceride, BUN, IP, Ca ++, Na +, K +
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) 105 7.97±0.43 6.7-9.0 129 8.79±0.39* 7.8-9.9 Hemoglobin (g/dl) 105 15.29±0.82 13.6-17.7 129 15.69±0.65* 13.9-17.3 Hematocrit (%) 105 44.95±3.44 37.9-52.2 129 46.19±3.53* 38.9-55.2 MCV (fl) 105 56.34±2.58 51.8-63.6 129 52.51±2.99* 46.5-60.0 MCH (pg) 105 19.18±0.59 17.9-20.9 129 17.85±0.64* 16.3-20.2 MCHC (g/dl) 105 34.09±1.39 30.6-36.8 129 34.10±2.15 29.4-38.3 RDW (%) 70 11.90±2.29 9.7-16.5 79 12.07±0.35 11.4-13.0 HDW (g/dl) 50 2.32±0.13 2.0-2.6 79 2.35±0.18 1.8-2.8 WBC (10 3 /µl) 105 10.35±2.45 4.9-16.3 129 9.19±2.35* 4.8-20.1 Neutrophil (%) 105 11.48±3.71 4.7-23.3 129 21.85±8.60* 8.1-44.6 Lymphocyte (%) 105 82.69±4.42 71.1-89.4 129 71.57±8.97* 44.8-86.5 Monocyte (%) 105 2.94±1.29 0.2-8.0 129 3.49±1.46* 0.21-10.0 Eosinophil (%) 105 0.82±0.35 0.2-2.2 129 1.33±0.50* 0.30-3.25 Basophil (%) 105 1.59±1.40 0.1-5.1 129 1.16±1.32 0.0-5.0 LUC (%) 50 1.01±0.33 0.5-1.9 79 0.96±0.44 0.3-2.3 Platelet (10 3 /µl) 105 1050.77±179.18 784-1500 129 971.45±126.77* 735-1418 MPV (fl) 70 6.12±0.98 5.2-12.2 70 6.28±0.86 5.0-8.5 PT (sec) 30 10.75±3.04 7.6-15.5 128 13.38±3.63* 8.1-18.3 APTT (sec) 30 16.52±2.20 7.9-20.1 128 18.19±1.27* 15.2-20.9 Females RBC (10 6 /µl) 104 7.72±0.45* 6.7-9.8 129 7.79±0.43 # 6.69-8.92 Hemoglobin (g/ dl) 104 14.66±0.83* 12.5-17.8 129 14.59±0.65 # 13.1-17.0 Hematocrit (%) 104 42.50±2.91* 35.5-54.4 129 42.60±3.26 # 36.9-51.8 MCV (fl) 104 55.06±2.34* 51.4-63.1 129 54.66±3.06 # 48.4-63.8 MCH (pg) 104 19.01±0.72 17.3-21.3 129 18.76±0.82 # 16.7-21.8 MCHC (g/dl) 104 34.58±1.22* 30.7-37.1 129 34.38±2.09 30.1-39.7 RDW (%) 70 11.30±2.05 9.4-15.2 79 10.98±0.43 # 10.0-12.2 HDW (g/dl) 50 2.26±0.16 1.8-2.6 79 2.25±0.20 # 1.8-2.7 WBC (10 3 /µl) 104 6.47±1.93* 3.0-12.0 129 5.55±1.78 #$ 3.0-14.3 Neutrophil (%) 104 12.11±5.96 4.9-54.1 129 14.62±6.69 #$ 4.9-58.1 Lymphocyte (%) 104 81.94±6.74 33.3-91.5 129 79.02±6.85 #$ 37.6-89.7 Monocyte (%) 104 2.84±1.29 0.1-7.5 129 2.94±1.03 #$ 0.8-6.1 Eosinophil (%) 104 1.20±0.49* 0.5-3.5 129 1.83±1.14 #$ 0.3-10.0 Basophil (%) 104 1.50±1.44 0.0-5.2 129 0.99±1.13 $ 0.0-3.5 LUC (%) 50 0.92±0.34 0.4-1.8 79 0.96±0.49 0.4-2.5 Platelet (10 3 /µl) 104 1088.21±137.58 815-1397 129 1015.43±140.67 #$ 674-1373 MPV (fl) 70 6.13±1.01 5.1-8.1 70 6.52±1.13 5.2-10.2 PT (sec) 29 10.95±3.79 7.3-17.0 128 13.49±4.12 $ 7.7-19.5 APTT (sec) 29 15.51±2.32 10.5-19.5 128 17.18±1.51 #$ 13.8-21.0 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). 4 13 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)
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) 105 98.25±25.95 63.9-228.8 129 101.09±22.10 64.1-168.1 ALT (IU/L) 105 39.81±9.33 26.5-101.4 129 45.50±9.19* 30.8-73.4 ALP (IU/L) 105 149.27±30.47 91.0-250.1 129 91.64±19.92* 58.4-180.4 TB (mg/dl) 70 0.18±0.03 0.14-0.28 129 0.20±0.03 0.07-0.29 Glucose (mg/dl) 105 127.94±17.92 86.9-209.2 129 131.02±15.56 95.4-188.4 TC (mg/dl) 105 95.55±17.15 44.0-139.0 129 108.65±18.72* 72.0-206.0 Triglyceride (mg/dl) 105 47.40±13.56 11.3-85.0 129 50.20±14.71 23.0-110.6 TP (g/dl) 70 6.00±0.24 5.22-6.71 129 6.50±0.52* 5.68-9.25 Albumin (g/dl) 105 3.25±0.23 2.69-3.86 129 3.15±0.21* 2.83-4.05 A/G ratio 105 1.19±0.18 0.93-1.72 129 0.95±0.07* 0.73-1.15 CPK (IU/L) 50 280.93±164.38 88.0-909.2 129 238.28±131.30 48.0-715.3 BUN (mg/dl) 105 17.35±2.51 11.8-25.4 129 16.97±2.78 12.1-26.1 Creatinine (mg/dl) 105 0.49±0.04 0.36-0.60 129 0.55±0.07* 0.25-0.83 IP (mg/dl) 105 8.78±0.70 7.5-10.8 129 7.36±1.09* 5.6-10.3 Ca ++ (mg/dl) 105 10.05±0.45 9.0-11.3 129 9.85±1.26 5.8-14.2 Na + (mmol/l) 94 144.24±1.57 141.0-149.0 129 144.19±3.56 129.0-155.0 K + (mmol/l) 94 4.70±0.36 3.81-6.48 129 4.51±0.38* 3.96-7.87 Cl - (mmol/l) 94 107.51±1.44 103.0-110.0 129 107.57±2.59 97.0-116.0 Females AST (IU/L) 105 96.19±17.98 67.3-166.0 129 100.02±20.65 67.5-179.9 ALT (IU/L) 105 31.57±4.94* 19.2-48.7 129 33.43±5.13 #$ 22.4-47.1 ALP (IU/L) 105 103.43±26.47* 59.0-196.0 129 63.81±17.71 #$ 30.1-116.0 TB (mg/dl) 70 0.21±0.07* 0.12-0.84 129 0.22±0.04 # 0.15-0.35 Glucose (mg/dl) 105 110.25±11.26* 84.3-142.4 129 110.42±12.24 # 80.5-149.4 TC (mg/dl) 105 87.19±16.76* 32.2-126.0 129 102.82±20.84 $ 51.0-155.0 Triglyceride (mg/dl) 105 33.36±11.36* 4.9-63.0 129 37.95±7.92 #$ 20.2-58.0 TP (g/dl) 70 5.83±0.30* 4.97-7.30 129 6.20±0.33 #$ 5.35-7.06 Albumin (g/dl) 105 3.28±0.28 2.69-4.27 129 3.21±0.18 2.73-3.68 A/G ratio 105 1.31±0.24* 0.96-1.97 129 1.08±0.08 #$ 0.92-1.32 CPK (IU/L) 50 259.48±156.59 49.0-782.0 129 264.90±185.99 44.0-1316.6 BUN (mg/dl) 105 18.99±3.08* 11.7-28.4 129 17.99±2.59 #$ 11.7-26.4 Creatinine (mg/dl) 105 0.51±0.07 0.29-0.63 129 0.61±0.07 #$ 0.35-0.79 IP (mg/dl) 105 7.95±0.78* 6.2-10.0 129 6.67±1.27 #$ 4.1-10.4 Ca ++ (mg/dl) 105 9.68±0.51* 7.8-11.1 129 9.52±1.00 4.6-11.0 Na + (mmol/l) 95 143.26±1.83* 139.0-148.0 128 144.08±2.66 $ 134.0-154.0 K + (mmol/l) 95 4.53±0.31* 3.97-5.70 128 4.27±0.46 #$ 3.59-7.89 Cl - (mmol/l) 95 108.29±1.85* 104.0-113.0 128 109.09±2.39 #$ 101.0-116.0 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. 4 13 x», 4 x,, ƒ,, s,,, w, 13 x,, w,, ƒ,, s,, ùkü. 4 13 x», f, ƒ,, s,,,,, š y šy, f, w, ƒ,, s,,,, ª ù ùkü. x x w š 4 13 n x ³
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) 105 312.21±23.740 267.13-399.36 129 435.09±30.590 326.71-508.72 Brain (g) 75 1.8405±0.0854 1.6717-2.0621 129 1.9855±0.1440 1.7500-3.3610 (%) 75 0.5854±0.0393 0.5118-0.6829 129 0.4582±0.0443 0.3979-0.8360 Pituitary gland (g) 70 0.0119±0.0117 0.0082-0.1080 129 0.0122±0.0017 0.0084-0.0212 (%) 70 0.0038±0.0038 0.0021-0.0345 129 0.0028±0.0004 0.0018-0.0049 Thyroid gland-left+right (g) 40 0.0164±0.0032 0.0092-0.0224 50 0.0191±0.0066 0.0121-0.0497 (%) 40 0.0052±0.0009 0.0034-0.0074 50 0.0045±0.0015 0.0028-0.0083 Thyroid gland-left (g) 40 0.0081±0.0020 0.0051-0.0131 50 0.0098±0.0059 0.0050-0.0379 (%) 40 0.0026±0.0006 0.0018-0.0042 50 0.0023±0.0013 0.0012-0.0083 Thyroid gland-right (g) 40 0.0083±0.0020 0.0035-0.0128 50 0.0093±0.0019 0.0061-0.0149 (%) 40 0.0026±0.0005 0.0013-0.0041 50 0.0022±0.0005 0.0014-0.0034 Heart (g) 105 1.1035±0.1144 0.9046-1.8449 129 1.3930±0.1128 1.0750-1.6520 (%) 105 0.3537±0.0278 0.2976-0.5414 129 0.3206±0.0210 0.2739-0.3729 Lung (g) 105 1.4373±0.1210 1.1755-1.7220 129 1.7809±0.1970 1.4345-3.1306 (%) 105 0.4614±0.0352 0.3701-0.5612 129 0.4099±0.0401 0.3341-0.6859 Thymus (g) 105 0.4884±0.0961 0.3430-1.0030 129 0.2908±0.0582 0.0330-0.4990 (%) 105 0.1564±0.0265 0.1021-0.2512 129 0.0670±0.0137 0.0088-0.1110 Spleen (g) 105 0.7227±0.0906 0.4866-1.0124 129 0.8068±0.1238 0.5252-1.4780 (%) 105 0.2317±0.0249 0.1822-0.3250 129 0.1856±0.0271 0.1239-0.3536 Liver (g) 105 9.2262±0.9352 7.1168-12.2383 129 10.8939±1.0637 8.1270-13.433 (%) 105 2.9542±0.1853 2.5341-3.4428 129 2.5025±0.1520 2.1591-2.9796 Kidney-left+right (g) 105 2.1533±0.2037 1.6745-2.6934 129 2.5850±0.2403 1.9486-3.1480 (%) 105 0.6899±0.0441 0.6137-0.8163 129 0.5946±0.0429 0.4971-0.7199 Kidney-left (g) 105 1.0696±0.1025 0.8109-1.3637 129 1.2844±0.1189 0.9572-1.5370 (%) 105 0.3427±0.0223 0.3036-0.4035 129 0.2955±0.0220 0.2464-0.3553 Kidney-right (g) 105 1.0837±0.1065 0.8476-1.3865 129 1.3006±0.1289 0.9590-1.6320 (%) 105 0.3472±0.0242 0.3001-0.4128 129 0.2991±0.0231 0.2102-0.3646 Adrenal gland-left+right (g) 105 0.0501±0.0063 0.0296-0.0703 129 0.0534±0.0074 0.0383-0.0825 (%) 105 0.0161±0.0020 0.0107-0.0223 129 0.0123±0.0017 0.0094-0.0186 Adrenal gland-left (g) 105 0.0255±0.0033 0.0174-0.0360 129 0.0271±0.0040 0.0183-0.0400 (%) 105 0.0082±0.0011 0.0060-0.0114 129 0.0063±0.0009 0.0041-0.0090 Adrenal gland-right (g) 105 0.0246±0.0034 0.0218-0.0255 129 0.0262±0.0039 0.0187-0.0425 (%) 105 0.0079±0.0011 0.0044-0.0109 129 0.0060±0.0009 0.0045-0.0096 Testis-left+right (g) 55 3.6020±0.2814 2.7044-4.2000 129 4.0187±0.2417 3.5420-4.6611 (%) 55 1.1596±0.1198 0.7640-1.3940 129 0.9266±0.0666 0.7710-1.1236 Testis-left (g) 55 1.8053±0.1509 1.0359-2.1050 129 2.0051±0.1173 1.7740-2.3020 (%) 55 0.5814±0.0641 0.3200-0.7025 129 0.4624±0.0328 0.3871-0.5669 Testis-right (g) 55 1.7966±0.1600 0.8609-2.1010 129 2.0136±0.1316 1.7440-2.3652 (%) 55 0.5782±0.0637 0.3009-0.6915 129 0.4643±0.0352 0.3809-0.5678 Epididymis-left+right (g) 54 0.9270±0.0556 0.7855-1.0796 109 1.3653±0.0998 1.1470-1.8270 (%) 54 0.2987±0.0252 0.2428-0.3587 109 0.3136±0.0263 0.2628-0.4154 Epididymis-left (g) 54 0.4613±0.0312 0.3825-0.5567 109 0.6790±0.0509 0.5767-0.9000 (%) 54 0.1487±0.0140 0.1182-0.1850 109 0.1559±0.0135 0.1300-0.2046 Epididymis-right (g) 55 0.4665±0.0303 0.3990-0.5401 109 0.6863±0.0574 0.5530-0.9270 (%) 55 0.1503±0.0126 0.1211-0.1745 109 0.1576±0.0145 0.1276-0.2108 Prostate (g) 95 0.4094±0.0959 0.1946-0.6760 129 0.5704±0.1438 0.1380-0.9310 (%) 95 0.1313±0.0316 0.0639-0.2131 129 0.1312±0.0320 0.0285-0.2087 a)the body weights were measured right before necropsy after overnight fasting.
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) 105 198.33±17.060 155.16-246.76 130 249.12±19.920 199.47-330.00 Brain (g) 75 1.6986±0.0915 1.3810-1.9511 130 1.7976±0.0804 1.4667-2.1750 (%) 75 0.8553±0.0661 0.7077-1.0348 130 0.7254±0.0576 0.5433-0.8858 Pituitary gland (g) 70 0.0117±0.0019 0.0077-0.0167 130 0.0132±0.0021 0.0092-0.0291 (%) 70 0.0059±0.0009 0.0042-0.0082 130 0.0053±0.0007 0.0037-0.0100 Thyroid gland-left+right (g) 40 0.0146±0.0037 0.0086-0.0261 50 0.0156±0.0024 0.0101-0.0242 (%) 40 0.0073±0.0022 0.0045-0.0155 50 0.0063±0.0011 0.0045-0.0102 Thyroid gland-left (g) 40 0.0072±0.0020 0.0038-0.0127 50 0.0078±0.0015 0.0041-0.0122 (%) 40 0.0036±0.0012 0.0020-0.0073 50 0.0032±0.0007 0.0018-0.0051 Thyroid gland-right (g) 40 0.0074±0.0021 0.0044-0.0138 50 0.0078±0.0016 0.0038-0.0120 (%) 40 0.0037±0.0011 0.0021-0.0082 50 0.0032±0.0006 0.0015-0.0051 Heart (g) 105 0.7762±0.0831 0.6176-1.1928 130 0.8823±0.0732 0.7267-1.1060 (%) 105 0.3919±0.0314 0.3310-0.5352 130 0.3550±0.0257 0.2747-0.4444 Lung (g) 105 1.1598±0.1130 0.8950-1.7510 130 1.3569±0.1121 1.1050-1.6790 (%) 105 0.5866±0.0520 0.4514-0.7679 130 0.5459±0.0390 0.4587-0.6645 Thymus (g) 105 0.3362±0.0718 0.1870-0.6166 130 0.2277±0.1187 0.1330-1.4640 (%) 105 0.1691±0.0296 0.0932-0.2569 130 0.0915±0.0467 0.0530-0.5810 Spleen (g) 105 0.5453±0.0798 0.3912-0.8468 130 0.5871±0.0755 0.3990-0.8500 (%) 105 0.2750±0.0318 0.1971-0.3799 130 0.2357±0.0243 0.1797-0.3049 Liver (g) 105 5.5126±0.6933 4.1260-7.6414 130 5.9782±0.6327 4.6418-7.6460 (%) 105 2.7742±0.1762 2.4255-3.4580 130 2.4016±0.1924 2.0235-3.0236 Kidney-left+right (g) 105 1.3841±0.1490 1.1390-1.9965 130 1.4808±0.1226 1.1870-1.8560 (%) 105 0.6983±0.0467 0.5854-0.8488 130 0.5953±0.0357 0.4919-0.6853 Kidney-left (g) 105 0.6844±0.0726 0.5610-0.9770 130 0.7396±0.0694 0.5900-1.0760 (%) 105 0.3453±0.0234 0.2844-0.4096 130 0.2972±0.0202 0.2335-0.3493 Kidney-right (g) 105 0.6997±0.0802 0.5700-1.0195 130 0.7413±0.0618 0.5880-0.9040 (%) 105 0.3530±0.0263 0.2991-0.4392 130 0.2981±0.0197 0.2532-0.3446 Adrenal gland-left+rigt (g) 105 0.0623±0.0068 0.0490-0.0866 130 0.0600±0.0077 0.0418-0.0881 (%) 105 0.0316±0.0036 0.0117-0.0216 130 0.0241±0.0028 0.0165-0.0308 Adrenal gland-left (g) 105 0.0316±0.0037 0.0230-0.0465 130 0.0309±0.0048 0.0202-0.0511 (%) 105 0.0160±0.0019 0.0117-0.0216 130 0.0124±0.0017 0.0080-0.0176 Adrenal gland-right (g) 105 0.0307±0.0035 0.0232-0.0401 130 0.0291±0.0036 0.0208-0.0372 (%) 105 0.0155±0.0018 0.0107-0.0204 130 0.0117±0.0014 0.0085-0.0146 Ovary-left+right (g) 105 0.0895±0.0147 0.0578-0.1278 130 0.0888±0.0172 0.0526-0.1511 (%) 105 0.0452±0.0068 0.0305-0.0655 130 0.0356±0.0061 0.0208-0.0556 Ovary-left (g) 105 0.0451±0.0090 0.0262-0.0693 130 0.0443±0.0099 0.0214-0.0725 (%) 105 0.0228±0.0044 0.0139-0.0335 130 0.0178±0.0036 0.0080-0.0305 Ovary-right (g) 105 0.0444±0.0078 0.0284-0.0661 130 0.0444±0.0095 0.0259-0.0820 (%) 105 0.0224±0.0035 0.0143-0.0320 130 0.0178±0.0035 0.0102-0.0266 Uterus (g) 80 0.5025±0.2344 0.2140-1.4945 90 0.6348±0.3087 0.3250-1.6083 (%) 80 0.2524±0.1166 0.1135-0.7970 90 0.2573±0.1308 0.1226-0.6888 a) The body weights were measured right before necropsy after overnight fasting. n w» ww. 4 13 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,
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,
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), 4-10. 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), 457-66. 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), 379-385. 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, 1979-1987. 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, 53-60. Bauck, L. and Stefkovic, G. (1986) Searching the records for clues about kidney disease in guineapigs. Vet. Med. 81, 1127 1130. Baylis, C. (2005) Changes in renal hemodynamics and structure in the aging kidney; sexual dimorphism and the nitric oxide system. Exp. Gerontol. 40(4), 271 278. 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), 277-302. 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. 671-718, 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), 525-532. Elmore, S.A. (2006) Enhanced Histopathology of the Thymus. Toxicol. Pathol. 34(5), 656-665.
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