272

Q Q Vol. 49, No. 4

QQQ
Q Q

QQ

F344
Q 19 Q 12
14 QQ

104 Q QQQ
QQ Q QQ Q Q Q Q Q Q QQ Q

QQQ Q

QQQ Q

A 104-Week Feeding Study of Genetically Modied Soybeans in F344 Rats

Yoshimitsu S6@6BDID , Yukie T696, Nobutaka FJ@JBDG>, Kuniaki T6N6B6, Hiroshi AC9D, Hiroshi T6@6=6H=>, Yoshikazu KJ7D, Akemichi N6<6H6L6, Norio Y6CD, Katsuhiro YJO6L6 and Akio O<6I6 Department of Environmental Health and Toxicology, Tokyo Metropolitan Institute of Public Health: 3 24 1 Hyakunin-cho, Shinjuku-ku, Tokyo 169 0073, Japan; Corresponding auther A chronic feeding study to evaluate the safety of genetically modied glyphosate-tolerant soybeans (GM soybeans) was conducted using F344 DuCrj rats. The rats were fed diet containing GM soybeans or Non-GM soybeans at the concentration of 30 in basal diet. Non-GM soybeans were a closely related strain to the GM soybeans. These two diets werre adjusted to an identical nutrient level. In this study, the inuence of GM soybeans in rats was compared with that of the Non-GM soybeans, and furthermore, to assess the e#ect of soybeans themselves, the groups of rats fed GM and Non-GM soybeans were compared with a group fed commercial diet (CE-2). General conditions were observed daily and body weight and food consumption were recorded. At the termination (104 weeks), animals were subjected to hematology, serum biochemistry, and pathological examinations. There were several di#erences in animal growth, food intake, organ weights and histological ndings between the rats fed the GM and/or Non-GM soybeans and the rats fed CE-2. However, body weight and food intake were similar for the rats fed the GM and Non-GM soybeans. Gross necropsy ndings, hematological and serum biochemical parameters, and organ weights showed no meaningful di#erence between rats fed the GM and Non-GM soybeans. In pathological observation, there was neither an increase in incidence nor any specic type of nonneoplastic or neoplastic lesions in the GM soybeans group in each sex. These results indicate that long-term intake of GM soybeans at the level of 30 in diet has no apparent adverse e#ect in rats. (Received December 14, 2007) rat; QQQ Key words: QQ genetically modied soybean; 104 Q QQQ week feeding study; QQQ toxicity test 104-

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274 Table 1.

Vol. 49, No. 4 Final body weights, food intake, soybean intake and survival rate of F344 rats fed diet containing GM and Non-GM soybeans for 104 weeks Final body weight Group g Male GM Non-GM CE-2 Female GM Non-GM CE-2
a) #

Food intake g/rat/day 12.6 12.6 13.2 0.7 0.6 0.8

Soybean intake g/kgBW/day 11.4 11.7 1.7 1.9

Survival rate

267 30a) 353 35 342 37 237 232 238 21 22 23

76 73 80 80 70 74

9.1 1.4# 8.7 1.0# 10.5 0.9

14.6 14.3

1.2 1.4

Values are mean SD. : Signicantly di#erent from CE-2 group, p 0.05

Fig. 3.

Food intake curves of male and female F344 rats fed diet containing GM and Non-GM soybeans for 104 weeks (n 10)

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Fig. 2. Growth curves of male and female F344 rats fed diet containing GM and No-GM soybeans for 104 weeks Initial number of rats; GM, Non-GM; n 2; n 35 50, CE-

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August 2008 Table 2.

Q Q

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104 Q QQ

275

Hematological data of male and female F344 rat fed diet containing GM and Non-GM soybeans for 104 weeks GM 103/mL 106/mL g/dL pg g/dL 103/mL 103/mL 106/mL g/dL pg g/dL 103/mL (27)a) 6.59 1.69b) 9.3 0.88 14.43 1.94# 45.08 4.58# 48.53 2.60 15.52 1.33 31.93 1.52 760 143 (29) 3.34 0.98 8.38 0.66 14.67 1.52 44.21 3.63 52.77 1.83 17.48 1.09 33.12 1.28 554 119 Non-GM (25) 6.76 1.43 9.42 0.83 14.93 1.47 45.62 3.55 48.52 2.32 15.83 1.10 32.67 1.17 763 143 (32) 3.52 1.10 8.71 0.35 15.29 0.42 45.98 1.71 52.79 0.83 17.56 0.45 33.26 0.74 593 54 CE-2 (15) 5.67 1.04 9.83 0.67 15.89 0.73 48.69 2.13 49.63 1.75 16.21 0.72 32.63 0.65 651 69 (11) 3.65 1.92 8.78 0.60 15.09 1.17 46.20 2.04 52.71 2.10 17.20 0.82 32.62 1.26 526 84

Parameter Male WBC RBC Hgb Hct MCV MCH MCHC PLT Female WBC RBC Hgb Hct MCV MCH MCHC PLT
a)

Number of rats examined. b)Values are mean SD. : Signicantly di#erent from Non-GM, p 0.05 # : Signicantly di#erent from CE-2, p 0.05 Table 3. Biochemical data of male and female F344 rats fed diet containing GM and Non-GM soybeans for 104 weeks GM g/dL IU/L mg/dL mg/dL U/L U/L g/dL g/dL IU/L mg/dL mg/dL U/L U/L g/dL (33)a) 2.34 0.18b) 322 71 134 27 0.54 0.04# 107 22 49.9 19.8# 6.59 0.36 (33) 2.71 0.25 261 69 123 23 0.57 0.04 116 31 45.0 11.3# 6.81 0.53 Non-GM (32) 2.37 0.19 318 61 128 26 0.54 0.05# 103 19 50.7 16.9# 6.71 0.37 (33) 2.65 0.22 282 106 121 17 0.56 0.05 101 21.0 42.9 10.2# 6.71 0.36 CE-2 (11) 2.38 0.17 374 80 136 40 0.49 0.04 117 33 68.6 23.6 6.73 0.37 (9) 2.54 0.23 298 43 112 22 0.58 0.05 120 26 70 16 6.53 0.35

Parameter Male ALB ALP TCHO CRE AST ALT TP Female ALB ALP TCHO CRE AST ALT TP
a) #

Number of rats examined. b)Values are mean SD. : Signicantly di#erent from CE-2, p 0.05

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276 Table 4. Organ GM Body weight g 368 30a) Absolute weight Brain mg 2,154 46 Heart mg 1,043 133 Lungs mg 1,145 113 Liver g 9.97 1.05 Kidneys mg 2,176 121# Spleen mg 690 117 Testes mg 3,011 536# Adrenals mg 42.0 5.3 Relative weight (weight/100 g body weight) Brain mg 589 49 Heart mg 285 43 lungs mg 313 36 Liver g 2.71 0.21# Kidneys mg 594 49# Spleen mg 207 99 Testes mg 823 159 Adrenals mg 11.4 1.7
a) #

Vol. 49, No. 4

Organ weights of male F344 rats fed diet containing GM and Non-GM soybeans for 104 weeks Group Non-GM (38)b) (38) (38) (38) (38) (38) (37) (38) (37) 353 2,121 990 1,084 9.56 2,187 622 3,071 42.1 606 282 309 2.71 624 177 878 12.0 35 65 77 74 1.11 127# 98 307# 5.4 62 22 32 0.20# 70# 32 109 2.0 (34) (34) (34) (34) (34) (34) (33) (33) (33) 343 2,092 964 1,065 10.05 2,337 691 2,551 44.6 CE-2 37 59 76 84 1.63 204 133 609 5.5 (28) (28) (28) (28) (28) (28) (28) (20) (27)

617 63 283 22 314 39 2.93 0.31 685 48 212 70 759 161 13.2 1.8

Values are mean SD. b) Number of rats examined. : Signicantly di#erent from CE-2 group, p 0.05 Table 5. Organ GM Non-GM (39)b) (39) (39) (39) (39) (39) (39) (39) (32) (38) 232 1,966 675 794 6.70 1,492 439 62.8 707 39.9 852 292 343 2.90 646 190 27.2 308 17.3 19 60 52 101 0.55# 94# 112 12.3 118# 2.6# 74 20 36 0.22# 52# 50 5.7 66 1.6# (34) (34) (34) (34) (34) (34) (34) (34) (33) (34) 238 1,937 714 804 7.42 1697 505 61.4 823 53.47 CE-2 23 37 56 50 0.75 95 162 11.6 197 5.48 (26) (26) (26) (26) (26) (26) (26) (25) (20) (26) Organ weights of female rats fed diet containing GM and Non-GM soybeans for 104 weeks Group

Body weight g 237 21a) Absolute weight Brain mg 1,969 36 Heart mg 714 68 Lungs mg 824 99 Liver g 6.84 0.79# Kidneys mg 1,543 127# Spleen mg 459 103 Ovaries mg 63.5 16.5 Uterus mg 711 120# Adrenals mg 43.5 4.2# Relative weight (weight/100 g body weight) Brain mg 838 82 Heart mg 302 29 Lungs mg 350 52 Liver g 2.89 0.26# Kidneys mg 624 58# Spleen mg 194 43 Ovaries mg 27.5 5.0 Uterus mg 296 50# Adrenals mg 18.7 2.6#
a) #

820 74 302 30 340 35 3.12 0.28 720 63 212 61 26.0 4.6 358 107 22.5 2.8

Values are mean SD. b) Number of rats examined. : Signicantly di#erent from CE-2, p 0.05

Q QQQQ Q Q Q Q Q Q

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Q QQQ Q QQQ

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(Table 6)

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August 2008 Table 6.

104 Nonneoplastic lesions in male and female F344 rats fed diets containing GM soybeans for 104 weeks Male/Group Female/Group CE-2 35 28 28 GM 49 39 39 Non-GM 50 35 35

277

Number of rats initially useda) Number of surviving rats at termination of study Number of rats examined microscopicallyb) Organs Liver Lesions Bile duct, proliferation brosis cyctic dilatation Altered cell foci, basophilic clear cell eosinophilic mixed Necrosis, focal Vacuolation, zonal focal Spongiosis Microgranuloma

GM 50 38 38

Non-GM 48 35 35

CE-2 35 26 26

38c) (100)d) 38 (100) 15 (35)# 38 (100) 27 (71) 7 (18) 25 (66)# 4 (11) 18 (47)# 6 (16) 11 (29)# 4 (11)#

35 35 15 35 27 11 15 3 16 3 5 4

(100) (100) (43)# (100) (77) (31) (43)# (9) (46)# (9) (14) (11)#

28 28 4 28 14 12 7 5 4 3 2 24

(100) (100) (14) (100) (50) (43) (25) (18) (14) (11) (7) (86)

33 20 3 39 13 6 10 6 8 5 2 7

(85)# (51)# (8) (100) (33) (15) (26)# (15) (21) (13) (5) (18)#

28 12 2 34 14 8 7 6 6 5 1 7

(80)# 7 (27) (34)# 1 (4) (6) 0 (0) (97) 26 (100) (40) 5 (19) (23) 1 (4) # (20) 0 (0) (17) 4 (15) (17) 3 (12) (14) 6 (23) (3) 1 (4) (20)# 26 (100)

Kidney Heart Lung

Nephropathy 21 (55) Calcication, cortico-medullary junction 0 (0) Myocardial inammation Myocardial brosis Calcication, vascular intima Inammation, focal, chronic Foamy cell aggregation, focal Hyperplasia, alveolar epithelium Cyst, anterior lobe Angiectasis, anterior lobe Cyst, Rathkes cleft Hyperplasia, anterior lobe C-cell, hyperplasia Ultimobranchial body Hyperplasia Cortex, vacuolation, focal, hyperplasia, focal accessory adrenal nodule Medulla, hyperplasia Pigmentation, hemosiderin Extramedullary hematopoiesis Congestion Atrophy Hyperplasia, stromal cell Atrophy, acinar cell, lobular Hypertrophy, acinar cell, focal Hyperplasia, acinar cell Hyperplasia, islet cell Hypertrophy, acinar cell, focal Atrophy, acinar cell, focal Atrophy, seminiferous tubules Interstitial cell hyperplasia Inammation, suppurative Inammation, chronic Hyperplasia Ectasia Adenosis (hyperplasia) Inammation, suppurative Inammation, chronic Hyperplasia Hyperplasia Cystic change 28 (74) 8 (21) 33 1 1 4 8 6 2 10 (87) (3) (3) (11) (21) (16) (5) (26)

18 (51) 2 (6) 21 (60) 6 (17) 31 2 3 6 13 3 1 7 (89) (6) (9) (17) (37) (9) (3) (20)

21 (75) 0 (0) 21 (75) 5 (18) 23 3 0 2 6 5 2 9 (82) (11) (0) (7) (21) (18) (7) (32)

8 (21)# 11 (28)# 30 (77) 10 (26) 20 1 0 2 21 5 16 10 (51) (3) (0) (5) (54) (13) (41) (26)

5 (14)# 11 (42) 8 (23)# 23 (88) 20 (57) 12 (34) 20 (57) 2 (6) 1 (3) 5 (14) 16 5 10 8 (46) (14) (29) (23) 21 (81) 11 (42) 18 0 0 1 15 7 6 5 (69) (0) (0) (4) (58) (27) (23) (19)

Pituitary

Thyroid gland Parathyroid gland Adrenal gland

11 (29) 0 (0) 0 (0) 7 2 3 2 (18) (5) (8) (5)

11 (31) 1 (3) 0 (0) 4 2 2 5 (11) (6) (6) (14)

5 (18) 1 (4) 2 (7) 7 1 8 2 (25) (4) (29) (7)

10 (26) 0 (0) 2 (5) 7 2 4 2 (18) (5) (10) (5)

8 (23) 1 (3) 1 (3) 7 2 6 2 (20) (6) (17) (6)

10 (38) 0 (0) 1 (4) 5 1 4 3 (19) (4) (15) (12)

Spleen

0 (0) 2 (5) 2 (5) 0 (0)# 2 (5) 7 1 9 0 (18)# (3) (24)# (0)

0 (0) 2 (6) 4 (11) 0 (0)# 1 (3) 10 2 6 0 (29)# (6) (17)# (0)

0 (0) 2 (7) 1 (4) 5 (18) 1 (4) 16 3 1 4 (57) (11) (4) (14)

2 (5) 2 (5) 3 (8) 6 (16) 5 (13) 3 2 0 1 (8)# (5) (0) (3)

0 (0) 0 (0) 1 (3) 4 (11) 3 (9) 2 3 0 2 (6)# (9) (0) (6)

0 (0) 3 (12) 0 (0) 5 (19) 5 (19) 7 3 2 1 (27) (12) (8) (4)

Bone marrow Pancreas

Parotid gland Testes Prostate

2 (5)# 3 (8) 12 (32) 16 (42) 1 (3) 0 (0) 6 (16) 3 (8) 0 (0) 2 (5) 30 (79) 1 (3)

1 (3)# 1 (3) 7 (20) 15 (43) 1 (3) 1 (3) 6 (17) 4 (11) 0 (0) 3 (9) 28 (80) 0 (0)

8 (29) 3 (11) 11 (39) 17 (61) 1 (4) 0 (0) 10 (36) 1 (4) 1 (4) 2 (7) 22 (79) 0 (0)

4 (10) 2 (5)

2 (6) 6 (17)

5 (19) 3 (12)

Mammary gland Preputial/Clitral gland

3 (8) 6 (15) 0 (0) 3 (8) 1 (3) 2 (5) 3 (8)

1 (3) 3 (9) 0 (0) 6 (17) 1 (3) 3 (9) 3 (9)

2 (8) 0 (0) 3 (12) 1 (4) 1 (4) 3 (12) 3 (12)

Uterus
a)

Two rats in the male Non-GM group and 1 rat in the female GM group were excluded from the 50 rats initially used in the study because of accidental early deaths. b) Nonneoplastic lesions were observed in the rats alived at the termination of the study. c) Number of rats with lesions. d) Incidence of lesions ( ). #: Signicantly di#erent from CE-2 group, p 0.05

278

Q Q Vol. 49, No. 4

QQQ Q QQ
GM Table 6

QQQ QQ Q QQQQ
Non-GM

Q
11), 12)

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CE-2

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(Table 7

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104 Q QQ

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CE-2

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CE-2 CE-2

Q
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Q Q

Q
(Table 8).

QQQQQ
Table 7.

Q QQQQQ Q Q Q Q

Grade and incidence of bile duct proliferation in F344 rats fed diet containing GM and Non-GM soybeans for 104 weeks Male/Group Female/Group GM 39 Non-GM 35 CE-2 26

QQQQ Q QQ
2)

Q Q QQ Q

Grade

GM 38a)

Non-GM CE-2 35 28

QQ QQQ Q Q Q
(Table 10)

Q QQQQQQ Q Q QQ QQQ QQ
F344

(100)b) (100) (100) (85) (80) (27) 0c) (0)d) 0 (0) 0 (0) 6 (15) 7 (20) 19 (73) 0 (0) 0 (0) 0 (0) 28 (72) 27 (77) 7 (27) 22 (58) 18 (51) 12 (43) 5 (13) 1 (3) 0 (0) 16 (42) 17 (49) 16 (57) 0 (0) 0 (0) 0 (0) Number of rats observed. b)Total incidence of lesion ( ). c) Number of rats with lesion. d)Incidence of lesion with each grade ( ). Grade of lesions: none, slight, moderate, marked Table 8.
a)

QQQ C QQQQ Q
7), 8), 13)

QQ

QQQQQ Q Q Q Q Q QQ Q Q Q

Q Q Q QQ Q Q

Q Q QQQ Q QQQ QQ Q

Nunber of basophilic, clear and eosinophilic altered hepatocellular foci in F344 rats fed diet containing GM and Non-GM soybeans for 104 weeks Group Type of foci GM Non-GM (35) 3.78 1.90# 0.87 0.80 0.21 0.41 (35) 7.56 2.90# 0.31 0.46 0.14 0.29 CE-2 (28) 1.69 1.26 0.71 1.00 0.3 0.42 (26) 3.53 2.77 0.09 0.20 0.02 0.10 (38) 4.21 2.25b) # 1.17 1.09 0.18 0.46 (39) 9.08 3.79# 0.22 0.38 0.08 0.18
a)

Sex

Male

Basophilic cell foci Clear cell foci Eosinophilic foci Basophilic cell foci Clear cell foci Eosinophilic foci

Female

a) #

Number of rats observed. b)Values represent mean : Signicantly di#erent from CE-2, p 0.05

SD (No. of foci/liver section).

Table 9.

Severity and incidence of chronic nephropathy in F344 rats fed diet containing GM and Non-GM soybeans for 104 weeks Male/Group Female/Group CE-2 28 (75) 7 (25) 15 (54) 6 (21) 0 (0) GM 39 (21)# 30 (77) 8 (21) 1 (2) 0 (0) Non-GM 35 (14)# 30 (86) 5 (14) 0 (0) 0 (0) CE-2 26 (42) 15 (58) 10 (38) 1 (4) 0 (0)

Grade

GM 38a) (55)b) 17c) (45)d) 18 (47) 2 (5) 1 (3)

Non-GM 35 (51) 17 (48) 17 (49) 1 (3) 0 (0)

a) Number of rats observed. b) Total incidence of lesion ( ). c) Number of rats with lesion. d) Incidence of lesion with each grade ( ). Grade of lesions: none, slight, moderate, marked # : Signicantly di#erent from CE-2 group, P 0.05.

August 2008 Table 10.

104 Neoplastic lesions in F344 rats fed diet containing GM and Non-GM soybeans for 104 weeks Group/Male Group/Female CE-2 35 28 35 28 GM 49 39 49 35 Non-GM 50 35 50 32

279

Number Number Number Number Organs

of of of of

rats initially used in studya) surviving rats at termination of study rats examined microscopicallyb) rats with tumor Type of tumors Interstitial cell, adenoma Adenoma Carcinoma Granulosa cell tumor Granulosa-theca cell tumor Polyp, endometrial stromal Adenoma, endometrial Carcinoma, endometrial Sarcoma, endometrial Leiomyoma Polyp Fibroadenoma Adenoma Adenocarcinoma Adenoma, anterior lobe Adenoma, c-cell Carcinoma, follicular cell Pheochromocytoma, benign Pheochromocytoma, malignant Adenoma Adenoma Adenocarcinoma Alveolar/bronchiolar adenoma Adenocarcinoma Adenocarcinoma, metastatic (uterus) Squamous cell carcinoma, metastatic (skin) Fibroma Lipoma Papilloma Mesothelioma Lipoma Fibroma Squamous cell carcinoma Basal cell adenoma Carcinoma, Zymbals gland Osteosarcoma Fibroma Oligodendroglioma Astrocytoma Mononuclear cell leukemia

GM 50 38 50 39

Non-GM 48 35 48 33

CE-2 35 26 35 28

Testes Preputial/Clitoral gland Ovary Uterus

6c) (12)d) # 3 (6) 1 (2)

4 (8)# 0 0

20 (57) 0 0

Vagina Mammary gland

1 (2) 0 0 13 8 1 2 1 3 (26) (16) (2) (4) (2) (6)

#

0 0 0 11 12 0 3 0 4 (23) (25) (6) (8)

0 0 1 (3) 5 6 1 2 0 4 0 0 1 (3) 0 0 0 0 1 (3) 0 2 (6) 0 1 (3) 0 0 0 0 0 0 1 (3) 1 (3)

1 1 1 1 8 1 2 0 1 0 1 1 1

(2) (2) (2) (2) (16) (2) (4) (2) (2) (2) (2)

2 0 0 1 7 2 0 1 0 0 0 1 0 7 9 1 1 0 1

(4)

(2) (14)# (4) (2)

(2)

1 1 0 0 12 0 0 1 0 1 0 0 0

(3) (3)

(34)

(3) (3)

Pituitary gland Thyroid gland Adrenal gland Pancreas islet Pancreas Intestine Lung

(14) 7 (14) (17) 10 (20)# (3) 0 (7) 1 (2) 0 (11) 0 0 0 0 0 1 (2) 0 0 0 0 0 1 (2) 2 (4) 0 0 0 0 0 0 0 7 (14)

(14) 11 (31) (18)# 1 (3) (2) 0 (2) 0 0 (2) 0 0 0 2 (6) 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 4 (11)

4 (8) 0

3 (6)# 1 (2) 2 (4) 0 0 0 0 1 (2) 2 (4) 2 (4) 1 (2) 1 (2) 0 0 0 0 0 0 0 2 (4)

1 (2) 0 1 (2) 0 0 0 0 0 0 0 0 0 0 0 1 (2) 0 0 1 (2) 0 4 (8)

2 (4) 1 (2) 0 1 (2) 1 (2) 0 1 (2) 4 (8) 0 3 (6) 1 (2) 1 (2) 0 1 (2) 1 (2) 0 0 3 (6)

Heart Kidney Urinary bladder Abdominal cavity Skin/Subcutis

Bone Spleen Brain Systemic

a) Two rats in the male Non-GM group and 1 rat in the female GM group were excluded from the 50 rats initially used in the study because of accidental early deaths. b) Number of rats examined include the number of deaths before the termination of the study. c) Number of rats with tumor. d) Incidence of tumor ( ). #: Signicantly di#erent from CE-2 group, p 0.05

CE-2 GM Non-GM GM C CE-2 Table 10

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Harrison, L. A., Bailey, M. R., Naylor, M. W. Ream, J. E., Hammond, B. G., Nida, D. L., Burnette, B. L., Nickson, T. E., Mitsky, T. A., Taylor, M. L., Fuchs, R. L., Padgette, S. R. The expressed protein in glyphosate-tolerant soybean, 5-enolpyruvylshikimate-3-phosphate synthase from Agrobacterium sp. strain CP4, Is rapidly digested in vitro and is not toxic to acutely gavaged mice. J. Nutr., 126, 728 740 (1996). Hammond, B. G., Vicini, J. L., Hartnel, G. F., Naylor, M. W., Knight, C. D., Robinson, E. H., Fuchs, R. L., Padgette, S. R. The feeding value of soybeans fed to rats, chickens, catsh and dairy cattle is not altered by genetic incorporation of glyphosate tolerance. J. Nutr., 126, 717 727, (1996). Zho, Y., Li, D., Wang, F., Yin, J., Jin, H. Nutritinal assessment and fate of DNA of soybean meal from Round up ready or conventional soybeans using rats. Arch. Animal Nutrition, 58, 295 310 (2004).

Q Q Q QQQ Q Q17), 18) Q QQ Q Q Q Q QQQ QQQ

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3)

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4)

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Teshima, R., Akiyama, H., Okunuki, H., Sakushima, J., Goda, Y., Onodera, H., Sawada, J., Toyoda, M. E#ect of GM and Non-GM soybeans on the immune system of BN rats and B10A mice. J. Food Hyg. Soc. Japan, 41, 188 193 (2000). Sakamoto, Y., Tada, Y., Fukumori, N., Tayama, K., Ando, H., Takahashi, H., Kubo, Y., Nagasawa, A., Yano, N., Yuzawa, K., Ogata, A. A 52-week feeding study of genetically modied soybeans in F 344 rats. J. Food Hyg. Soc. Japan, 48, 41 50 (2007). Reeves, P. G., Nielsen, F. G., Fahey, G. C. Jr. AIN-93 puried diets for laboratory rodents: Final report of the American Institute of Nutrition Ad Hoc writing committee on the reformulation of the AIN-76 A rodent diet. J. Nutr., 123, 1939 1951 (1993). Coleman, G. L., Barthold, S. W., Osbaldiston, G. W., Foster, S. J, Jonas, A. M. Pathological changes during aging in barrier-reared Fischer 344 male rats. J. Gerontology, 32, 258 278 (1977). Goodman, D. G., Ward, J. M., Squire, R. A. Chu, K. C., Linhart, M. S. Neoplatic and nonneoplastic lesions in aging F 344 rats. Toxicol. Appl. Pharmacol., 48, 237 248 (1979). Enomoto, M., Hirouchi, Y., Iwata, H., Non-neoplastic lesions in rodent bioassays. J. Toxicol. Pathol., 7, 317 328 (1994). Harada, T, Maronpot, R. R, Booman, G. A., Morris, R. W., Stitzel, K. A. Foci of cellular alteration in the rats liver. J. Toxicol. Pathol., 3, 161 188 (1990). Montgomery, C. A. and Seel, J. C. Kidney, In Pathology of the Fischer rat. Reference and Atlas, Ed. by Boor, G. A., Eustis, S. L., Elwell, M. R., Montgomery, C. A., MacKenzie, W. F., eds., Academic Press, Inc., 1990, p. 132 134.

5)

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9)

10)

11)

GM Q

Non-GM Q GM Q

30

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282 12) 13) 1994, p. 193 209. (ISBN4-521-00491-1) Haseman, J. K., Hailey, J. R., Morris, R. W. Spontaneous neoplasm incidences in Fischer 344 rats and B6C3F1 mice in two-year carcinogenicity studies: A national toxicology program update. Toxicologic Pathology, 26, 428 441 (1998). 13 p. 25 27 (1992). (ISBN4-8052-0333-1) Bucher, J. R., Haseman, J. K., Herbert, R. A., Hejtmancik, M. Ryan, M. J. Toxicity and carcinogenicity studies of oxazepam in the F344 rat. Toxicol. Sci., 42, 1 12 (1998). Knaak, J. B., Leung, H. W., Stott, W. T., Busch, J. Bilsky, J. Toxicology of mono-, di, and triethanolamine. Rev. Environ. Contam. Toxicol., 149, 1 86 (1997). Iwasaki, K., Gleiser, C. A., Masoro, E. J., MacMahan, C. A., Seo, E-J., Yu, B. P. The inuence of dietary protein source on longevity and age-related disease processes of Fischer rats. J. Gerontology, Biological Sciences, 43, B5 B12 (1988). Shimokawa, I., Higami, Y., Hubbard, G. B., McMahan, C. A., Masoro, E. J., Yu, B. P. Diet and the suitability of the male Fischer 344 rat as a model for aging research. J. Gerontology, Biological Sciences, 48, B27 32 (1993). Gumbmann, M. R., Dugan, G. M, Spangler, W. L., Baker, E. C. and Rackis, J. J. Pancreatic response in rats and mice to trypsin inhibitors from soy and potato after short- and long-term dietary exposure. J. Nutr., 119, 1598 1609 (1989). Bu, L., Setchell, K. D.R., Lephart, E. D. Inuences of dietary soy isoavones on metabolism but not nociception and stress hormone responses in ovariectomized female rats. Reproductive Biology and Endocrinology,

Vol. 49, No. 4 3(58), 1 8 (2005). Kim, H. K., Nelson-Dooley, C., Della-Fera, M. A., Yang, J. Y., Zhang, W., Duan, J., Hartzell, D. L., Hamrick, M. W., Baile, C. A. Genistein decreases food intake, body weight and fat pad weight and causes adipose tissue apoptosis in ovariectomized female mice. J. Nutr., 136, 409 414 (2006). McClain, R. M., Wolz, E., Davidovich, A., Pfannkuch, F., Edwards, J. A. Bausch, J. Acute, subchronic and chronic safety studies with genistein in rats. Food and Chemical Toxicology, 44, 56 80 (2006). Wanless, I. R., Medline, A. Role of estrogen as promoters of hepatic neoplasia. Lab Invest., 46, 313 320 (1982). Dombrowski, F., Flaschka, C., Klotz, L, von Netzer, B., Schulz, C., Lehnert, H., Evert, M. Hepatocellular neoplasms after intrahepatic transplantation of ovarian fragments into ovariectomized rats. Hepatology, 43, 857 867 (2006). Blechet, C., Lecomte, P., De Calan, L., Beutter, P., Guyee tant, S. Expression of sex steroid hormone receptors in C cell hyperplasia and medullary thyroid carcinoma. Virchows Arch., 450, 433 439 (2007). Chatani, F., Nonoyama, T., Sudo, K., Miyajima, H., Takeyama, M., Thakatsuka, D., Mori, H., Motsumoto, K. Stimulatory e#ect of luteinizing horomone on the development and maintenance of 5 alpha-reduced steroidproducing testicular interstitial cell tumors in F 344 rats. Russell, J. J., Sta#eldt, E. F., Wright, B. J., Prapuolenis, A., Carnes, B. A., Peraino, C. E#ects of rat strain, diet composition, and Phenobarbital on hepatic g-glutamyl transpeptidase histochemistry and on the induction of altered hepatocyte foci and hepatic tumors by diethylnitrosamine. Cancer Research, 45, 1130 1134 (1987).

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