Transgenic rat models for mutagenesis and carcinogenesis

Takehiko Nohmi; Kenichi Masumura; Naomi Toyoda-Hokaiwado

doi:10.1186/s41021-016-0072-6

Genes and Environment

Table 1 Summary of experimental data of transgenic rat models for mutagenesis

From: Transgenic rat models for mutagenesis and carcinogenesis

Agents	Animal	Dose	Route	Sex	Age (weeks)	Administration time/Sampling time (days)	Tissue	Transgenic assays	Positive response	Reference
Acetaminophen	gpt delta rat (SD)	10000 ppm	Diet	Female	11	91/91	Liver	gpt	-	[167]
Acrylamide	Big Blue rat (F344)	1.4 mM	Drinking water	Male	7	60/60	Liver	cII	-	[168]
							Bone marrow	cII	-	Ibid
							Thyroid	cII	-	Ibid
							Testis	cII		Ibid
	gpt delta rat (F344)	0.7 mM	Drinking water	Female	7	60/60	Liver	cII	-	Ibid
							Bone marrow	cII	+	Ibid
							Thyroid	cII	+	ibid
							Mammary gland	cII	-	Ibid
				Male	7	60/60	Liver	cII	-	Ibid
				Female	7	60/60	Liver	cII	-	Ibid
		80 ppm	Drinking water	Male	3	28/28	Testis	gpt	+	[169]
		80 ppm					Liver	gpt	-	Ibid
		40 ppm					Testis	gpt	-	Ibid
		40 ppm					Liver	gpt	-	Ibid
		20 ppm					Testis	gpt	-	Ibid
		20 ppm					Liver	gpt	-	Ibid
		80 ppm	Drinking water	Male	11	28/28	Testis	gpt	-	Ibid
		80 ppm					Liver	gpt	-	Ibid
		40 ppm					Testis	gpt	-	Ibid
		20 ppm					Liver	gpt	-	Ibid
							Testis	gpt	-	Ibid
							Liver	gpt	-	ibid
Aflatoxin B1	Big Blue rat (F344)	0.5 mg/kg	Gavage	Male	13	1/14	Liver	lacI	+	[105]
		0.5 mg/kg	Gavage	Female	13	1/14	Liver	lacI	+	Ibid
		0.5 mg/kg	Gavage	Female	6–8	1/14	Liver	lacI	+	[170]
		0.5 mg/kg	Gavage	Female	6–8	1/14	Liver	cII	+	[109]
		0.25 mg/kg	Intraperitoneal	Male	13–19	1/14	Liver	lacI	+	[18]
2-Amino-3-methylimidazo[4,5-f]quinoline (IQ)	Big Blue rat (F344)	20 mg.kg	Gavage	Male	5	1/14	Liver	lacI	+	[171]
							Colon	lacI	+	Ibid
							Kidney	lacI	+	Ibid
		20 mg/kg x5	Gavage	Male	5	5/18	Liver	lacI	+	Ibid
							Colon	lacI	+	Ibid
							Kidney	lacI	+	Ibid
		200 ppm	Diet	Male	8	21/21	Liver	cII	+	[172]
		200 ppm	Diet	Male	8	21/21	Colon	cII	+	Ibid
		70 ppm	Diet	Male	8	21/21	Liver	cII	+	Ibid
					8	21/21	Colon	cII	+	Ibid
					9–12	21/21	Liver	cII	+	[100]
					9–12	21/21	Colon	cII	+	Ibid
		20 ppm	Diet	Male	8	21/21	Liver	cII	-	[172]
		20 ppm	Diet	Male	8	21/21	Colon	cII	-	Ibid
	gpt delta rat (SD)	300 ppm	Diet	Female	11	91/91	Liver	gpt	+	[167]
2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline (MeIQx)	Big Blue rat (F344)	100 ppm	Diet	Male	6	112/112	Liver	lacI	+	[85]
							Colon	lacI	+	Ibid
							Zymbal gland	lacI	+	Ibid
							Kidney	lacI	-	Ibid
							Spleen	lacI	-	Ibid
							Lung	lacI	-	Ibid
							Testis	lacI	-	Ibid
							Heart	lacI	-	Ibid
							Brain	lacI	-	Ibid
							Fat tissue	lacI	-	Ibid
							Skeletal muscle	lacI	-	Ibid
		10 ppm	Diet	Male	6	112/112	Liver	lacI	+	Ibid
		1 ppm	Diet	Male	6	112/112	Liver	lacI	-	Ibid
		0.1 ppm	Diet	Male	6	112/112	Liver	lacI	-	Ibid
		0.01 ppm	Diet	Male	6	112/112	Liver	lacI	-	Ibid
		0.001 ppm	Diet	Male	6	112/112	Liver	lacI	-	Ibid
2-Amino-1-methyl-6-phenylimidazo(4,5-b)pyridine (PhIP)	Big Blue rat (F344)	100 mg/kg, bw	Intraperitoneal	Male	8+22	1/14	Colon	lacI	+	[102]
		100 mg/kg, bw	Intraperitoneal	Female	8+22	1/14	Colon	lacI	+	Ibid
		75 mg/kg ×10	Oral	Female	7	12/54	Mammary gland	lacI	+	[40]
		75 mg/kg ×10	Oral	Female	22	12/54	Mammary gland	lacI	+	Ibid
		70 mg/kg ×12	Gavage	Male	13–15	28/30	Liver	cII	-	[41]
							Kidney	cII	-	Ibid
							Prostate	cII	+	Ibid
							Seminal vesicle	cII	+	Ibid
							Colon	cII	+	Ibid
							Spleen	cII	+	Ibid
		70 mg/kg ×24	Gavage	Male	13–15	56/60	Liver	cII	-	Ibid
							Kidney	cII	-	Ibid
							Prostate	cII	+	Ibid
							Seminal vesicle	cII	+	Ibid
							Colon	cII	+	Ibid
							Spleen	cII	+	Ibid
		400 ppm	Diet	Male	6	60/67	Colon mucosa	lacI	+	[23, 44]
				Male	6	60/67	Colon mucosa	cII	+	[23]
				Female	6	60/67	Colon mucosa	lacI	+	[23, 44]
				Female	6	60/67	Colon mucosa	cII	+	[23]
		200 ppm	Diet	Male	7	61/68	Distal colon	lacI	+	[45, 173]
							Proximal colon	lacI	+	Ibid
							Cecum	lacI	+	Ibid
							Prostate	lacI	+	[42]
				Female	7	61/68	Distal colon	lacI	+	[45]
							Proximal colon	lacI	+	Ibid
							Cecum	lacI	+	Ibid
		100 ppm	Diet	Male and Female	7	47/54	Distal colon	lacI	+	[174]
				Male and Female	7	47/54	Cecum	lacI	+	Ibid
				Male	7	47/54	Kidney	lacI	+	[98]
				Female	7	47/54	Kidney	lacI	+	Ibid
	Big Blue rat (F344 × SD)F1	65 mg/kg ×10	Gavage	Female	6	12/350–441	Mammary gland	lacI	+	[39]
Amosite asbestos	Big Blue rat (F344)	2 mg/rat	Intratracheal	Male	11	1/28	Lung	lacI	-	[103, 126]
		2 mg/rat	Intratracheal	Male	11	1/112	Lung	lacI	+	Ibid
		2 mg/rat ×4	Intratracheal	Male	11	28/56	Lung	lacI	-	Ibid
		2 mg/rat ×4	Intratracheal	Male	11	28/133	Lung	lacI	+	Ibid
		1 mg/rat	Intratracheal	Male	11	1/28	Lung	lacI	-	Ibid
		1 mg/rat	Intratracheal	Male	11	1/112	Lung	lacI	-	Ibid
Aristolochic acid	Big Blue rat (F344)	10 mg/kg	Gavage	Male	6	84/84	Kidney	cII	+	[112, 113]
							Liver	cII	+	[112]
							Testis	cII	-	[175]
		1.0 mg/kg	Gavage	Male	6	84/84	Kidney	cII	+	[112, 113]
		1.0 mg/kg	Gavage	Male	6	84/84	Liver	cII	+	[112]
		0.1 mg/kg	Gavage	Male	6	84/84	Kidney	cII	+	[112, 113]
		0.1 mg/kg	Gavage	Male	6	84/84	Liver	cII	-	[112]
	Big Blue rat (F344)	10 mg/kg	Gavage	Male	6	84/84	Spleen	cII	+	[176]
		1.0 mg/kg	Gavage		6	84/84	Spleen	cII	+	Ibid
		0.1 mg/kg	Gavage		6	84/84	Spleen	cII	-	Ibid
	gpt delta rat (F344)	1 mg/kg	Gavage	Male	7	28/31	Kidney	gpt	+	[177]
	gpt delta rat (F344)	0.3 mg/kg	Gavage	Male	7	28/31	Liver	gpt	+	Ibid
Benzo[a]pyrene (BP)	Big Blue rat (F344)	100 mg/kg, bw	Intraperitoneal	Male	8+22	1/14	Liver	lacI	+	[102]
		100 mg/kg, bw	Intraperitoneal	Female	8+22	1/14	Liver	lacI	+	Ibid
		5 mg/rat	Intraperitoneal	Female	10	1/28	Omentum	lacI	+	[178]
						1/84	Omentum	lacI	+	Ibid
						1/168	Omentum	lacI	+	Ibid
	gpt delta rat (SD)	125 mg/kg	Intraperitoneal	Male	9–10	1/7	Liver	gpt	+	[17]
		125 mg/kg	Intraperitoneal	Male	9–10	1/7	Liver	Spi^–	+	Ibid
		62.5 mg/kg	Intraperitoneal	Male	9–10	1/7	Liver	gpt	+	Ibid
		62.5 mg/kg	Intraperitoneal	Male	9–10	1/7	Liver	Spi⁻	-	Ibid
Bitumen fumes	Big Blue rat (F344)	6 hr ×5	Inhalation	Male	8	5/35	Lung	cII	-	[132]
Bitumen fumes	Big Blue rat (F344)	6 hr ×5	Inhalation	Male	8	5/35	Lung	cII		Ibid
N-butyl-N-(4-hydroxybutyl)nitrosamine	Big Blue rat (F344)	0.05 %	Drinking water	Male	8	14/42	urothelial cells (urinary bladder)	cII	+	[179]
							smooth muscle cells (urinary bladder)	cII	-	Ibid
							Ureter	cII	-	Ibid
							Kidney	cII	-	Ibid
							Liver	cII	-	Ibid
						42/70	urothelial cells (urinary bladder)	cII	+	Ibid
							smooth muscle cells (urinary bladder)	cII	+	Ibid
							Ureter	cII	-	Ibid
							Kidney	cII	-	Ibid
							Liver	cII	-	Ibid
Citrinin	gpt delta rat (F344)	40 mg/kg (decreased to 30 mg/kg at day 4)	Gavage	Male		28/31	Kidney	gpt	-	[65]
Citrinin	gpt delta rat (F344)	20 mg/kg	Gavage	Male		28/31	Kidney	gpt	-	Ibid
Comfrey	Big Blue rat (F344)	2 %	Diet	Male	6	84/84	Liver	cII	+	[180]
Conjugated linoleic acid	Big Blue rat (F344)	1 %(w/w)	Diet	Male and Female	7	54/61	Distal colon	lacI	-	[174]
							Cecum	lacI	-	Ibid
							Kidney	lacI	-	[98]
Crocidolite	Big Blue rat (F344)	5 mg/rat	Intraperitoneal	Female	10	1/28	Omentum	lacI	-	[178]
						1/84	Omentum	lacI	+	Ibid
						1/168	Omentum	lacI	+	Ibid
		2 mg/rat	Intraperitoneal	Female	10	1/28	Omentum	lacI	-	Ibid
						1/84	Omentum	lacI	-	Ibid
						1/168	Omentum	lacI	-	Ibid
Cyproterone acetate	Big Blue rat (F344)	160 mg/kg	Gavage	Female	12	1/14	Liver	lacI	+	[90]
		100 mg/kg	Gavage	Female	12	1/1	Liver	lacI	+	Ibid
						1/2	Liver	lacI	+	Ibid
						1/3	Liver	lacI	+	Ibid
						1/7	Liver	lacI	+	Ibid
						1/14	Liver	lacI	+	Ibid
						1/28	Liver	lacI	+	Ibid
						1/42	Liver	lacI	+	Ibid
						1/56	Liver	lacI	+	Ibid
		80 mg/kg	Gavage	Female	12	1/14	Liver	lacI	+	Ibid
		40 mg/kg	Gavage	Female	12	1/14	Liver	lacI	+	Ibid
		20 mg/kg	Gavage	Female	12	1/14	Liver	lacI	+	Ibid
		10 mg/kg	Gavage	Female	12	1/14	Liver	lacI	+	Ibid
		5 mg/kg	Gavage	Female	12	1/14	Liver	lacI	-	Ibid
		5 mg/kg ×21	Gavage	Female	11–12	21/22	Liver	lacI	+	[181]
		1.0 mg/kg ×21	Gavage	Female	11–12	21/22	Liver	lacI	-	Ibid
		0.2 mg/kg ×21	Gavage	Female	11–12	21/22	Liver	lacI	-	Ibid
Daidzein	Big Blue rat (F344)	1 g/kg	Diet	Female	7	112/112	Mammary gland	lacI	-	[95]
		1 g/kg	Diet	Female	7	112/112	Uterus	lacI	-	[96]
		0.25 g/kg	Diet	Female	7	112/112	Mammary gland	lacI	-	[95]
		0.25 g/kg	Diet	Female	7	112/112	Uterus	lacI	-	[96]
	Big Blue rat (F344), ovariectomized	1 g/kg	Diet	Female	7	112/112	Uterus	lacI	-	[96]
	Big Blue rat (F344), ovariectomized	0.25 g/kg	Diet	Female	7	112/112	Uterus	lacI	-	Ibid
Diallyl sulfide (DAS)	Big Blue rat (F344)	200 mg/kg ×2	Gavage	Male	7–10	7/21	Esophagus	lacI	-	[93]
2,4-diaminotoluene (2,4-DAT)	gpt delta rat (F344)	30 mg/kg	Gavage	Male	7	28/31	Liver	gpt	+	[55]
	gpt delta rat (F344)	10 mg/kg	Gavage	Male	7	28/31	Liver	gpt	+	Ibid
	gpt delta rat (F344)	500 ppm	Diet	Male	7	91/91	Liver	gpt, Spi⁻	+	[7]
		500 ppm	Diet	Male	7	91/91	Kidney	gpt	-	Ibid
		250 ppm	Diet	Male	7	91/91	Liver	gpt, Spi⁻	+	Ibid
		250 ppm	Diet	Male	7	91/91	Kidney	gpt	-	Ibid
		125 ppm	Diet	Male	7	91/91	Liver	gpt	+	Ibid
		125 ppm	Diet	Male	7	91/91	Liver	Spi-	-	Ibid
		125 ppm	Diet	Male	7	91/91	Kidney	gpt	-	Ibid
2,6-diaminotoluene (2.6-DAT)	gpt delta rat (F344)	60 mg/kg	Gavage	Male	7	28/31	Liver	gpt	-	[55]
	gpt delta rat (F344)	500 ppm	Diet	Male	7	91/91	Liver	gpt, Spi⁻	-	[7]
	gpt delta rat (F344)	500 ppm	Diet	Male	7	91/91	kideny	gpt	-	Ibid
1,2,3,4-Diepoxybutane	Big Blue rat (F344)	3.8 ppm, 6 hr ×5×2	Inhalation	Female and Male	6–8	14/49	Spleen	lacI	-	[182]
1,2,3,4-Diepoxybutane	Big Blue rat (F344)	3.8 ppm, 6 hr ×5×2	Inhalation	Female and Male	6–8	14/28	Bone marrow	lacI	+	Ibid
Diesel exhaust (DE)	Big Blue rat (F344)	6 mg SPM/m³, 12 hr/day	Inhalation	Male	6	28/31	Lung	lacI	+	[130]
		1 mg SPM/m³, 12 hr/day	Inhalation	Male	6	28/31	Lung	lacI	-	ibid
		80 mg DEP/kg	Diet	Male	8	21/21	Lung	cII	-	[131]
		20 mg DEP/kg	Diet	Male	8	21/21	Lung	cII	-	Ibid
		8 mg DEP/kg	Diet	Male	8	21/21	Lung	cII	-	Ibid
		2 mg DEP/kg	Diet	Male	8	21/21	Lung	cII	-	Ibid
		0.8 mg DEP/kg	Diet	Male	8	21/21	Lung	cII	-	Ibid
		0.2 mg DEP/kg	Diet	Male	8	21/21	Lung	cII	-	Ibid
Di(2-ethyl-hexyl)phthalate (DEHP)	gpt delta rat (SD)	12000 ppm	Diet	Female	11	91/91	Liver	gpt	-	[167]
Di(2-ethyl-hexyl)phthalate (DEHP)	gpt delta rat (SD)	12000 ppm	Diet	Female	11	91/91	Liver	Spi⁻	-	Ibid
Diethylnitrosamine	gpt delta rat (F344)	20 mg/kg (once a week)	Intraperitoneal	Male	7	91/91	Liver	gpt, Spi⁻	+	[7]
Diethylnitrosamine	gpt delta rat (F344)	20 mg/kg (once a week)	Intraperitoneal	Male	7	91/91	kidney	gpt	+	ibid
5-p-Dimethylaminophenylazobenzthiazole (5BT)	Big Blue rat (F344)	10 mg/kg ×10	Gavage	Male	12	10/20	Liver	lacI	+	[61]
5-p-Dimethylaminophenylazobenzthiazole (5BT)	Big Blue rat (F344)	0.03 %	Diet	Male	12	10/20	Liver	lacI	+	ibid
6-p-Dimethylaminophenylazobenzthiazole (6BT)	Big Blue rat (F344)	10 mg/kg ×10	Gavage	Male	12	10/20	Liver	lacI	+	[61, 183]
6-p-Dimethylaminophenylazobenzthiazole (6BT)	Big Blue rat (F344)	0.03 %	Diet	Male	12	10/20	Liver	lacI	+	ibid
7,12-Dimethylbenzanthracene (DMBA)	Big Blue rat (F344)	130 mg/kg	Gavage	Female	7	1/14	Splenic lymphocyte	lacI	+	[27]
						1/14	Mammary gland	lacI	+	[184]
						1/14	Bone marrow	lacI	+	[26]
						1/42	Splenic lymphocyte	lacI	+	[27]
						1/42	Mammary gland	lacI	+	[184]
						1/42	Bone marrow	lacI	+	[26]
						1/70	Splenic lymphocyte	lacI	+	[27]
						1/70	Mammary gland	lacI	+	[18]
						1/70	Bone marrow	lacI	+	[26]
						1/98	Splenic lymphocyte	lacI	+	[27]
						1/98	Mammary gland	lacI	+	[184]
						1/98	Bone marrow	lacI	+	[26]
		80 mg/kg	Gavage	Female	7	1/112	Liver	cII	+	[94]
		80 mg/kg	Gavage	Female	7		Uterus	lacI	+	[96]
		75 mg/kg	Gavage	Female	7	1/14	Splenic lymphocyte	lacI	-	[27]
						1/42	Splenic lymphocyte	lacI	+	Ibid
						1/70	Splenic lymphocyte	lacI	+	Ibid
						1/98	Splenic lymphocyte	lacI	+	Ibid
						1/126	Splenic lymphocyte	lacI	-	Ibid
		20 mg/kg	Gavage	Female	7	1/14	Splenic lymphocyte	lacI	-	[27]
						1/14	Mammary gland	lacI	-	[184]
						1/14	Bone marrow	lacI	+	[26]
						1/42	Splenic lymphocyte	lacI	+	[27]
						1/42	Mammary gland	lacI	-	[184]
						1/42	Bone marrow	lacI	+	[26]
						1/70	Splenic lymphocyte	lacI	-	[27]
						1/70	Mammary gland	lacI	-	[184]
						1/70	Bone marrow	lacI	+	[26]
						1/98	Splenic lymphocyte	lacI	-	[27]
						1/98	Mammary gland	lacI	-	[18])
						1/98	Bone marrow	lacI	+	[26]
						1/126	Splenic lymphocyte	lacI	-	[27]
						1/126	Mammary gland	lacI	-	[184]
	Big Blue rat (F344), ovariectomized	80 mg/kg	Gavage	Female	7	1/112	Heart	lacI	+	[185]
							Liver	cII	+	[94]
							Uterus	lacI	+	[96]
Dimethylnitrosamine (DMN)	Big Blue rat (F344)	6.0 mg/kg ×9	Gavage	Male	12	11/12	Liver	lacI	+	[20]
		6.0 mg/kg ×9	Gavage	Male	12	11/12	Liver	cII	+	Ibid
		2.0 mg/kg ×9	Gavage	Male	12	11/12	Liver	lacI	+	Ibid
		2.0 mg/kg ×9	Gavage	Male	12	11/12	Liver	cII	+	Ibid
		0.6 mg/kg ×9	Gavage	Male	12	11/12	Liver	lacI	-	Ibid
		0.6 mg/kg ×9	Gavage	Male	12	11/12	Liver	cII	-	Ibid
		0.2 mg/kg ×9	Gavage	Male	12	11/12	Liver	lacI	-	Ibid
		0.2 mg/kg ×9	Gavage	Male	12	11/12	Liver	cII	-	Ibid
	Big Blue rat (F344)	25 ppm	Drinking water			14/14	Liver	cII		[186]
		10 ppm	Drinking water			14/14	Liver	cII		Ibid
		5 ppm	Drinking water			14/14	Liver	cII		Ibid
		1 ppm	Drinking water			14/14	Liver	cII		Ibid
		0.1 ppm	Drinking water			14/14	Liver	cII		Ibid
Ellagic acid	Big Blue rat (F344)	4 g/kg	Diet	Male	7–10	42/42	Esophagus	lacI	-	[93]
1,2-Epoxy-3-butene	Big Blue rat (F344)	29.9 ppm, 6 hr ×5×2	Inhalation	Female	6–8	14/49	Spleen	lacI	-	[182]
1,2-Epoxy-3-butene	Big Blue rat (F344)	29.9 ppm, 6 hr ×5×2	Inhalation	Female	6–8	14/28	Bone marrow	lacI	+	Ibid
Estragole	gpt delta rat (F344)	600 mg/kg	Gavage	Male	5	5 days per week x 4 weeks	Liver	gpt	(72) toxic but 2 of 5 survived rats showed positive responses
		200 mg/kg	Gavage	Male	5	5 days per week x 4 weeks	Liver	gpt	+	ibid
		66 mg/kg	Gavage	Male	5	5 days per week x 4 weeks	Liver	gpt	-	Ibid
		22 mg/kg	Gavage	Male	5	5 days per week x 4 weeks	Liver	gpt	-	Ibid
N-ethyl-N-nitrosourea (ENU)	Big Blue rat (F344)	100 mg/kg	Intraperitoneal	Male	8+22	1/14	Liver	lacI	+	[102]
	Big Blue rat (F344)	100 mg/kg	Intraperitoneal	Female	8+22	1/14	Liver	lacI	+	Ibid
	gpt delta rat (SD)	100 mg/kg	Intraperitoneal	Male	5	1/7	Liver	gpt	+	[17]
		100 mg/kg	Intraperitoneal	Male	5	1/7	Liver	Spi⁻	-	Ibid
		50 mg/kg ×5	Intraperitoneal	Male	10	5/7	Liver	gpt	+	Ibid
						5/21	Liver	gpt	+	Ibid
						5/35	Liver	gpt	+	Ibid
						5/70	Liver	gpt	+	Ibid
17beta-estradiol	Big Blue rat (F344)	0.005 g/kg	Diet	Female	7	112/112	Mammary gland	lacI	-	[95]
	Big Blue rat (F344)	0.005 g/kg	Diet	Female	7	112/112	Uterus	lacI	-	[96]
	Big Blue rat (F344), ovariectomized	0.005 g/kg	Diet	Female	7	112/112	Heart	lacI	-	[95]
	Big Blue rat (F344), ovariectomized	0.005 g/kg	Diet	Female	7	112/112	Uterus	lacI	-	[96]
Ethanol	Big Blue rat (F344)	5 %	Drinking water	Male	7–10	21/21	Esophagus	lacI	-	[93]
Fructose	Big Blue rat (F344)	30 %	Diet	Male	9–12	35/35	Liver	cII	-	[101]
Fructose	Big Blue rat (F344)	30 %	Diet	Male	9–12	35/35	Colon	cII	+−	Ibid
Furan	Big Blue rat (F344)	30 mg/kg	Gavage	Male	7	56/56	Liver	cII	-	[187]
		16 mg/kg	Gavage	Male	7	56/56	Liver	cII	-	Ibid
		8 mg/kg	Gavage	Male	7	56/56	Liver	cII	-	Ibid
		2 mg/kg	Gavage	Male	7	56/56	Liver	cII	-	Ibid
Genistein	Big Blue rat (F344)	1 g/kg	Diet	Female	7	112/112	Mammary gland	lacI	-	[95]
					7	112/112	Liver	cII	-	[94]
					7	112/112	Uterus	lacI	-	[96]
		0.25 g/kg	Diet	Female	7	112/112	Mammary gland	lacI	-	[95]
		0.25 g/kg	Diet	Female	7	112/112	Uterus	lacI	-	[96]
	Big Blue rat (F344), ovariectomized	1 g/kg	Diet	Female	7	112/112	Heart	lacI	-	[185]
							Uterus	lacI	-	[96]
							Liver	cII	-	[94]
		0.25 g/kg	Diet	Female	7	112/112	Heart	lacI	-	[185]
		0.25 g/kg	Diet	Female	7	112/112	Uterus	lacI	-	[96]
Glass wool fibres	Big Blue rat (F344)	2 mg/rat	Intratracheal	Male	11	1/28	Lung	lacI	-	[127, 188]
		2 mg/rat	Intratracheal	Male	11	1/112	Lung	lacI	-	Ibid
		2 mg/rat x4	Intratracheal	Male	11	28/56	Lung	lacI	-	Ibid
		2 mg/rat x4	Intratracheal	Male	11	28/133	Lung	lacI	-	Ibid
		1 mg/rat	Intratracheal	Male	11	1/28	Lung	lacI	-	Ibid
		1 mg/rat	Intratracheal	Male	11	1/112	Lung	lacI	-	Ibid
Glucose	Big Blue rat (F344)	30 %	Diet	Male	9–12	35/35	Liver	cII	-	[101]
Glucose	Big Blue rat (F344)	30 %	Diet	Male	9–12	35/35	Colon	cII	+−	Ibid
Glycidamide	Big Blue rat (F344)	1.4 mM	Drinking water	Male	7	60/60	Liver	cII	-	[168]
							Bone marrow	cII	+	Ibid
							Thyroid	cII	+	Ibid
							Testis	cII	-	Ibid
				Female	7	60/60	Liver	cII	-	Ibid
							Bone marrow	cII	+	Ibid
							Thyroid	cII	+	Ibid
							Mammary gland	cII	-	Ibid
		0.7 mM	Drinking water	Male	7	60/60	Liver	cII	-	Ibid
		0.7 mM	Drinking water	Female	7	60/60	Liver	cII	-	Ibid
Hexavalent chromium [Cr(VI)] (as sodium dichromate dihydrate)	Big Blue rat (F344)	180 ppm (as Cr(VI))	Drinking water	Male	10	28/31	Oral cavity (gingival/bubbal)	cII	-	[189]
	Big Blue rat (F344)	180 ppm (as Cr(VI))	Drinking water	Male	10	28/31	Oral cavity (gingival/palate)	cII	-	Ibid
N-hydroxy-2-acetylaminofluorene	Big Blue rat (F344)	25 mg/kg ×1	Intraperitoneal	Male	6	1/42	Liver	lacI	+	[28, 190]
		25 mg/kg ×2	Intraperitoneal	Male	6	5/42	Liver	lacI	+	Ibid
		25 mg/kg ×4	Intraperitoneal	Male	6	13/42	Liver	lacI	+	Ibid
		25 mg/kg ×4	Intraperitoneal	Male	6	13/42	Spleen lymphocytes	lacI	+	Ibid
4-Hydroxy-PCB3 (4-OH-PCB3)	Big Blue rat (F344)	82 mg/kg ×4	Intraperitoneal	Male	6	22/38	Liver	lacI	+−	[133]
4-Hydroxy-PCB3 (4-OH-PCB3)	Big Blue rat (F344)	82 mg/kg ×4	Intraperitoneal	Male	6	22/38	Lung	lacI	+−	[135]
alpha-Hydroxytamoxifen	Big Blue rat (F344)	54 μmol/kg ×21	Intraperitoneal	Female	8	21/51	Liver	cII	+	[22]
							Liver	lacI	+	[191]
							Uterus	lacI	-	Ibid
		0.103 mmol/kg ×10	Gavage	Female	6–8	10/56	Liver	lacI	+	[192]
Lard	Big Blue rat (F344)	30 %	Diet	Male	8	21/21	Liver	cII	-	[193]
		30 %	Diet	Male	8	21/21	Colon	cII	-	Ibid
		10 %	Diet	Male	8	21/21	Liver	cII	-	Ibid
		10 %	Diet	Male	8	21/21	Colon	cII	-	Ibid
		3 %	Diet	Male	8	21/21	Liver	cII	-	Ibid
		3 %	Diet	Male	8	21/21	Colon	cII	-	Ibid
Leucomalachite green	Big Blue rat (F344)	543 ppm	Diet	Female	6	28/28	Liver	lacI	-	[79]
		543 ppm				112/112	Liver	lacI	-	[79, 81]
						224/224	Liver	lacI	-	[79]
		272 ppm	Diet	Female	6	28/28	Liver	lacI	-	Ibid
						112/112	Liver	lacI	-	Ibid
						224/224	Liver	lacI	-	Ibid
		91 ppm	Diet	Female	6	112/112	Liver	lacI	-	Ibid
N-Methyl-amyl-nitrosamine	Big Blue rat (Sprague Dawley/Big Blue F1)	25 mg/kg ×10	Intraperitoneal		10	64/70	Esophagus	lacI	+	[194]
3-Methylcholanthrene	Big Blue rat (F344)	80 mg/kg ×4	Intraperitoneal	Male	6	22/38	Liver	lacI	+	[133]
3-Methylcholanthrene	Big Blue rat (F344)	80 mg/kg ×4	Intraperitoneal	Male	6	22/38	Lung	lacI	+	[135]
4-Monochlorobiphenyl (PCB3)	Big Blue rat (F344)	113 mg/kg ×4	Intraperitoneal	Male	6	22/38	Liver	lacI	+	[133]
4-Monochlorobiphenyl (PCB3)	Big Blue rat (F344)	113 mg/kg ×4	Intraperitoneal	Male	6	22/38	Lung	lacI	+	[135]
Madder color and lucidin-3-O-primeveroside (LuP)	gpt delta rat (F344)	Madder color 5.0 % w/w	Diet	Male	5	56/56	Kidney	gpt, Spi⁻	+	[73]
Madder color and lucidin-3-O-primeveroside (LuP)	gpt delta rat (F344)	LuP 0.3 % w/w	Diet	Male	5	56/56	Kidney	gpt, Spi⁻	+	Ibid
3-MCPD	gpt delta rat (F344)	40 mg/kg	Gavege	Male	6	5 times per week x 4 weeks/1	Kidney and testis	gpt, Spi⁻	-	[66]
3-MCPD	gpt delta rat (F344)	the equimolar esters	Gavege	Male	6	5 times per week x 4 weeks/1	Kidney and testis	gpt, Spi⁻	-	Ibid
Methyleugenol	gpt delta rat (F344)	100 mg/kg	Gavage	Male and female	5	91/91	Liver	gpt, Spi⁻	+	[74]
		30 mg/kg	Gavage	Male and female	5	91/91	Liver	gpt, Spi⁻	-	Ibid
		10 mg/kg	Gavage	Male and female	5	91/91	Liver	gpt, Spi⁻	-	Ibid
Nickel subsulfide (Ni₃S₂)	Big Blue rat (F344)	6 mg/kg (130 mg/m³), 2 h	Inhalation	Male	9	1/14	Lung	lacI	-	[123]
	Big Blue rat (F344)	6 mg/kg (130 mg/m³), 2 h	Inhalation	Male	9	1/14	Nasal mucosa	lacI	-	Ibid
	gpt delta rat (F344)	1 mg/animal	Intratracheally instillation	Male	12	28/28	Lung	gpt, Spi⁻	-	[124]
		0.5 mg/animal	Intratracheally instillation	Male	12	28/28	Lung	gpt, Spi⁻	-	Ibid
		1 mg/animal	Intratracheally instillation	Male	12	90/90	Lung	gpt, Spi⁻	-	ibid
		0.5 mg/animal	Intratracheally instillation	Male	12	90/90	Lung	gpt, Spi⁻	-	Ibid
N-nitrosomethylbenzylamine	Big Blue rat (F344)	2 mg/kg ×2	Subcutaneous	Male	7–10	7/21	Esophagus	lacI	+	[93]
6-Nitrochrysene	Big Blue rat (F344 × SD)F1	100 μmole/rat x 8	Oral	Female	5	50/274	Mammary gland	cII	+	[195]
6-Nitrochrysene	Big Blue rat (F344 × SD)F1	50 μmole/rat x 8	Oral	Female	5	50/274	Mammary gland	cII	+	Ibid
N-nitrosopyrrolidine	gpt delta rat (SD)	200 ppm	Drinking water	Female	11	91/91	Liver	gpt	+	[167]
4-nitroquinoline-1-oxide	Big Blue rat (F344)	10 ppm	Drinking water	Male	10–11	28/31	Oral cavity (gingival/bubbal)	cII	+	[196]
							Oral cavity (gingival/palate)	cII	+	Ibid
							Liver	cII	-	Ibid
							Bone marrow	cII	-	Ibid
	Big Blue rat (F344)	10 ppm	Drinking water	Male	10	28/31	Oral cavity (gingival/bubbal)	cII	+	[189]
	Big Blue rat (F344)	10 ppm	Drinking water	Male	10	28/31	Oral cavity (gingival/palate)	cII	+	Ibid
Ochratoxin A	gpt delta rat (F344)	5 ppm	Diet	Male and female	5	28/28	outer medulla of kidney	gpt	-	[50]
				Male and female	5	28/28	outer medulla of kidney	Spi⁻	+	Ibid
				Male and female	5	91/91	whole kidney	gpt, Spi⁻	-	ibid
		5 ppm	Diet	Male	5	28/28	outer medulla of kidney	Spi⁻	+	[65]
Phenacetin	gpt delta rat (SD)	0.50 %	Diet	Male and female	7	182/182	Kidney	gpt, Spi⁻	-	[52]
				Male and female	7	182/182	Liver	gpt	+	Ibid
				Male and female	7	182/182	Liver	Spi⁻	-	ibid
				Male	7	364/364	Kidney	gpt	+	Ibid
				Male	7	364/364	Kideney	Spi⁻	-	Ibid
				Female	7	364/364	Kideney	gpt, Spi⁻	-	Ibid
				Male	7	364/364	Liver	gpt, Spi⁻	+	Ibid
				Female	7	364/364	Liver	gpt, Spi⁻	+	Ibid
Potassium Bromate (KBrO₃)	Big Blue rat (F344)	500 ppm	Drinking water	Male	6	112/112	Kidney	lacI	+	[87]
		125 ppm	Drinking water	Male	6	112/112	Kidney	lacI	-	Ibid
		30 ppm	Drinking water	Male	6	112/112	Kidney	lacI	-	Ibid
		8 ppm	Drinking water	Male	6	112/112	Kidney	lacI	-	Ibid
		2 ppm	Drinking water	Male	6	112/112	Kidney	lacI	-	Ibid
		0.2 ppm	Drinking water	Male	6	112/112	Kidney	lacI	-	Ibid
		0.02 ppm	Drinking water	Male	6	112/112	Kidney	lacI	-	Ibid
		0.002 ppm	Drinking water	Male	6	112/112	Kidney	lacI	-	Ibid
	gpt delta rat (SD)	500 ppm	Drinking water	Male	5	7/7	Kidney	gpt	-	[119]
						7/7	Kidney	Spi⁻	-	Ibid
						35/35	Kidney	gpt	-	Ibid
						35/35	Kidney	Spi⁻	-	Ibid
						63/63	Kidney	gpt	-	Ibid
						63/63	Kidney	Spi⁻	+	Ibid
						91/91	Kidney	gpt	-	Ibid
						91/91	Kidney	Spi⁻	+	Ibid
		250 ppm	Drinking water	Male	5	91/91	Kidney	gpt	-	Ibid
		250 ppm	Drinking water	Male	5	91/91	Kidney	Spi⁻	-	Ibid
		125 ppm	Drinking water	Male	5	91/91	Kidney	gpt	-	Ibid
		125 ppm	Drinking water	Male	5	91/91	Kidney	Spi⁻	-	Ibid
		60 ppm	Drinking water	Male	5	91/91	Kidney	gpt	-	Ibid
		60 ppm	Drinking water	Male	5	91/91	Kidney	Spi⁻	-	Ibid
	gpt delta rat (F344)	500 ppm	Drinking water	Male	5	63/63	Kidney	gpt	-	[120]
				Male	5	63/63	Kidney	Spi⁻	-	Ibid
				Female	5	63/63	Kidney	gpt	+	Ibid
				Female	5	63/63	Kidney	Spi⁻	-	Ibid
Riddelliine	Big Blue rat (F344)	1.0 mg/kg ×5 ×12	Gavage	Female	6	82/83	Liver	cII	+	[115]
		0.3 mg/kg ×5 ×12	Gavage	Female	6	82/83	Liver	cII	+	ibid
					6	82/83	Liver parenchymal cells	cII	-	[116]
					6	82/83	Liver endothelial cells	cII	+	Ibid
		0.1 mg/kg ×5 ×12	Gavage	Female	6	82/83	Liver	cII	+	[115]
Rock wool fibers	Big Blue rat (F344)	2 mg/rat	Intratracheal	Male	11	1/28	Lung	lacI	-	[127, 188]
		2 mg/rat	Intratracheal	Male	11	1/112	Lung	lacI	+	Ibid
		2 mg/rat ×4	Intratracheal	Male	11	28/56	Lung	lacI	-	Ibid
		2 mg/rat ×4	Intratracheal	Male	11	28/133	Lung	lacI	+	ibid
		1 mg/rat	Intratracheal	Male	11	1/28	Lung	lacI	-	Ibid
		1 mg/rat	Intratracheal	Male	11	1/112	Lung	lacI	+	Ibid
Selenium (as sodium selenite) with dimethylhydrazine (DMH) injection	Big Blue rat (F344)	2 μg Se/g diet with DMH injection	Diet			63–84/63–84 (DMH (25 mg/kg body weight, i.p., weekly, twice) was injected after 3 weeks of the diet.	Liver	cII	+	[197]
		2 μg Se/g diet with DMH injection	Diet				Colon	cII	+	Ibid
		0.2 μg Se/g diet with DMH injection	Diet			63–84/63–84 (DMH (25 mg/kg body weight, i.p., weekly, twice) was injected after 3 weeks of the diet.	Liver	cII	+	Ibid
							Colon	cII	+	Ibid
							Colon	cII	*No effect of Se.	Ibid
Sucrose	Big Blue rat (F344)	30 %	Diet	Male	9–12	35/35	Liver	cII	-	[101]
		30 %	Diet	Male	9–12	35/35	Colon	cII	+−	Ibid
		34.50 %	Diet	Male	8–12	21/21	Liver	cII	-	[136]
		34.50 %	Diet	Male	8–12	21/21	Colon	cII	+	ibid
		13.80 %	Diet	Male	8–12	21/21	Liver	cII	-	Ibid
		13.80 %	Diet	Male	8–12	21/21	Colon	cII	+	Ibid
		6.90 %	Diet	Male	8–12	21/21	Liver	cII	-	Ibid
		6.90 %	Diet	Male	8–12	21/21	Colon	cII	-	Ibid
		13.40 %	Diet	Male	9–12	21/21	Liver	cII	-	[100]
		13.40 %	Diet	Male	9–12	21/21	Colon	cII	+	Ibid
		3.45 %	Diet	Male	9–12	21/21	Liver	cII	-	Ibid
		3.45 %	Diet	Male	9–12	21/21	Colon	cII	+	Ibid
2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD)	Big Blue rat (F344)	2 μig/kg ×12	Gavage	Male	8	42/56	Liver	lacI	-	[128]
2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD)	Big Blue rat (F344)	2 μig/kg ×12	Gavage	Female	8	42/56	Liver	lacI	-	Ibid
Tamoxifen	Big Blue rat (F344)	54 μmol/kg ×21	Intraperitoneal	Female	8	21/51	Liver	cII	+	[22]
							Liver	lacI	+	[191]
							Uterus	lacI	-	Ibid
		20 mg/kg ×42	Gavage	Female	6–8, 16–18	42/56	Liver	lacI	+	[170]
					6–8, 16–18	42/56		cII	+	[109]
					6–8	42/42	Liver	lacI	+	[110]
						42/56	Liver	lacI	+	Ibid
						42/126	Liver	lacI	+	Ibid
						42/210	Liver	lacI	+	Ibid
		10 mg/kg ×42	Gavage	Female	6–8	42/56	Liver	lacI	+	[170]
		10 mg/kg ×42	Gavage	Female				cII	+−	[109]
	gpt delta rat (F344)	40 mg/kg	Gavege	Female		21/21	Liver	gpt, Spi⁻	+	[58]
		40 mg/kg	Gavege	Female		21/21	Kidney	gpt, Spi⁻	-	Ibid
		20 mg/kg	Gavege	Female		21/21	Liver	gpt, Spi⁻	+	Ibid
		20 mg/kg	Gavege	Female		21/21	Kidney	gpt, Spi⁻	-	Ibid
		500 ppm	Diet	Female		91/91	Liver	gpt, Spi⁻	+	Ibid
		500 ppm	Diet	Female		91/91	Kidney	gpt, Spi⁻	-	Ibid
		250 ppm	Diet	Female		91/91	Liver	gpt, Spi⁻	+	Ibid
		250 ppm	Diet	Female		91/91	Kidney	gpt, Spi⁻	-	Ibid
Thiotepa Toremifene	Big Blue rat (F344)	1.4 mg/kg ×12	Intraperitoneal	Male	7	28/35	Spleen lymphocytes	lacI	+	[29]
	Big Blue rat (F344)	20 mg/kg ×42	Gavage	Female	6–8	42/56	Liver	lacI	-	[170]
	gpt delta rat (F344)	40 mg/kg	Gavege	Female		21/21	Liver	gpt, Spi⁻	-	[58]
	gpt delta rat (F344)	40 mg/kg	Gavege	Female		21/21	Kidney	gpt, Spi⁻	-	Ibid
Tris(2,3-dibromopropyl)phosphate (TDBP)	Big Blue rat (F344)	2000 ppm	Diet	Male	6–8	45/45	Kidney (outer medulla)	lacI	+	[47]
							Kidney (inner medulla)	lacI	+	Ibid
							Kidney (cortex)	lacI	+	Ibid
		100 ppm	Diet	Male	6–8	45/45	Kidney (outer medulla)	lacI	+	Ibid
							Kidney (inner medulla)	lacI	+	Ibid
							Kidney (cortex)	lacI	+	Ibid
Uracil	Big Blue rat (F344)	3 %	Diet	Male	6	14/14	Bladder	lacI	-	[25]
						70/70	Bladder	lacI	+	Ibid
						140/140	Bladder	lacI	+	Ibid
						357/357	Bladder	lacI	+	Ibid

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