Reference SummaryEastin WC, Toxicol Pathol 2001;29 Suppl():60-80

Title

Tg.AC genetically altered mouse: assay working group overview of available data.

Authors

Eastin WC; Mennear JH; Tennant RW; Stoll RE; Branstetter DG; Bucher JR; McCullough B; Binder RL; Spalding JW; Mahler JF

Journal

Toxicol Pathol

Volume

29 Suppl

Issue

Year

2001

Pages

60-80

Abstract

In a Government/Industry/Academic partnership to evaluate alternative approaches to carcinogenicity testing, 21 pharmaceutical agents representing a variety of chemical and pharmacological classes and possessing known human and or rodent carcinogenic potential were selected for study in several rodent models. The studies from this partnership project, coordinated by the International Life Sciences Institute, provide additional data to better understand the models' limitations and sensitivity in identifying carcinogens. The results of these alternative model studies were reviewed by members of Assay Working Groups (AWG) composed of scientists from government and industry with expertise in toxicology, genetics, statistics, and pathology. The Tg.AC genetically manipulated mouse was one of the models selected for this project based on previous studies indicating that Tg.AC mice seem to respond to topical application of either mutagenic or nonmutagenic carcinogens with papilloma formation at the site of application. This communication describes the results and AWG interpretations of studies conducted on 14 chemicals administered by the topical and oral (gavage and/or diet) routes to Tg.AC genetically manipulated mice. Cyclosporin A, an immunosuppresant human carcinogen, ethinyl estradiol and diethylstilbestrol (human hormone carcinogens) and clofibrate, an hepatocarcinogenic peroxisome proliferator in rodents, were considered clearly positive in the topical studies. In the oral studies, ethinyl estradiol and diethylstilbestrol were negative, cyclosporin was considered equivocal, and results were not available for the clofibrate study. Of the 3 genotoxic human carcinogens (phenacetin, melphalan, and cyclophosphamide), phenacetin was negative by both the topical and oral routes. Melphalan and cyclophosphamide are, respectively, direct and indirect DNA alkylating agents and topical administration of both caused equivocal responses. With the exception of clofibrate, Tg.AC mice did not exhibit tumor responses to the rodent carcinogens that were putative human noncarcinogens, (di(2-ethylhexyl) phthalate, methapyraline HCl, phenobarbital Na, reserpine, sulfamethoxazole or WY-14643, or the nongenotoxic, noncarcinogen, sulfisoxazole) regardless of route of administration. Based on the observed responses in these studies, it was concluded by the AWG that the Tg.AC model was not overly sensitive and possesses utility as an adjunct to the battery of toxicity studies used to establish human carcinogenic risk.

Links

J:73017 – MGI References
11695563 – National Library of Medicine/PubMed

Models

Strain Model Name Treatment Agent(s) Organ Affected Frequency Model Details
FVB/NTac-Tg(Hba-x-v-Ha-ras)TG.ACLed Erythrocyte leukemia - erythroleukemia Erythrocyte

0 - 3.3

FVB/NTac-Tg(Hba-x-v-Ha-ras)TG.ACLed Erythrocyte leukemia - erythroleukemia Erythrocyte

6.7 - 8.3

FVB/NTac-Tg(Hba-x-v-Ha-ras)TG.ACLed Erythrocyte leukemia - erythroleukemia
  • cyclophosphamide (Cytoxan)
Erythrocyte

0 - 26.7

FVB/NTac-Tg(Hba-x-v-Ha-ras)TG.ACLed Forestomach hyperplasia - squamous
  • dimethyl vinyl chloride (DMVC)
Forestomach

86.7 - 93.3

FVB/NTac-Tg(Hba-x-v-Ha-ras)TG.ACLed Forestomach hyperplasia - squamous Forestomach

86.7 - 100

FVB/NTac-Tg(Hba-x-v-Ha-ras)TG.ACLed Forestomach hyperplasia - squamous
  • sulfamethoxazole (SMX)
Forestomach

86.7 - 100

FVB/NTac-Tg(Hba-x-v-Ha-ras)TG.ACLed Forestomach lesion
  • dimethyl vinyl chloride (DMVC)
Forestomach

100

FVB/NTac-Tg(Hba-x-v-Ha-ras)TG.ACLed Forestomach lesion Forestomach

21.4 - 46.2

FVB/NTac-Tg(Hba-x-v-Ha-ras)TG.ACLed Forestomach lesion
  • reserpine
Forestomach

30.8 - 63.6

FVB/NTac-Tg(Hba-x-v-Ha-ras)TG.ACLed Forestomach papilloma Forestomach

44.9 - 66.7

FVB/NTac-Tg(Hba-x-v-Ha-ras)TG.ACLed Forestomach papilloma Forestomach

21.7 - 25.4

FVB/NTac-Tg(Hba-x-v-Ha-ras)TG.ACLed Forestomach papilloma
  • diethylstilbestrol (DES)
Forestomach

20 - 60

FVB/NTac-Tg(Hba-x-v-Ha-ras)TG.ACLed Forestomach squamous cell papilloma Forestomach

57.1 - 80

FVB/NTac-Tg(Hba-x-v-Ha-ras)TG.ACLed Forestomach squamous cell papilloma
  • melphalan (L-phenylalanine mustard) (L-sarcolysin)
Forestomach

92.9 - 100

FVB/NTac-Tg(Hba-x-v-Ha-ras)TG.ACLed Forestomach tumor Forestomach

0 - 80

FVB/NTac-Tg(Hba-x-v-Ha-ras)TG.ACLed Forestomach tumor
  • dimethyl vinyl chloride (DMVC)
Forestomach

77.8 - 93.3

FVB/NTac-Tg(Hba-x-v-Ha-ras)TG.ACLed Forestomach tumor
  • Cyclosporin A
Forestomach

11.1 - 40

FVB/NTac-Tg(Hba-x-v-Ha-ras)TG.ACLed Forestomach tumor
  • ethinyl estradiol (EE)
Forestomach

46.7 - 73.3

FVB/NTac-Tg(Hba-x-v-Ha-ras)TG.ACLed Forestomach tumor Forestomach

0 - 42.9

FVB/NTac-Tg(Hba-x-v-Ha-ras)TG.ACLed Forestomach tumor
  • sulfisoxazole
Forestomach

0 - 20

FVB/NTac-Tg(Hba-x-v-Ha-ras)TG.ACLed Forestomach tumor
  • dimethyl vinyl chloride (DMVC)
Forestomach

53.3 - 86.7

FVB/NTac-Tg(Hba-x-v-Ha-ras)TG.ACLed Forestomach tumor
  • sulfamethoxazole (SMX)
Forestomach

0 - 26.7

FVB/NTac-Tg(Hba-x-v-Ha-ras)TG.ACLed Forestomach tumor
  • diethylhexylphthalate (DEHP)
Forestomach

45.5 - 83.3

FVB/NTac-Tg(Hba-x-v-Ha-ras)TG.ACLed Forestomach tumor
  • WY-14,643
Forestomach

41.7 - 60

FVB/NTac-Tg(Hba-x-v-Ha-ras)TG.ACLed Forestomach tumor
  • reserpine
Forestomach

0 - 62.5

FVB/NTac-Tg(Hba-x-v-Ha-ras)TG.ACLed Forestomach tumor
  • phenobarbital (PB)
Forestomach

0

FVB/NTac-Tg(Hba-x-v-Ha-ras)TG.ACLed Forestomach tumor
  • phenacetin
Forestomach

0 - 71.4

FVB/NTac-Tg(Hba-x-v-Ha-ras)TG.ACLed Forestomach tumor
  • cyclophosphamide (Cytoxan)
Forestomach

30.8 - 60

FVB/NTac-Tg(Hba-x-v-Ha-ras)TG.ACLed Leukocyte lymphoma Leukocyte

0.6 - 1.7

FVB/NTac-Tg(Hba-x-v-Ha-ras)TG.ACLed Leukocyte lymphoma Leukocyte

0 - 1.7

FVB/NTac-Tg(Hba-x-v-Ha-ras)TG.ACLed Leukocyte tumor Leukocyte

0

FVB/NTac-Tg(Hba-x-v-Ha-ras)TG.ACLed Leukocyte tumor
  • dimethyl vinyl chloride (DMVC)
Leukocyte

0

FVB/NTac-Tg(Hba-x-v-Ha-ras)TG.ACLed Leukocyte tumor
  • Cyclosporin A
Leukocyte

0 - 23.1

FVB/NTac-Tg(Hba-x-v-Ha-ras)TG.ACLed Liver hepatocellular adenoma
  • WY-14,643
Liver

13.3

FVB/NTac-Tg(Hba-x-v-Ha-ras)TG.ACLed Liver hyperplasia - oval cell
  • WY-14,643
Liver

observed

FVB/NTac-Tg(Hba-x-v-Ha-ras)TG.ACLed Lung - Alveolus hyperplasia - focal
  • cyclophosphamide (Cytoxan)
Lung - Alveolus

observed

FVB/NTac-Tg(Hba-x-v-Ha-ras)TG.ACLed Lung tumor Lung

1.1 - 2.2

FVB/NTac-Tg(Hba-x-v-Ha-ras)TG.ACLed Lung tumor Lung

1.7 - 5.0

FVB/NTac-Tg(Hba-x-v-Ha-ras)TG.ACLed Nose adenoma
  • sulfisoxazole
Bone - Jaw - Maxilla

observed

FVB/NTac-Tg(Hba-x-v-Ha-ras)TG.ACLed Ovary - Corpus luteum hyperplasia
  • diethylstilbestrol (DES)
Ovary - Corpus luteum

observed

FVB/NTac Ovary - Corpus luteum hyperplasia
  • diethylstilbestrol (DES)
Ovary - Corpus luteum

observed

FVB/NTac Ovary - Corpus luteum hyperplasia
  • ethinyl estradiol (EE)
Ovary - Corpus luteum

observed

FVB/NTac-Tg(Hba-x-v-Ha-ras)TG.ACLed Salivary gland carcinoma Salivary gland

1.7 - 2.8

FVB/NTac-Tg(Hba-x-v-Ha-ras)TG.ACLed Salivary gland carcinoma Salivary gland

0 - 1.7

FVB/NTac-Tg(Hba-x-v-Ha-ras)TG.ACLed Skin - Dermis papilloma
  • melphalan (L-phenylalanine mustard) (L-sarcolysin)
Vulva

observed

FVB/NTac-Tg(Hba-x-v-Ha-ras)TG.ACLed Skin - Dorsal region papilloma
  • 12-O-tetradecanoylphorbol-13-acetate (TPA)
Skin - Dorsal region

very high - 100

FVB/NTac-Tg(Hba-x-v-Ha-ras)TG.ACLed Skin - Dorsal region papilloma Skin - Dorsal region

6.7 - 40

FVB/NTac-Tg(Hba-x-v-Ha-ras)TG.ACLed Skin - Dorsal region papilloma
  • Cyclosporin A
Skin - Dorsal region

33.3 - 73.3

FVB/NTac-Tg(Hba-x-v-Ha-ras)TG.ACLed Skin - Dorsal region papilloma
  • diethylstilbestrol (DES)
Skin - Dorsal region

0 - 80

FVB/NTac-Tg(Hba-x-v-Ha-ras)TG.ACLed Skin - Dorsal region tumor
  • 12-O-tetradecanoylphorbol-13-acetate (TPA)
Skin - Dorsal region

60 - 100

FVB/NTac-Tg(Hba-x-v-Ha-ras)TG.ACLed Skin - Dorsal region tumor Skin - Dorsal region

0 - 20

FVB/NTac-Tg(Hba-x-v-Ha-ras)TG.ACLed Skin - Dorsal region tumor
  • ethinyl estradiol (EE)
Skin - Dorsal region

0 - 86.7

FVB/NTac-Tg(Hba-x-v-Ha-ras)TG.ACLed Skin - Dorsal region tumor
  • 12-O-tetradecanoylphorbol-13-acetate (TPA)
Skin - Dorsal region

33.3 - 100

FVB/NTac-Tg(Hba-x-v-Ha-ras)TG.ACLed Skin - Dorsal region tumor Skin - Dorsal region

0 - 21.4

FVB/NTac-Tg(Hba-x-v-Ha-ras)TG.ACLed Skin - Dorsal region tumor
  • sulfisoxazole
Skin - Dorsal region

0 - 20

FVB/NTac-Tg(Hba-x-v-Ha-ras)TG.ACLed Skin - Dorsal region tumor
  • sulfamethoxazole (SMX)
Skin - Dorsal region

4.2 - 10.7

FVB/NTac-Tg(Hba-x-v-Ha-ras)TG.ACLed Skin - Dorsal region tumor
  • diethylhexylphthalate (DEHP)
Skin - Dorsal region

0 - 10

FVB/NTac-Tg(Hba-x-v-Ha-ras)TG.ACLed Skin - Dorsal region tumor
  • WY-14,643
Skin - Dorsal region

0 - 27.3

FVB/NTac-Tg(Hba-x-v-Ha-ras)TG.ACLed Skin - Dorsal region tumor
  • benzene
Skin - Dorsal region

86.7 - 93.3

FVB/NTac-Tg(Hba-x-v-Ha-ras)TG.ACLed Skin - Dorsal region tumor
  • clofibrate
Skin - Dorsal region

0 - 100

FVB/NTac-Tg(Hba-x-v-Ha-ras)TG.ACLed Skin - Dorsal region tumor
  • methapyrilene
Skin - Dorsal region

0 - 6.7

FVB/NTac-Tg(Hba-x-v-Ha-ras)TG.ACLed Skin - Dorsal region tumor
  • reserpine
Skin - Dorsal region

6.7 - 26.7

FVB/NTac-Tg(Hba-x-v-Ha-ras)TG.ACLed Skin - Dorsal region tumor
  • phenobarbital (PB)
Skin - Dorsal region

0

FVB/NTac-Tg(Hba-x-v-Ha-ras)TG.ACLed Skin - Dorsal region tumor
  • phenacetin
Skin - Dorsal region

0 - 13.3

FVB/NTac-Tg(Hba-x-v-Ha-ras)TG.ACLed Skin - Dorsal region tumor
  • melphalan (L-phenylalanine mustard) (L-sarcolysin)
Skin - Dorsal region

0 - 40

FVB/NTac-Tg(Hba-x-v-Ha-ras)TG.ACLed Skin - Dorsal region tumor
  • cyclophosphamide (Cytoxan)
Skin - Dorsal region

0 - 20

FVB/NTac-Tg(Hba-x-v-Ha-ras)TG.ACLed Skin papilloma
  • 12-O-tetradecanoylphorbol-13-acetate (TPA)
Skin

85 - 88

FVB/NTac-Tg(Hba-x-v-Ha-ras)TG.ACLed Skin papilloma
  • 12-O-tetradecanoylphorbol-13-acetate (TPA)
Skin

93 - 96

FVB/NTac-Tg(Hba-x-v-Ha-ras)TG.ACLed Skin squamous cell papilloma Scrotum

6.7

FVB/NTac-Tg(Hba-x-v-Ha-ras)TG.ACLed Skin squamous cell papilloma
  • cyclophosphamide (Cytoxan)
Scrotum

13.3 - 100

FVB/NTac-Tg(Hba-x-v-Ha-ras)TG.ACLed Skin squamous cell papilloma Vulva

13.3

FVB/NTac-Tg(Hba-x-v-Ha-ras)TG.ACLed Skin squamous cell papilloma
  • cyclophosphamide (Cytoxan)
Vulva

observed - 90.9

FVB/NTac-Tg(Hba-x-v-Ha-ras)TG.ACLed Skin tumor Skin

0 - 40

FVB/NTac-Tg(Hba-x-v-Ha-ras)TG.ACLed Skin tumor Skin

0 - 1.7

FVB/NTac-Tg(Hba-x-v-Ha-ras)TG.ACLed Skin tumor
  • diethylstilbestrol (DES)
Skin

0 - 33.3

FVB/NTac-Tg(Hba-x-v-Ha-ras)TG.ACLed Skin tumor
  • ethinyl estradiol (EE)
Skin

6.7 - 20

FVB/NTac-Tg(Hba-x-v-Ha-ras)TG.ACLed Skin tumor (Unspecified organ)

0

FVB/NTac-Tg(Hba-x-v-Ha-ras)TG.ACLed Skin tumor
  • melphalan (L-phenylalanine mustard) (L-sarcolysin)
(Unspecified organ)

0

FVB/NTac-Tg(Hba-x-v-Ha-ras)TG.ACLed Skin tumor Vulva

6.7

FVB/NTac-Tg(Hba-x-v-Ha-ras)TG.ACLed Skin tumor
  • melphalan (L-phenylalanine mustard) (L-sarcolysin)
Vulva

20 - 80

FVB/NTac-Tg(Hba-x-v-Ha-ras)TG.ACLed Skin tumor
  • melphalan (L-phenylalanine mustard) (L-sarcolysin)
Skin

20 - 80

FVB/NTac-Tg(Hba-x-v-Ha-ras)TG.ACLed Skin tumor
  • 12-O-tetradecanoylphorbol-13-acetate (TPA)
Skin

93.3

FVB/NTac-Tg(Hba-x-v-Ha-ras)TG.ACLed Skin tumor
  • cyclophosphamide (Cytoxan)
Skin

13.3 - 100

FVB/NTac-Tg(Hba-x-v-Ha-ras)TG.ACLed Skin tumor
  • cyclophosphamide (Cytoxan)
Vagina

observed

FVB/NTac-Tg(Hba-x-v-Ha-ras)TG.ACLed Skin tumor - squamous Skin

26.7 - 28.6

FVB/NTac-Tg(Hba-x-v-Ha-ras)TG.ACLed Skin tumor - squamous
  • ethinyl estradiol (EE)
Skin

13.3 - 93.3

FVB/NTac-Tg(Hba-x-v-Ha-ras)TG.ACLed Tooth tumor Tooth

7.0 - 30.0

FVB/NTac-Tg(Hba-x-v-Ha-ras)TG.ACLed Tooth tumor Tooth

18.3 - 26.7

FVB/NTac-Tg(Hba-x-v-Ha-ras)TG.ACLed Tooth tumor
  • Cyclosporin A
Tooth

7.0 - 30.0

FVB/NTac-Tg(Hba-x-v-Ha-ras)TG.ACLed Uterus - Endometrium hyperplasia - cystic
  • diethylstilbestrol (DES)
Uterus - Endometrium

observed

FVB/NTac Uterus - Endometrium hyperplasia - cystic
  • diethylstilbestrol (DES)
Uterus - Endometrium

observed

FVB/NTac Uterus - Endometrium hyperplasia - cystic
  • ethinyl estradiol (EE)
Uterus - Endometrium

observed

FVB/NTac-Tg(Hba-x-v-Ha-ras)TG.ACLed (Unspecified organ) hyperplasia
  • diethylstilbestrol (DES)
(Unspecified organ)

observed

FVB/NTac-Tg(Hba-x-v-Ha-ras)TG.ACLed (Unspecified organ) hyperplasia
  • ethinyl estradiol (EE)
(Unspecified organ)

observed

FVB/NTac (Unspecified organ) lesion
  • cyclophosphamide (Cytoxan)
(Unspecified organ)

0

FVB/NTac-Tg(Hba-x-v-Ha-ras)TG.ACLed (Unspecified organ) tumor (Unspecified organ)

0 - 2.2

FVB/NTac-Tg(Hba-x-v-Ha-ras)TG.ACLed (Unspecified organ) tumor (Unspecified organ)

1.7 - 3.3

FVB/NTac-Tg(Hba-x-v-Ha-ras)TG.ACLed (Unspecified organ) tumor
  • phenobarbital (PB)
(Unspecified organ)

0