Title
Evaluation of the Xpa-Deficient Transgenic Mouse Model for Short-Term Carcinogenicity Testing: 9-Month Studies with Haloperidol, Reserpine, Phenacetin, and D-Mannitol
Author
Lina, B.A.R.
Woutersen, R.A.
Bruijntjes, J.P.
van Benthem, J.
van den Berg, J.A.H.
Monbaliu, J.
Thoolen, B.J.J.M.
Beems, R.B.
van Kreijl, C.F.
TNO Voeding
Publication year
2004
Abstract
As part of the international evaluation program coordinated by ILSI/HESI, the potential of DNA repair deficient Xpa-/- mice and the double knockout Xpa-/-.p53+/- mice for short term carcinogenicity assays was evaluated. For comparison also wild-type C57BL/6 mice (WT) were included in these studies. Four test compounds were administered to groups of 15 male and 15 female Xpa-/- mice, Xpa -/-.p53+/- mice and WT mice for 39 weeks. The model compounds investigated were haloperidol, reserpine (nongenotoxic rodent carcinogens, putative human noncarcinogens), phenacetin (genotoxic rodent carcinogen, suspected human carcinogen), and D-mannitol (noncarcinogen in rodents and humans). The test compounds were administered as admixture to rodent diet at levels up to 25 mg/kg diet for haloperidol, 7.5 mg/kg diet for reserpine, 0.75% for phenacetin, and 10% for D-mannitol. These levels included the maximum tolerable dose (MTD). Survival was not affected with any of the test compounds. Haloperidol, reserpine and D-mannitol were negative in the carcinogenicity assay with Xpa-/- and Xpa-/-.p53 +/- mice, showing low and comparable tumor incidences in controls and high-dose animals. The results obtained with phenacetin may be designated equivocal in Xpa-/-.p53+/- mice, based on the occurrence of a single rare tumor in the target organ (kidney) accompanied by a low incidence of hyperplastic renal lesions and a high incidence of karyomegaly. These results are in agreement with the currently known carcinogenic potential of the 4 test compounds in humans.
Subject
Biology
Toxicology and Applied Pharmacology
Carcinogenicity testing
Carcinogens
DNA repair deficient
Knockout mice
Xpa
Xpa/p53
haloperidol
mannitol
phenacetin
reserpine
animal experiment
animal tissue
article
cancer incidence
carcinogen testing
controlled study
DNA repair
evaluation
female
hyperplasia
kidney tumor
knockout mouse
male
maximum tolerated dose
mouse
nonhuman
priority journal
rare disease
survival
target organ
transgenic mouse
Administration, Oral
Animals
Carcinogenicity Tests
Diet
Disease Models, Animal
DNA-Binding Proteins
Dose-Response Relationship, Drug
Haloperidol
Mannitol
Mice
Mice, Inbred C57BL
Mice, Knockout
Mice, Transgenic
Neoplasms, Experimental
Phenacetin
Reproducibility of Results
Reserpine
Time Factors
Xeroderma Pigmentosum Group A Protein
Animalia
Mus musculus
Rodentia
To reference this document use:
http://resolver.tudelft.nl/uuid:7b301dca-d891-4e8a-abd8-97d32e52861a
DOI
https://doi.org/10.1080/01926230490274344
TNO identifier
237631
ISSN
0192-6233
Source
Toxicologic Pathology, 32 (2), 192-201
Document type
article