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Evaluation of the Xpa-Deficient Transgenic Mouse Model for Short-Term Carcinogenicity Testing: 9-Month Studies with Haloperidol, Reserpine, Phenacetin, and D-Mannitol

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Author: Lina, B.A.R. · Woutersen, R.A. · Bruijntjes, J.P. · Benthem, J. van · Berg, J.A.H. van den · Monbaliu, J. · Thoolen, B.J.J.M. · Beems, R.B. · Kreijl, C.F. van
Type:article
Date:2004
Institution: TNO Voeding
Source:Toxicologic Pathology, 2, 32, 192-201
Identifier: 237631
doi: doi:10.1080/01926230490274344
Keywords: 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

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.